microstructure and function of the lungs · mucus secretion mucus is a hydrated gel that is a key...
TRANSCRIPT
Microstructure and function of
the lungs
Professor Tracy Hussell
Director of the Manchester
Collaborative Centre for
Inflammation Research
1
Outline
bull Cellular composition of healthy airways
bull Control of airflow
bull Tolerance of the Environment
bull Diseases affecting airflow
ndash Asthma
ndash Chronic Obstructive Pulmonary Disease (COPD)
ndash Infection
2
Essential function of the airways
Gas exchange system
bull Conducts O2 into the body
bull Remove CO2 from the body
Facilitated by
bull mechanical stability
bull control of calibre
bull filtering and
cleansing
3
Lungs are susceptible to many
diseases that may reduce function
Asthma
Chronic obstructive
pulmonary disease
(COPD)
Mesothelioma
Acute respiratory
distress syndrome
(ARDS)
Idiopathic pulmonary
fibrosis
Sarcoidosis
Pulmonary
hypertension Cystic fibrosis
Infection
Bronchitis
Pneumonia Pleurisy
Trachea
Bronchi
Alveoli
4
Structure of a healthy airway
5 Advantages of a multi-lobed structure
Why are there different cells at different locations
Trachea
Primary bronchus
Secondary bronchus
Tertiary bronchus
Smaller bronchi
Bronchioles
Terminal bronchioles
Respiratory bronchioles
Alveolar sacs (150 million)
Ciliated epithelium Basal cell Goblet cell Club cell Serous cell Brush cell Alveolar type I Alveolar type II
BeacuteruBeacute K et al ATLA 37 89ndash141 2009
C
O
N
D
U
C
T
I
N
G
6
Specialised cellular function of epithelial cells
Ciliated epithelium Protective barrier mucociliary clearance Basal cell Renew damaged cells Goblet cell Mucus secretion Club cell Production of surfactant (lubricant ) Serous cell Antibacterial secretions Brush cell Unknown helliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip Alveolar type I Gas exchange Alveolar type II Production of surfactant
7
Proximal region - trachea
C-shaped rings of hyaline cartilage support trachea mucosa and
prevent tube collapse during inspiration
Lumen
Epithelium
Cartilage
8
Basic structure of the conducting airway
Cartilage
9
Airway associated cells ndash different roles
Categoryfunction Cell type ndash over 40 different types
Lining cells Ciliated intermediate brush basal epithelium
Contractile cells Smooth muscle
Secretory cells Goblet (epithelium) mucous serous (glands)
Connective tissue Fibroblast interstitial cell produce
elastin collagen proteoglycans cartilage
Neuroendocrine Nerves ganglia neuroendocrine cells neuroepithelial
bodies
Vascular cells Endothelial smooth muscle pericyte
Immune cells Mast cell dendritic cell lymphocyte eosinophil
macrophage neutrophil
10
The epithelium is not simply a barrier
11
Functions of the conducting airway epithelium
bull Protection by secretion and movement
of mucus by cilia towards the pharynx ndash
mucociliary clearance
bull Physical barrier to pathogens ndash
junctional components between cells (tight adherens
desmosomes)
bull Production of regulatory and inflammatory mediators
ndash Chemokines (eg IL-8 and IL-6)- attract inflammatory cells
ndash Cytokines (eg GM-CSF and TGF-β) ndash cell signalling
ndash Proteases (eg plasminogen activators MMPs)- migration
degradation of ECM growth factor activation
Mucus secretion
Mucus is a hydrated gel that is a
key component of airway defence
The principal gel-forming
components are MUCINS
produced by goblet and mucous
cells
Mucociliary transport
Submucosal gland
Mucus
Goblet
cell Functions
bull Barrier to pathogens
particulates and allergens
bull Maintenance of hydration
bull Serous cells secrete
antibacterials (eg lysozyme)
bull Glands also secrete water and
salts (eg Na+ and Cl-)
13
Function of airway smooth muscle
TONE
(airway calibre)
Contraction
Relaxation
STRUCTURE
Spiral
organisation
SECRETION
Mediators
Cytokines
Chemokines
14
Tertiary bronchus
bull Reduced cartilage
more smooth muscle
bull Fewer goblet cells and
submucosal glands
bull Increase in club cells
producing surfactant
15
Bronchiole
16
bull Single layer of ciliated epithelium
bull No cartilage
bull Reduced smooth muscle
bull No goblet cells or submucosal
glands
bull More club cells producing surfactant
Distal region ndash site of gas exchange
bull Alveoli - passive gas exchange
with capillary network ndash 150
million
bull Collagen elastic fibres and
fibroblasts and macrophages
present in septal junctions
bull Several alveoli grouped into
lobules surrounded by
connective tissue
17
Lung parenchyma
bull Type I alveolar cells - simple squamous
epithelium non-ciliated and main site of gas
exchange ndash covers 90 of alveolus
bull Type II alveolar cells (septal cells) ndash produce
surfactant to reduce surface tension preventing
alveoli collapse and renew type I cells
Type II alveolar cells
Type I alveolar cells
18
Control of airflow
bull Relaxation of smooth muscle = bronchodilation = increased airflow
bull Constriction of smooth muscle = bronchoconstriction = reduced airflow
Inflammation ndash driven constriction
of airway smooth muscle
Smooth muscle tone controlled by
autonomic nervous system
adrenal medullary hormones and
local factors
Autonomic nervous system
Parasympathetic Sympathetic
Muscarinic
beta2 alpha
- Constricts smooth muscle
- Causes mucus gland secretion
- Constricts
blood vessels
- Relaxes smooth muscle
19
Regulators of airflow
bull Nerves
- parasympathetic (cholinergic - constriction)
- sympathetic (adrenergic - dilation)
bull Regulatory and inflammatory mediators
- mast cell histamine - constriction
- arachidonic acid metabolites ndashconstrict and dilate
(eg prostaglandins leukotrienes)
- cytokines ndash constrict and dilate increase mucus
- hormones (eg adrenaline)
bull Proteinases (eg neutrophil elastase)
bull Reactive gas species (eg O2- NO)
Airway disease = Loss of normal control
20
SEM showing two alveolar macrophages (MP) in the alveolar space (ALV)
Airway macrophages a collision of functions
bull Induction of
inflammation
pathogens
bull Inhibition of
inflammation
clearance of self
cells and
extracellular
matrix turnover
products
Epithelial regulation of immunity
Tolerance
level set to
high =
bacterial
escape
Tolerance levels set too low
26
Respiratory diseases with loss of airway function
bull Common conditions
Asthma ndash ~5 of population in industrialised countries
COPD ndash 4th leading cause of death in UK and USA
Cystic fibrosis ndash lethal autosomal recessive gene defect (~12000 Caucasians)
bull Airway remodelling
- goblet cell hyperplasia
- submucosal gland hypertrophy
- fibrosis
- smooth muscle hypertrophy (asthma)
- alveolar destruction (COPD)
27
Asthma
bull Symptoms cough wheeze
shortness of breath and tightness of
the chest
bull Increased airway hyper-reactivity to
a variety of stimuli (smooth muscle
sensitive to constriction)
bull Airway narrowing and airflow
obstruction - usually reversible
(spontaneously or with drugs)
bull Wide spectrum of symptoms and
different severities of disease-
different phenotypes
Normal
Asthma
28
Asthma pathophysiology
CHRONIC
INFLAMMATION
AIRWAY
REMODELLING
29
Pathological changes in the asthmatic
airway- remodelling
bull Mucus hypersecretion
bull Denuded epithelium
bull Goblet cell hyperplasia
bull Reticular thickening
bull Appearance of myofibroblasts
bull Smooth muscle cell hypertrophy
bull Angiogenesis
bull Plasma extravasation
30
Improved therapies
Current
bull Relievers ndash inhalers are usually blue or green
ndash Bronchodilators cause smooth muscle to relax
ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur
bull Preventers ndash inhalers are usually brown orange or red
ndash Inhaled corticosteroids reduce inflammation in the airways
ndash Used daily even when there are no symptoms
bull Combination ndash A bronchodilatoranti-inflammatory drug
5-10 steroid resistant - severe
31
Chronic Obstructive Pulmonary Disease ndash COPD
bull Globally 64 million people have
COPD
bull Smoking main cause
bull Consists of a number of conditions
including emphysema and chronic
bronchitis
bull Symptoms of cough shortness of
breath tight chest wheeze
bull Can lead to irreversible airway
obstruction ndash no cure
32
Effect of smoking on FEV1
(Forced expiratory volume in 1 second)
Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33
Global Initiative on Obstructive Lung
Disease (GOLD)
GOLD has classified COPD as ldquoa disease
state characterised by airflow limitation that
is not fully reversible The airflow limitation
is usually both progressive and associated
with an abnormal inflammatory response of
the lungs to noxious particles or gasesrdquo
World Health Organization The GOLD global strategy for the
management and prevention of COPD 2001wwwgoldcopdorg 34
GOLD 1-4 classification with 4 most severe
Summary
bull Airways conduct air in and out of the lung mechanical stability
bull Airways comprised of many cell types with specific functions
- control of contractionrelaxation
- mucociliary clearance of foreign particles
- reduction of surface tension
bull Structural cells may also be lsquoregulatoryrsquo- cross-talk between cells
bull Immunity must display appropriate inflammatory tone
bull Respiratory disease leads to loss of lsquocontrolrsquo
- inflammation
- remodelling
- tissue breakdown
Additional information on websites Asthma UK
British Lung Foundation
35
Outline
bull Cellular composition of healthy airways
bull Control of airflow
bull Tolerance of the Environment
bull Diseases affecting airflow
ndash Asthma
ndash Chronic Obstructive Pulmonary Disease (COPD)
ndash Infection
2
Essential function of the airways
Gas exchange system
bull Conducts O2 into the body
bull Remove CO2 from the body
Facilitated by
bull mechanical stability
bull control of calibre
bull filtering and
cleansing
3
Lungs are susceptible to many
diseases that may reduce function
Asthma
Chronic obstructive
pulmonary disease
(COPD)
Mesothelioma
Acute respiratory
distress syndrome
(ARDS)
Idiopathic pulmonary
fibrosis
Sarcoidosis
Pulmonary
hypertension Cystic fibrosis
Infection
Bronchitis
Pneumonia Pleurisy
Trachea
Bronchi
Alveoli
4
Structure of a healthy airway
5 Advantages of a multi-lobed structure
Why are there different cells at different locations
Trachea
Primary bronchus
Secondary bronchus
Tertiary bronchus
Smaller bronchi
Bronchioles
Terminal bronchioles
Respiratory bronchioles
Alveolar sacs (150 million)
Ciliated epithelium Basal cell Goblet cell Club cell Serous cell Brush cell Alveolar type I Alveolar type II
BeacuteruBeacute K et al ATLA 37 89ndash141 2009
C
O
N
D
U
C
T
I
N
G
6
Specialised cellular function of epithelial cells
Ciliated epithelium Protective barrier mucociliary clearance Basal cell Renew damaged cells Goblet cell Mucus secretion Club cell Production of surfactant (lubricant ) Serous cell Antibacterial secretions Brush cell Unknown helliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip Alveolar type I Gas exchange Alveolar type II Production of surfactant
7
Proximal region - trachea
C-shaped rings of hyaline cartilage support trachea mucosa and
prevent tube collapse during inspiration
Lumen
Epithelium
Cartilage
8
Basic structure of the conducting airway
Cartilage
9
Airway associated cells ndash different roles
Categoryfunction Cell type ndash over 40 different types
Lining cells Ciliated intermediate brush basal epithelium
Contractile cells Smooth muscle
Secretory cells Goblet (epithelium) mucous serous (glands)
Connective tissue Fibroblast interstitial cell produce
elastin collagen proteoglycans cartilage
Neuroendocrine Nerves ganglia neuroendocrine cells neuroepithelial
bodies
Vascular cells Endothelial smooth muscle pericyte
Immune cells Mast cell dendritic cell lymphocyte eosinophil
macrophage neutrophil
10
The epithelium is not simply a barrier
11
Functions of the conducting airway epithelium
bull Protection by secretion and movement
of mucus by cilia towards the pharynx ndash
mucociliary clearance
bull Physical barrier to pathogens ndash
junctional components between cells (tight adherens
desmosomes)
bull Production of regulatory and inflammatory mediators
ndash Chemokines (eg IL-8 and IL-6)- attract inflammatory cells
ndash Cytokines (eg GM-CSF and TGF-β) ndash cell signalling
ndash Proteases (eg plasminogen activators MMPs)- migration
degradation of ECM growth factor activation
Mucus secretion
Mucus is a hydrated gel that is a
key component of airway defence
The principal gel-forming
components are MUCINS
produced by goblet and mucous
cells
Mucociliary transport
Submucosal gland
Mucus
Goblet
cell Functions
bull Barrier to pathogens
particulates and allergens
bull Maintenance of hydration
bull Serous cells secrete
antibacterials (eg lysozyme)
bull Glands also secrete water and
salts (eg Na+ and Cl-)
13
Function of airway smooth muscle
TONE
(airway calibre)
Contraction
Relaxation
STRUCTURE
Spiral
organisation
SECRETION
Mediators
Cytokines
Chemokines
14
Tertiary bronchus
bull Reduced cartilage
more smooth muscle
bull Fewer goblet cells and
submucosal glands
bull Increase in club cells
producing surfactant
15
Bronchiole
16
bull Single layer of ciliated epithelium
bull No cartilage
bull Reduced smooth muscle
bull No goblet cells or submucosal
glands
bull More club cells producing surfactant
Distal region ndash site of gas exchange
bull Alveoli - passive gas exchange
with capillary network ndash 150
million
bull Collagen elastic fibres and
fibroblasts and macrophages
present in septal junctions
bull Several alveoli grouped into
lobules surrounded by
connective tissue
17
Lung parenchyma
bull Type I alveolar cells - simple squamous
epithelium non-ciliated and main site of gas
exchange ndash covers 90 of alveolus
bull Type II alveolar cells (septal cells) ndash produce
surfactant to reduce surface tension preventing
alveoli collapse and renew type I cells
Type II alveolar cells
Type I alveolar cells
18
Control of airflow
bull Relaxation of smooth muscle = bronchodilation = increased airflow
bull Constriction of smooth muscle = bronchoconstriction = reduced airflow
Inflammation ndash driven constriction
of airway smooth muscle
Smooth muscle tone controlled by
autonomic nervous system
adrenal medullary hormones and
local factors
Autonomic nervous system
Parasympathetic Sympathetic
Muscarinic
beta2 alpha
- Constricts smooth muscle
- Causes mucus gland secretion
- Constricts
blood vessels
- Relaxes smooth muscle
19
Regulators of airflow
bull Nerves
- parasympathetic (cholinergic - constriction)
- sympathetic (adrenergic - dilation)
bull Regulatory and inflammatory mediators
- mast cell histamine - constriction
- arachidonic acid metabolites ndashconstrict and dilate
(eg prostaglandins leukotrienes)
- cytokines ndash constrict and dilate increase mucus
- hormones (eg adrenaline)
bull Proteinases (eg neutrophil elastase)
bull Reactive gas species (eg O2- NO)
Airway disease = Loss of normal control
20
SEM showing two alveolar macrophages (MP) in the alveolar space (ALV)
Airway macrophages a collision of functions
bull Induction of
inflammation
pathogens
bull Inhibition of
inflammation
clearance of self
cells and
extracellular
matrix turnover
products
Epithelial regulation of immunity
Tolerance
level set to
high =
bacterial
escape
Tolerance levels set too low
26
Respiratory diseases with loss of airway function
bull Common conditions
Asthma ndash ~5 of population in industrialised countries
COPD ndash 4th leading cause of death in UK and USA
Cystic fibrosis ndash lethal autosomal recessive gene defect (~12000 Caucasians)
bull Airway remodelling
- goblet cell hyperplasia
- submucosal gland hypertrophy
- fibrosis
- smooth muscle hypertrophy (asthma)
- alveolar destruction (COPD)
27
Asthma
bull Symptoms cough wheeze
shortness of breath and tightness of
the chest
bull Increased airway hyper-reactivity to
a variety of stimuli (smooth muscle
sensitive to constriction)
bull Airway narrowing and airflow
obstruction - usually reversible
(spontaneously or with drugs)
bull Wide spectrum of symptoms and
different severities of disease-
different phenotypes
Normal
Asthma
28
Asthma pathophysiology
CHRONIC
INFLAMMATION
AIRWAY
REMODELLING
29
Pathological changes in the asthmatic
airway- remodelling
bull Mucus hypersecretion
bull Denuded epithelium
bull Goblet cell hyperplasia
bull Reticular thickening
bull Appearance of myofibroblasts
bull Smooth muscle cell hypertrophy
bull Angiogenesis
bull Plasma extravasation
30
Improved therapies
Current
bull Relievers ndash inhalers are usually blue or green
ndash Bronchodilators cause smooth muscle to relax
ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur
bull Preventers ndash inhalers are usually brown orange or red
ndash Inhaled corticosteroids reduce inflammation in the airways
ndash Used daily even when there are no symptoms
bull Combination ndash A bronchodilatoranti-inflammatory drug
5-10 steroid resistant - severe
31
Chronic Obstructive Pulmonary Disease ndash COPD
bull Globally 64 million people have
COPD
bull Smoking main cause
bull Consists of a number of conditions
including emphysema and chronic
bronchitis
bull Symptoms of cough shortness of
breath tight chest wheeze
bull Can lead to irreversible airway
obstruction ndash no cure
32
Effect of smoking on FEV1
(Forced expiratory volume in 1 second)
Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33
Global Initiative on Obstructive Lung
Disease (GOLD)
GOLD has classified COPD as ldquoa disease
state characterised by airflow limitation that
is not fully reversible The airflow limitation
is usually both progressive and associated
with an abnormal inflammatory response of
the lungs to noxious particles or gasesrdquo
World Health Organization The GOLD global strategy for the
management and prevention of COPD 2001wwwgoldcopdorg 34
GOLD 1-4 classification with 4 most severe
Summary
bull Airways conduct air in and out of the lung mechanical stability
bull Airways comprised of many cell types with specific functions
- control of contractionrelaxation
- mucociliary clearance of foreign particles
- reduction of surface tension
bull Structural cells may also be lsquoregulatoryrsquo- cross-talk between cells
bull Immunity must display appropriate inflammatory tone
bull Respiratory disease leads to loss of lsquocontrolrsquo
- inflammation
- remodelling
- tissue breakdown
Additional information on websites Asthma UK
British Lung Foundation
35
Essential function of the airways
Gas exchange system
bull Conducts O2 into the body
bull Remove CO2 from the body
Facilitated by
bull mechanical stability
bull control of calibre
bull filtering and
cleansing
3
Lungs are susceptible to many
diseases that may reduce function
Asthma
Chronic obstructive
pulmonary disease
(COPD)
Mesothelioma
Acute respiratory
distress syndrome
(ARDS)
Idiopathic pulmonary
fibrosis
Sarcoidosis
Pulmonary
hypertension Cystic fibrosis
Infection
Bronchitis
Pneumonia Pleurisy
Trachea
Bronchi
Alveoli
4
Structure of a healthy airway
5 Advantages of a multi-lobed structure
Why are there different cells at different locations
Trachea
Primary bronchus
Secondary bronchus
Tertiary bronchus
Smaller bronchi
Bronchioles
Terminal bronchioles
Respiratory bronchioles
Alveolar sacs (150 million)
Ciliated epithelium Basal cell Goblet cell Club cell Serous cell Brush cell Alveolar type I Alveolar type II
BeacuteruBeacute K et al ATLA 37 89ndash141 2009
C
O
N
D
U
C
T
I
N
G
6
Specialised cellular function of epithelial cells
Ciliated epithelium Protective barrier mucociliary clearance Basal cell Renew damaged cells Goblet cell Mucus secretion Club cell Production of surfactant (lubricant ) Serous cell Antibacterial secretions Brush cell Unknown helliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip Alveolar type I Gas exchange Alveolar type II Production of surfactant
7
Proximal region - trachea
C-shaped rings of hyaline cartilage support trachea mucosa and
prevent tube collapse during inspiration
Lumen
Epithelium
Cartilage
8
Basic structure of the conducting airway
Cartilage
9
Airway associated cells ndash different roles
Categoryfunction Cell type ndash over 40 different types
Lining cells Ciliated intermediate brush basal epithelium
Contractile cells Smooth muscle
Secretory cells Goblet (epithelium) mucous serous (glands)
Connective tissue Fibroblast interstitial cell produce
elastin collagen proteoglycans cartilage
Neuroendocrine Nerves ganglia neuroendocrine cells neuroepithelial
bodies
Vascular cells Endothelial smooth muscle pericyte
Immune cells Mast cell dendritic cell lymphocyte eosinophil
macrophage neutrophil
10
The epithelium is not simply a barrier
11
Functions of the conducting airway epithelium
bull Protection by secretion and movement
of mucus by cilia towards the pharynx ndash
mucociliary clearance
bull Physical barrier to pathogens ndash
junctional components between cells (tight adherens
desmosomes)
bull Production of regulatory and inflammatory mediators
ndash Chemokines (eg IL-8 and IL-6)- attract inflammatory cells
ndash Cytokines (eg GM-CSF and TGF-β) ndash cell signalling
ndash Proteases (eg plasminogen activators MMPs)- migration
degradation of ECM growth factor activation
Mucus secretion
Mucus is a hydrated gel that is a
key component of airway defence
The principal gel-forming
components are MUCINS
produced by goblet and mucous
cells
Mucociliary transport
Submucosal gland
Mucus
Goblet
cell Functions
bull Barrier to pathogens
particulates and allergens
bull Maintenance of hydration
bull Serous cells secrete
antibacterials (eg lysozyme)
bull Glands also secrete water and
salts (eg Na+ and Cl-)
13
Function of airway smooth muscle
TONE
(airway calibre)
Contraction
Relaxation
STRUCTURE
Spiral
organisation
SECRETION
Mediators
Cytokines
Chemokines
14
Tertiary bronchus
bull Reduced cartilage
more smooth muscle
bull Fewer goblet cells and
submucosal glands
bull Increase in club cells
producing surfactant
15
Bronchiole
16
bull Single layer of ciliated epithelium
bull No cartilage
bull Reduced smooth muscle
bull No goblet cells or submucosal
glands
bull More club cells producing surfactant
Distal region ndash site of gas exchange
bull Alveoli - passive gas exchange
with capillary network ndash 150
million
bull Collagen elastic fibres and
fibroblasts and macrophages
present in septal junctions
bull Several alveoli grouped into
lobules surrounded by
connective tissue
17
Lung parenchyma
bull Type I alveolar cells - simple squamous
epithelium non-ciliated and main site of gas
exchange ndash covers 90 of alveolus
bull Type II alveolar cells (septal cells) ndash produce
surfactant to reduce surface tension preventing
alveoli collapse and renew type I cells
Type II alveolar cells
Type I alveolar cells
18
Control of airflow
bull Relaxation of smooth muscle = bronchodilation = increased airflow
bull Constriction of smooth muscle = bronchoconstriction = reduced airflow
Inflammation ndash driven constriction
of airway smooth muscle
Smooth muscle tone controlled by
autonomic nervous system
adrenal medullary hormones and
local factors
Autonomic nervous system
Parasympathetic Sympathetic
Muscarinic
beta2 alpha
- Constricts smooth muscle
- Causes mucus gland secretion
- Constricts
blood vessels
- Relaxes smooth muscle
19
Regulators of airflow
bull Nerves
- parasympathetic (cholinergic - constriction)
- sympathetic (adrenergic - dilation)
bull Regulatory and inflammatory mediators
- mast cell histamine - constriction
- arachidonic acid metabolites ndashconstrict and dilate
(eg prostaglandins leukotrienes)
- cytokines ndash constrict and dilate increase mucus
- hormones (eg adrenaline)
bull Proteinases (eg neutrophil elastase)
bull Reactive gas species (eg O2- NO)
Airway disease = Loss of normal control
20
SEM showing two alveolar macrophages (MP) in the alveolar space (ALV)
Airway macrophages a collision of functions
bull Induction of
inflammation
pathogens
bull Inhibition of
inflammation
clearance of self
cells and
extracellular
matrix turnover
products
Epithelial regulation of immunity
Tolerance
level set to
high =
bacterial
escape
Tolerance levels set too low
26
Respiratory diseases with loss of airway function
bull Common conditions
Asthma ndash ~5 of population in industrialised countries
COPD ndash 4th leading cause of death in UK and USA
Cystic fibrosis ndash lethal autosomal recessive gene defect (~12000 Caucasians)
bull Airway remodelling
- goblet cell hyperplasia
- submucosal gland hypertrophy
- fibrosis
- smooth muscle hypertrophy (asthma)
- alveolar destruction (COPD)
27
Asthma
bull Symptoms cough wheeze
shortness of breath and tightness of
the chest
bull Increased airway hyper-reactivity to
a variety of stimuli (smooth muscle
sensitive to constriction)
bull Airway narrowing and airflow
obstruction - usually reversible
(spontaneously or with drugs)
bull Wide spectrum of symptoms and
different severities of disease-
different phenotypes
Normal
Asthma
28
Asthma pathophysiology
CHRONIC
INFLAMMATION
AIRWAY
REMODELLING
29
Pathological changes in the asthmatic
airway- remodelling
bull Mucus hypersecretion
bull Denuded epithelium
bull Goblet cell hyperplasia
bull Reticular thickening
bull Appearance of myofibroblasts
bull Smooth muscle cell hypertrophy
bull Angiogenesis
bull Plasma extravasation
30
Improved therapies
Current
bull Relievers ndash inhalers are usually blue or green
ndash Bronchodilators cause smooth muscle to relax
ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur
bull Preventers ndash inhalers are usually brown orange or red
ndash Inhaled corticosteroids reduce inflammation in the airways
ndash Used daily even when there are no symptoms
bull Combination ndash A bronchodilatoranti-inflammatory drug
5-10 steroid resistant - severe
31
Chronic Obstructive Pulmonary Disease ndash COPD
bull Globally 64 million people have
COPD
bull Smoking main cause
bull Consists of a number of conditions
including emphysema and chronic
bronchitis
bull Symptoms of cough shortness of
breath tight chest wheeze
bull Can lead to irreversible airway
obstruction ndash no cure
32
Effect of smoking on FEV1
(Forced expiratory volume in 1 second)
Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33
Global Initiative on Obstructive Lung
Disease (GOLD)
GOLD has classified COPD as ldquoa disease
state characterised by airflow limitation that
is not fully reversible The airflow limitation
is usually both progressive and associated
with an abnormal inflammatory response of
the lungs to noxious particles or gasesrdquo
World Health Organization The GOLD global strategy for the
management and prevention of COPD 2001wwwgoldcopdorg 34
GOLD 1-4 classification with 4 most severe
Summary
bull Airways conduct air in and out of the lung mechanical stability
bull Airways comprised of many cell types with specific functions
- control of contractionrelaxation
- mucociliary clearance of foreign particles
- reduction of surface tension
bull Structural cells may also be lsquoregulatoryrsquo- cross-talk between cells
bull Immunity must display appropriate inflammatory tone
bull Respiratory disease leads to loss of lsquocontrolrsquo
- inflammation
- remodelling
- tissue breakdown
Additional information on websites Asthma UK
British Lung Foundation
35
Lungs are susceptible to many
diseases that may reduce function
Asthma
Chronic obstructive
pulmonary disease
(COPD)
Mesothelioma
Acute respiratory
distress syndrome
(ARDS)
Idiopathic pulmonary
fibrosis
Sarcoidosis
Pulmonary
hypertension Cystic fibrosis
Infection
Bronchitis
Pneumonia Pleurisy
Trachea
Bronchi
Alveoli
4
Structure of a healthy airway
5 Advantages of a multi-lobed structure
Why are there different cells at different locations
Trachea
Primary bronchus
Secondary bronchus
Tertiary bronchus
Smaller bronchi
Bronchioles
Terminal bronchioles
Respiratory bronchioles
Alveolar sacs (150 million)
Ciliated epithelium Basal cell Goblet cell Club cell Serous cell Brush cell Alveolar type I Alveolar type II
BeacuteruBeacute K et al ATLA 37 89ndash141 2009
C
O
N
D
U
C
T
I
N
G
6
Specialised cellular function of epithelial cells
Ciliated epithelium Protective barrier mucociliary clearance Basal cell Renew damaged cells Goblet cell Mucus secretion Club cell Production of surfactant (lubricant ) Serous cell Antibacterial secretions Brush cell Unknown helliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip Alveolar type I Gas exchange Alveolar type II Production of surfactant
7
Proximal region - trachea
C-shaped rings of hyaline cartilage support trachea mucosa and
prevent tube collapse during inspiration
Lumen
Epithelium
Cartilage
8
Basic structure of the conducting airway
Cartilage
9
Airway associated cells ndash different roles
Categoryfunction Cell type ndash over 40 different types
Lining cells Ciliated intermediate brush basal epithelium
Contractile cells Smooth muscle
Secretory cells Goblet (epithelium) mucous serous (glands)
Connective tissue Fibroblast interstitial cell produce
elastin collagen proteoglycans cartilage
Neuroendocrine Nerves ganglia neuroendocrine cells neuroepithelial
bodies
Vascular cells Endothelial smooth muscle pericyte
Immune cells Mast cell dendritic cell lymphocyte eosinophil
macrophage neutrophil
10
The epithelium is not simply a barrier
11
Functions of the conducting airway epithelium
bull Protection by secretion and movement
of mucus by cilia towards the pharynx ndash
mucociliary clearance
bull Physical barrier to pathogens ndash
junctional components between cells (tight adherens
desmosomes)
bull Production of regulatory and inflammatory mediators
ndash Chemokines (eg IL-8 and IL-6)- attract inflammatory cells
ndash Cytokines (eg GM-CSF and TGF-β) ndash cell signalling
ndash Proteases (eg plasminogen activators MMPs)- migration
degradation of ECM growth factor activation
Mucus secretion
Mucus is a hydrated gel that is a
key component of airway defence
The principal gel-forming
components are MUCINS
produced by goblet and mucous
cells
Mucociliary transport
Submucosal gland
Mucus
Goblet
cell Functions
bull Barrier to pathogens
particulates and allergens
bull Maintenance of hydration
bull Serous cells secrete
antibacterials (eg lysozyme)
bull Glands also secrete water and
salts (eg Na+ and Cl-)
13
Function of airway smooth muscle
TONE
(airway calibre)
Contraction
Relaxation
STRUCTURE
Spiral
organisation
SECRETION
Mediators
Cytokines
Chemokines
14
Tertiary bronchus
bull Reduced cartilage
more smooth muscle
bull Fewer goblet cells and
submucosal glands
bull Increase in club cells
producing surfactant
15
Bronchiole
16
bull Single layer of ciliated epithelium
bull No cartilage
bull Reduced smooth muscle
bull No goblet cells or submucosal
glands
bull More club cells producing surfactant
Distal region ndash site of gas exchange
bull Alveoli - passive gas exchange
with capillary network ndash 150
million
bull Collagen elastic fibres and
fibroblasts and macrophages
present in septal junctions
bull Several alveoli grouped into
lobules surrounded by
connective tissue
17
Lung parenchyma
bull Type I alveolar cells - simple squamous
epithelium non-ciliated and main site of gas
exchange ndash covers 90 of alveolus
bull Type II alveolar cells (septal cells) ndash produce
surfactant to reduce surface tension preventing
alveoli collapse and renew type I cells
Type II alveolar cells
Type I alveolar cells
18
Control of airflow
bull Relaxation of smooth muscle = bronchodilation = increased airflow
bull Constriction of smooth muscle = bronchoconstriction = reduced airflow
Inflammation ndash driven constriction
of airway smooth muscle
Smooth muscle tone controlled by
autonomic nervous system
adrenal medullary hormones and
local factors
Autonomic nervous system
Parasympathetic Sympathetic
Muscarinic
beta2 alpha
- Constricts smooth muscle
- Causes mucus gland secretion
- Constricts
blood vessels
- Relaxes smooth muscle
19
Regulators of airflow
bull Nerves
- parasympathetic (cholinergic - constriction)
- sympathetic (adrenergic - dilation)
bull Regulatory and inflammatory mediators
- mast cell histamine - constriction
- arachidonic acid metabolites ndashconstrict and dilate
(eg prostaglandins leukotrienes)
- cytokines ndash constrict and dilate increase mucus
- hormones (eg adrenaline)
bull Proteinases (eg neutrophil elastase)
bull Reactive gas species (eg O2- NO)
Airway disease = Loss of normal control
20
SEM showing two alveolar macrophages (MP) in the alveolar space (ALV)
Airway macrophages a collision of functions
bull Induction of
inflammation
pathogens
bull Inhibition of
inflammation
clearance of self
cells and
extracellular
matrix turnover
products
Epithelial regulation of immunity
Tolerance
level set to
high =
bacterial
escape
Tolerance levels set too low
26
Respiratory diseases with loss of airway function
bull Common conditions
Asthma ndash ~5 of population in industrialised countries
COPD ndash 4th leading cause of death in UK and USA
Cystic fibrosis ndash lethal autosomal recessive gene defect (~12000 Caucasians)
bull Airway remodelling
- goblet cell hyperplasia
- submucosal gland hypertrophy
- fibrosis
- smooth muscle hypertrophy (asthma)
- alveolar destruction (COPD)
27
Asthma
bull Symptoms cough wheeze
shortness of breath and tightness of
the chest
bull Increased airway hyper-reactivity to
a variety of stimuli (smooth muscle
sensitive to constriction)
bull Airway narrowing and airflow
obstruction - usually reversible
(spontaneously or with drugs)
bull Wide spectrum of symptoms and
different severities of disease-
different phenotypes
Normal
Asthma
28
Asthma pathophysiology
CHRONIC
INFLAMMATION
AIRWAY
REMODELLING
29
Pathological changes in the asthmatic
airway- remodelling
bull Mucus hypersecretion
bull Denuded epithelium
bull Goblet cell hyperplasia
bull Reticular thickening
bull Appearance of myofibroblasts
bull Smooth muscle cell hypertrophy
bull Angiogenesis
bull Plasma extravasation
30
Improved therapies
Current
bull Relievers ndash inhalers are usually blue or green
ndash Bronchodilators cause smooth muscle to relax
ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur
bull Preventers ndash inhalers are usually brown orange or red
ndash Inhaled corticosteroids reduce inflammation in the airways
ndash Used daily even when there are no symptoms
bull Combination ndash A bronchodilatoranti-inflammatory drug
5-10 steroid resistant - severe
31
Chronic Obstructive Pulmonary Disease ndash COPD
bull Globally 64 million people have
COPD
bull Smoking main cause
bull Consists of a number of conditions
including emphysema and chronic
bronchitis
bull Symptoms of cough shortness of
breath tight chest wheeze
bull Can lead to irreversible airway
obstruction ndash no cure
32
Effect of smoking on FEV1
(Forced expiratory volume in 1 second)
Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33
Global Initiative on Obstructive Lung
Disease (GOLD)
GOLD has classified COPD as ldquoa disease
state characterised by airflow limitation that
is not fully reversible The airflow limitation
is usually both progressive and associated
with an abnormal inflammatory response of
the lungs to noxious particles or gasesrdquo
World Health Organization The GOLD global strategy for the
management and prevention of COPD 2001wwwgoldcopdorg 34
GOLD 1-4 classification with 4 most severe
Summary
bull Airways conduct air in and out of the lung mechanical stability
bull Airways comprised of many cell types with specific functions
- control of contractionrelaxation
- mucociliary clearance of foreign particles
- reduction of surface tension
bull Structural cells may also be lsquoregulatoryrsquo- cross-talk between cells
bull Immunity must display appropriate inflammatory tone
bull Respiratory disease leads to loss of lsquocontrolrsquo
- inflammation
- remodelling
- tissue breakdown
Additional information on websites Asthma UK
British Lung Foundation
35
Structure of a healthy airway
5 Advantages of a multi-lobed structure
Why are there different cells at different locations
Trachea
Primary bronchus
Secondary bronchus
Tertiary bronchus
Smaller bronchi
Bronchioles
Terminal bronchioles
Respiratory bronchioles
Alveolar sacs (150 million)
Ciliated epithelium Basal cell Goblet cell Club cell Serous cell Brush cell Alveolar type I Alveolar type II
BeacuteruBeacute K et al ATLA 37 89ndash141 2009
C
O
N
D
U
C
T
I
N
G
6
Specialised cellular function of epithelial cells
Ciliated epithelium Protective barrier mucociliary clearance Basal cell Renew damaged cells Goblet cell Mucus secretion Club cell Production of surfactant (lubricant ) Serous cell Antibacterial secretions Brush cell Unknown helliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip Alveolar type I Gas exchange Alveolar type II Production of surfactant
7
Proximal region - trachea
C-shaped rings of hyaline cartilage support trachea mucosa and
prevent tube collapse during inspiration
Lumen
Epithelium
Cartilage
8
Basic structure of the conducting airway
Cartilage
9
Airway associated cells ndash different roles
Categoryfunction Cell type ndash over 40 different types
Lining cells Ciliated intermediate brush basal epithelium
Contractile cells Smooth muscle
Secretory cells Goblet (epithelium) mucous serous (glands)
Connective tissue Fibroblast interstitial cell produce
elastin collagen proteoglycans cartilage
Neuroendocrine Nerves ganglia neuroendocrine cells neuroepithelial
bodies
Vascular cells Endothelial smooth muscle pericyte
Immune cells Mast cell dendritic cell lymphocyte eosinophil
macrophage neutrophil
10
The epithelium is not simply a barrier
11
Functions of the conducting airway epithelium
bull Protection by secretion and movement
of mucus by cilia towards the pharynx ndash
mucociliary clearance
bull Physical barrier to pathogens ndash
junctional components between cells (tight adherens
desmosomes)
bull Production of regulatory and inflammatory mediators
ndash Chemokines (eg IL-8 and IL-6)- attract inflammatory cells
ndash Cytokines (eg GM-CSF and TGF-β) ndash cell signalling
ndash Proteases (eg plasminogen activators MMPs)- migration
degradation of ECM growth factor activation
Mucus secretion
Mucus is a hydrated gel that is a
key component of airway defence
The principal gel-forming
components are MUCINS
produced by goblet and mucous
cells
Mucociliary transport
Submucosal gland
Mucus
Goblet
cell Functions
bull Barrier to pathogens
particulates and allergens
bull Maintenance of hydration
bull Serous cells secrete
antibacterials (eg lysozyme)
bull Glands also secrete water and
salts (eg Na+ and Cl-)
13
Function of airway smooth muscle
TONE
(airway calibre)
Contraction
Relaxation
STRUCTURE
Spiral
organisation
SECRETION
Mediators
Cytokines
Chemokines
14
Tertiary bronchus
bull Reduced cartilage
more smooth muscle
bull Fewer goblet cells and
submucosal glands
bull Increase in club cells
producing surfactant
15
Bronchiole
16
bull Single layer of ciliated epithelium
bull No cartilage
bull Reduced smooth muscle
bull No goblet cells or submucosal
glands
bull More club cells producing surfactant
Distal region ndash site of gas exchange
bull Alveoli - passive gas exchange
with capillary network ndash 150
million
bull Collagen elastic fibres and
fibroblasts and macrophages
present in septal junctions
bull Several alveoli grouped into
lobules surrounded by
connective tissue
17
Lung parenchyma
bull Type I alveolar cells - simple squamous
epithelium non-ciliated and main site of gas
exchange ndash covers 90 of alveolus
bull Type II alveolar cells (septal cells) ndash produce
surfactant to reduce surface tension preventing
alveoli collapse and renew type I cells
Type II alveolar cells
Type I alveolar cells
18
Control of airflow
bull Relaxation of smooth muscle = bronchodilation = increased airflow
bull Constriction of smooth muscle = bronchoconstriction = reduced airflow
Inflammation ndash driven constriction
of airway smooth muscle
Smooth muscle tone controlled by
autonomic nervous system
adrenal medullary hormones and
local factors
Autonomic nervous system
Parasympathetic Sympathetic
Muscarinic
beta2 alpha
- Constricts smooth muscle
- Causes mucus gland secretion
- Constricts
blood vessels
- Relaxes smooth muscle
19
Regulators of airflow
bull Nerves
- parasympathetic (cholinergic - constriction)
- sympathetic (adrenergic - dilation)
bull Regulatory and inflammatory mediators
- mast cell histamine - constriction
- arachidonic acid metabolites ndashconstrict and dilate
(eg prostaglandins leukotrienes)
- cytokines ndash constrict and dilate increase mucus
- hormones (eg adrenaline)
bull Proteinases (eg neutrophil elastase)
bull Reactive gas species (eg O2- NO)
Airway disease = Loss of normal control
20
SEM showing two alveolar macrophages (MP) in the alveolar space (ALV)
Airway macrophages a collision of functions
bull Induction of
inflammation
pathogens
bull Inhibition of
inflammation
clearance of self
cells and
extracellular
matrix turnover
products
Epithelial regulation of immunity
Tolerance
level set to
high =
bacterial
escape
Tolerance levels set too low
26
Respiratory diseases with loss of airway function
bull Common conditions
Asthma ndash ~5 of population in industrialised countries
COPD ndash 4th leading cause of death in UK and USA
Cystic fibrosis ndash lethal autosomal recessive gene defect (~12000 Caucasians)
bull Airway remodelling
- goblet cell hyperplasia
- submucosal gland hypertrophy
- fibrosis
- smooth muscle hypertrophy (asthma)
- alveolar destruction (COPD)
27
Asthma
bull Symptoms cough wheeze
shortness of breath and tightness of
the chest
bull Increased airway hyper-reactivity to
a variety of stimuli (smooth muscle
sensitive to constriction)
bull Airway narrowing and airflow
obstruction - usually reversible
(spontaneously or with drugs)
bull Wide spectrum of symptoms and
different severities of disease-
different phenotypes
Normal
Asthma
28
Asthma pathophysiology
CHRONIC
INFLAMMATION
AIRWAY
REMODELLING
29
Pathological changes in the asthmatic
airway- remodelling
bull Mucus hypersecretion
bull Denuded epithelium
bull Goblet cell hyperplasia
bull Reticular thickening
bull Appearance of myofibroblasts
bull Smooth muscle cell hypertrophy
bull Angiogenesis
bull Plasma extravasation
30
Improved therapies
Current
bull Relievers ndash inhalers are usually blue or green
ndash Bronchodilators cause smooth muscle to relax
ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur
bull Preventers ndash inhalers are usually brown orange or red
ndash Inhaled corticosteroids reduce inflammation in the airways
ndash Used daily even when there are no symptoms
bull Combination ndash A bronchodilatoranti-inflammatory drug
5-10 steroid resistant - severe
31
Chronic Obstructive Pulmonary Disease ndash COPD
bull Globally 64 million people have
COPD
bull Smoking main cause
bull Consists of a number of conditions
including emphysema and chronic
bronchitis
bull Symptoms of cough shortness of
breath tight chest wheeze
bull Can lead to irreversible airway
obstruction ndash no cure
32
Effect of smoking on FEV1
(Forced expiratory volume in 1 second)
Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33
Global Initiative on Obstructive Lung
Disease (GOLD)
GOLD has classified COPD as ldquoa disease
state characterised by airflow limitation that
is not fully reversible The airflow limitation
is usually both progressive and associated
with an abnormal inflammatory response of
the lungs to noxious particles or gasesrdquo
World Health Organization The GOLD global strategy for the
management and prevention of COPD 2001wwwgoldcopdorg 34
GOLD 1-4 classification with 4 most severe
Summary
bull Airways conduct air in and out of the lung mechanical stability
bull Airways comprised of many cell types with specific functions
- control of contractionrelaxation
- mucociliary clearance of foreign particles
- reduction of surface tension
bull Structural cells may also be lsquoregulatoryrsquo- cross-talk between cells
bull Immunity must display appropriate inflammatory tone
bull Respiratory disease leads to loss of lsquocontrolrsquo
- inflammation
- remodelling
- tissue breakdown
Additional information on websites Asthma UK
British Lung Foundation
35
Why are there different cells at different locations
Trachea
Primary bronchus
Secondary bronchus
Tertiary bronchus
Smaller bronchi
Bronchioles
Terminal bronchioles
Respiratory bronchioles
Alveolar sacs (150 million)
Ciliated epithelium Basal cell Goblet cell Club cell Serous cell Brush cell Alveolar type I Alveolar type II
BeacuteruBeacute K et al ATLA 37 89ndash141 2009
C
O
N
D
U
C
T
I
N
G
6
Specialised cellular function of epithelial cells
Ciliated epithelium Protective barrier mucociliary clearance Basal cell Renew damaged cells Goblet cell Mucus secretion Club cell Production of surfactant (lubricant ) Serous cell Antibacterial secretions Brush cell Unknown helliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip Alveolar type I Gas exchange Alveolar type II Production of surfactant
7
Proximal region - trachea
C-shaped rings of hyaline cartilage support trachea mucosa and
prevent tube collapse during inspiration
Lumen
Epithelium
Cartilage
8
Basic structure of the conducting airway
Cartilage
9
Airway associated cells ndash different roles
Categoryfunction Cell type ndash over 40 different types
Lining cells Ciliated intermediate brush basal epithelium
Contractile cells Smooth muscle
Secretory cells Goblet (epithelium) mucous serous (glands)
Connective tissue Fibroblast interstitial cell produce
elastin collagen proteoglycans cartilage
Neuroendocrine Nerves ganglia neuroendocrine cells neuroepithelial
bodies
Vascular cells Endothelial smooth muscle pericyte
Immune cells Mast cell dendritic cell lymphocyte eosinophil
macrophage neutrophil
10
The epithelium is not simply a barrier
11
Functions of the conducting airway epithelium
bull Protection by secretion and movement
of mucus by cilia towards the pharynx ndash
mucociliary clearance
bull Physical barrier to pathogens ndash
junctional components between cells (tight adherens
desmosomes)
bull Production of regulatory and inflammatory mediators
ndash Chemokines (eg IL-8 and IL-6)- attract inflammatory cells
ndash Cytokines (eg GM-CSF and TGF-β) ndash cell signalling
ndash Proteases (eg plasminogen activators MMPs)- migration
degradation of ECM growth factor activation
Mucus secretion
Mucus is a hydrated gel that is a
key component of airway defence
The principal gel-forming
components are MUCINS
produced by goblet and mucous
cells
Mucociliary transport
Submucosal gland
Mucus
Goblet
cell Functions
bull Barrier to pathogens
particulates and allergens
bull Maintenance of hydration
bull Serous cells secrete
antibacterials (eg lysozyme)
bull Glands also secrete water and
salts (eg Na+ and Cl-)
13
Function of airway smooth muscle
TONE
(airway calibre)
Contraction
Relaxation
STRUCTURE
Spiral
organisation
SECRETION
Mediators
Cytokines
Chemokines
14
Tertiary bronchus
bull Reduced cartilage
more smooth muscle
bull Fewer goblet cells and
submucosal glands
bull Increase in club cells
producing surfactant
15
Bronchiole
16
bull Single layer of ciliated epithelium
bull No cartilage
bull Reduced smooth muscle
bull No goblet cells or submucosal
glands
bull More club cells producing surfactant
Distal region ndash site of gas exchange
bull Alveoli - passive gas exchange
with capillary network ndash 150
million
bull Collagen elastic fibres and
fibroblasts and macrophages
present in septal junctions
bull Several alveoli grouped into
lobules surrounded by
connective tissue
17
Lung parenchyma
bull Type I alveolar cells - simple squamous
epithelium non-ciliated and main site of gas
exchange ndash covers 90 of alveolus
bull Type II alveolar cells (septal cells) ndash produce
surfactant to reduce surface tension preventing
alveoli collapse and renew type I cells
Type II alveolar cells
Type I alveolar cells
18
Control of airflow
bull Relaxation of smooth muscle = bronchodilation = increased airflow
bull Constriction of smooth muscle = bronchoconstriction = reduced airflow
Inflammation ndash driven constriction
of airway smooth muscle
Smooth muscle tone controlled by
autonomic nervous system
adrenal medullary hormones and
local factors
Autonomic nervous system
Parasympathetic Sympathetic
Muscarinic
beta2 alpha
- Constricts smooth muscle
- Causes mucus gland secretion
- Constricts
blood vessels
- Relaxes smooth muscle
19
Regulators of airflow
bull Nerves
- parasympathetic (cholinergic - constriction)
- sympathetic (adrenergic - dilation)
bull Regulatory and inflammatory mediators
- mast cell histamine - constriction
- arachidonic acid metabolites ndashconstrict and dilate
(eg prostaglandins leukotrienes)
- cytokines ndash constrict and dilate increase mucus
- hormones (eg adrenaline)
bull Proteinases (eg neutrophil elastase)
bull Reactive gas species (eg O2- NO)
Airway disease = Loss of normal control
20
SEM showing two alveolar macrophages (MP) in the alveolar space (ALV)
Airway macrophages a collision of functions
bull Induction of
inflammation
pathogens
bull Inhibition of
inflammation
clearance of self
cells and
extracellular
matrix turnover
products
Epithelial regulation of immunity
Tolerance
level set to
high =
bacterial
escape
Tolerance levels set too low
26
Respiratory diseases with loss of airway function
bull Common conditions
Asthma ndash ~5 of population in industrialised countries
COPD ndash 4th leading cause of death in UK and USA
Cystic fibrosis ndash lethal autosomal recessive gene defect (~12000 Caucasians)
bull Airway remodelling
- goblet cell hyperplasia
- submucosal gland hypertrophy
- fibrosis
- smooth muscle hypertrophy (asthma)
- alveolar destruction (COPD)
27
Asthma
bull Symptoms cough wheeze
shortness of breath and tightness of
the chest
bull Increased airway hyper-reactivity to
a variety of stimuli (smooth muscle
sensitive to constriction)
bull Airway narrowing and airflow
obstruction - usually reversible
(spontaneously or with drugs)
bull Wide spectrum of symptoms and
different severities of disease-
different phenotypes
Normal
Asthma
28
Asthma pathophysiology
CHRONIC
INFLAMMATION
AIRWAY
REMODELLING
29
Pathological changes in the asthmatic
airway- remodelling
bull Mucus hypersecretion
bull Denuded epithelium
bull Goblet cell hyperplasia
bull Reticular thickening
bull Appearance of myofibroblasts
bull Smooth muscle cell hypertrophy
bull Angiogenesis
bull Plasma extravasation
30
Improved therapies
Current
bull Relievers ndash inhalers are usually blue or green
ndash Bronchodilators cause smooth muscle to relax
ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur
bull Preventers ndash inhalers are usually brown orange or red
ndash Inhaled corticosteroids reduce inflammation in the airways
ndash Used daily even when there are no symptoms
bull Combination ndash A bronchodilatoranti-inflammatory drug
5-10 steroid resistant - severe
31
Chronic Obstructive Pulmonary Disease ndash COPD
bull Globally 64 million people have
COPD
bull Smoking main cause
bull Consists of a number of conditions
including emphysema and chronic
bronchitis
bull Symptoms of cough shortness of
breath tight chest wheeze
bull Can lead to irreversible airway
obstruction ndash no cure
32
Effect of smoking on FEV1
(Forced expiratory volume in 1 second)
Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33
Global Initiative on Obstructive Lung
Disease (GOLD)
GOLD has classified COPD as ldquoa disease
state characterised by airflow limitation that
is not fully reversible The airflow limitation
is usually both progressive and associated
with an abnormal inflammatory response of
the lungs to noxious particles or gasesrdquo
World Health Organization The GOLD global strategy for the
management and prevention of COPD 2001wwwgoldcopdorg 34
GOLD 1-4 classification with 4 most severe
Summary
bull Airways conduct air in and out of the lung mechanical stability
bull Airways comprised of many cell types with specific functions
- control of contractionrelaxation
- mucociliary clearance of foreign particles
- reduction of surface tension
bull Structural cells may also be lsquoregulatoryrsquo- cross-talk between cells
bull Immunity must display appropriate inflammatory tone
bull Respiratory disease leads to loss of lsquocontrolrsquo
- inflammation
- remodelling
- tissue breakdown
Additional information on websites Asthma UK
British Lung Foundation
35
Specialised cellular function of epithelial cells
Ciliated epithelium Protective barrier mucociliary clearance Basal cell Renew damaged cells Goblet cell Mucus secretion Club cell Production of surfactant (lubricant ) Serous cell Antibacterial secretions Brush cell Unknown helliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip Alveolar type I Gas exchange Alveolar type II Production of surfactant
7
Proximal region - trachea
C-shaped rings of hyaline cartilage support trachea mucosa and
prevent tube collapse during inspiration
Lumen
Epithelium
Cartilage
8
Basic structure of the conducting airway
Cartilage
9
Airway associated cells ndash different roles
Categoryfunction Cell type ndash over 40 different types
Lining cells Ciliated intermediate brush basal epithelium
Contractile cells Smooth muscle
Secretory cells Goblet (epithelium) mucous serous (glands)
Connective tissue Fibroblast interstitial cell produce
elastin collagen proteoglycans cartilage
Neuroendocrine Nerves ganglia neuroendocrine cells neuroepithelial
bodies
Vascular cells Endothelial smooth muscle pericyte
Immune cells Mast cell dendritic cell lymphocyte eosinophil
macrophage neutrophil
10
The epithelium is not simply a barrier
11
Functions of the conducting airway epithelium
bull Protection by secretion and movement
of mucus by cilia towards the pharynx ndash
mucociliary clearance
bull Physical barrier to pathogens ndash
junctional components between cells (tight adherens
desmosomes)
bull Production of regulatory and inflammatory mediators
ndash Chemokines (eg IL-8 and IL-6)- attract inflammatory cells
ndash Cytokines (eg GM-CSF and TGF-β) ndash cell signalling
ndash Proteases (eg plasminogen activators MMPs)- migration
degradation of ECM growth factor activation
Mucus secretion
Mucus is a hydrated gel that is a
key component of airway defence
The principal gel-forming
components are MUCINS
produced by goblet and mucous
cells
Mucociliary transport
Submucosal gland
Mucus
Goblet
cell Functions
bull Barrier to pathogens
particulates and allergens
bull Maintenance of hydration
bull Serous cells secrete
antibacterials (eg lysozyme)
bull Glands also secrete water and
salts (eg Na+ and Cl-)
13
Function of airway smooth muscle
TONE
(airway calibre)
Contraction
Relaxation
STRUCTURE
Spiral
organisation
SECRETION
Mediators
Cytokines
Chemokines
14
Tertiary bronchus
bull Reduced cartilage
more smooth muscle
bull Fewer goblet cells and
submucosal glands
bull Increase in club cells
producing surfactant
15
Bronchiole
16
bull Single layer of ciliated epithelium
bull No cartilage
bull Reduced smooth muscle
bull No goblet cells or submucosal
glands
bull More club cells producing surfactant
Distal region ndash site of gas exchange
bull Alveoli - passive gas exchange
with capillary network ndash 150
million
bull Collagen elastic fibres and
fibroblasts and macrophages
present in septal junctions
bull Several alveoli grouped into
lobules surrounded by
connective tissue
17
Lung parenchyma
bull Type I alveolar cells - simple squamous
epithelium non-ciliated and main site of gas
exchange ndash covers 90 of alveolus
bull Type II alveolar cells (septal cells) ndash produce
surfactant to reduce surface tension preventing
alveoli collapse and renew type I cells
Type II alveolar cells
Type I alveolar cells
18
Control of airflow
bull Relaxation of smooth muscle = bronchodilation = increased airflow
bull Constriction of smooth muscle = bronchoconstriction = reduced airflow
Inflammation ndash driven constriction
of airway smooth muscle
Smooth muscle tone controlled by
autonomic nervous system
adrenal medullary hormones and
local factors
Autonomic nervous system
Parasympathetic Sympathetic
Muscarinic
beta2 alpha
- Constricts smooth muscle
- Causes mucus gland secretion
- Constricts
blood vessels
- Relaxes smooth muscle
19
Regulators of airflow
bull Nerves
- parasympathetic (cholinergic - constriction)
- sympathetic (adrenergic - dilation)
bull Regulatory and inflammatory mediators
- mast cell histamine - constriction
- arachidonic acid metabolites ndashconstrict and dilate
(eg prostaglandins leukotrienes)
- cytokines ndash constrict and dilate increase mucus
- hormones (eg adrenaline)
bull Proteinases (eg neutrophil elastase)
bull Reactive gas species (eg O2- NO)
Airway disease = Loss of normal control
20
SEM showing two alveolar macrophages (MP) in the alveolar space (ALV)
Airway macrophages a collision of functions
bull Induction of
inflammation
pathogens
bull Inhibition of
inflammation
clearance of self
cells and
extracellular
matrix turnover
products
Epithelial regulation of immunity
Tolerance
level set to
high =
bacterial
escape
Tolerance levels set too low
26
Respiratory diseases with loss of airway function
bull Common conditions
Asthma ndash ~5 of population in industrialised countries
COPD ndash 4th leading cause of death in UK and USA
Cystic fibrosis ndash lethal autosomal recessive gene defect (~12000 Caucasians)
bull Airway remodelling
- goblet cell hyperplasia
- submucosal gland hypertrophy
- fibrosis
- smooth muscle hypertrophy (asthma)
- alveolar destruction (COPD)
27
Asthma
bull Symptoms cough wheeze
shortness of breath and tightness of
the chest
bull Increased airway hyper-reactivity to
a variety of stimuli (smooth muscle
sensitive to constriction)
bull Airway narrowing and airflow
obstruction - usually reversible
(spontaneously or with drugs)
bull Wide spectrum of symptoms and
different severities of disease-
different phenotypes
Normal
Asthma
28
Asthma pathophysiology
CHRONIC
INFLAMMATION
AIRWAY
REMODELLING
29
Pathological changes in the asthmatic
airway- remodelling
bull Mucus hypersecretion
bull Denuded epithelium
bull Goblet cell hyperplasia
bull Reticular thickening
bull Appearance of myofibroblasts
bull Smooth muscle cell hypertrophy
bull Angiogenesis
bull Plasma extravasation
30
Improved therapies
Current
bull Relievers ndash inhalers are usually blue or green
ndash Bronchodilators cause smooth muscle to relax
ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur
bull Preventers ndash inhalers are usually brown orange or red
ndash Inhaled corticosteroids reduce inflammation in the airways
ndash Used daily even when there are no symptoms
bull Combination ndash A bronchodilatoranti-inflammatory drug
5-10 steroid resistant - severe
31
Chronic Obstructive Pulmonary Disease ndash COPD
bull Globally 64 million people have
COPD
bull Smoking main cause
bull Consists of a number of conditions
including emphysema and chronic
bronchitis
bull Symptoms of cough shortness of
breath tight chest wheeze
bull Can lead to irreversible airway
obstruction ndash no cure
32
Effect of smoking on FEV1
(Forced expiratory volume in 1 second)
Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33
Global Initiative on Obstructive Lung
Disease (GOLD)
GOLD has classified COPD as ldquoa disease
state characterised by airflow limitation that
is not fully reversible The airflow limitation
is usually both progressive and associated
with an abnormal inflammatory response of
the lungs to noxious particles or gasesrdquo
World Health Organization The GOLD global strategy for the
management and prevention of COPD 2001wwwgoldcopdorg 34
GOLD 1-4 classification with 4 most severe
Summary
bull Airways conduct air in and out of the lung mechanical stability
bull Airways comprised of many cell types with specific functions
- control of contractionrelaxation
- mucociliary clearance of foreign particles
- reduction of surface tension
bull Structural cells may also be lsquoregulatoryrsquo- cross-talk between cells
bull Immunity must display appropriate inflammatory tone
bull Respiratory disease leads to loss of lsquocontrolrsquo
- inflammation
- remodelling
- tissue breakdown
Additional information on websites Asthma UK
British Lung Foundation
35
Proximal region - trachea
C-shaped rings of hyaline cartilage support trachea mucosa and
prevent tube collapse during inspiration
Lumen
Epithelium
Cartilage
8
Basic structure of the conducting airway
Cartilage
9
Airway associated cells ndash different roles
Categoryfunction Cell type ndash over 40 different types
Lining cells Ciliated intermediate brush basal epithelium
Contractile cells Smooth muscle
Secretory cells Goblet (epithelium) mucous serous (glands)
Connective tissue Fibroblast interstitial cell produce
elastin collagen proteoglycans cartilage
Neuroendocrine Nerves ganglia neuroendocrine cells neuroepithelial
bodies
Vascular cells Endothelial smooth muscle pericyte
Immune cells Mast cell dendritic cell lymphocyte eosinophil
macrophage neutrophil
10
The epithelium is not simply a barrier
11
Functions of the conducting airway epithelium
bull Protection by secretion and movement
of mucus by cilia towards the pharynx ndash
mucociliary clearance
bull Physical barrier to pathogens ndash
junctional components between cells (tight adherens
desmosomes)
bull Production of regulatory and inflammatory mediators
ndash Chemokines (eg IL-8 and IL-6)- attract inflammatory cells
ndash Cytokines (eg GM-CSF and TGF-β) ndash cell signalling
ndash Proteases (eg plasminogen activators MMPs)- migration
degradation of ECM growth factor activation
Mucus secretion
Mucus is a hydrated gel that is a
key component of airway defence
The principal gel-forming
components are MUCINS
produced by goblet and mucous
cells
Mucociliary transport
Submucosal gland
Mucus
Goblet
cell Functions
bull Barrier to pathogens
particulates and allergens
bull Maintenance of hydration
bull Serous cells secrete
antibacterials (eg lysozyme)
bull Glands also secrete water and
salts (eg Na+ and Cl-)
13
Function of airway smooth muscle
TONE
(airway calibre)
Contraction
Relaxation
STRUCTURE
Spiral
organisation
SECRETION
Mediators
Cytokines
Chemokines
14
Tertiary bronchus
bull Reduced cartilage
more smooth muscle
bull Fewer goblet cells and
submucosal glands
bull Increase in club cells
producing surfactant
15
Bronchiole
16
bull Single layer of ciliated epithelium
bull No cartilage
bull Reduced smooth muscle
bull No goblet cells or submucosal
glands
bull More club cells producing surfactant
Distal region ndash site of gas exchange
bull Alveoli - passive gas exchange
with capillary network ndash 150
million
bull Collagen elastic fibres and
fibroblasts and macrophages
present in septal junctions
bull Several alveoli grouped into
lobules surrounded by
connective tissue
17
Lung parenchyma
bull Type I alveolar cells - simple squamous
epithelium non-ciliated and main site of gas
exchange ndash covers 90 of alveolus
bull Type II alveolar cells (septal cells) ndash produce
surfactant to reduce surface tension preventing
alveoli collapse and renew type I cells
Type II alveolar cells
Type I alveolar cells
18
Control of airflow
bull Relaxation of smooth muscle = bronchodilation = increased airflow
bull Constriction of smooth muscle = bronchoconstriction = reduced airflow
Inflammation ndash driven constriction
of airway smooth muscle
Smooth muscle tone controlled by
autonomic nervous system
adrenal medullary hormones and
local factors
Autonomic nervous system
Parasympathetic Sympathetic
Muscarinic
beta2 alpha
- Constricts smooth muscle
- Causes mucus gland secretion
- Constricts
blood vessels
- Relaxes smooth muscle
19
Regulators of airflow
bull Nerves
- parasympathetic (cholinergic - constriction)
- sympathetic (adrenergic - dilation)
bull Regulatory and inflammatory mediators
- mast cell histamine - constriction
- arachidonic acid metabolites ndashconstrict and dilate
(eg prostaglandins leukotrienes)
- cytokines ndash constrict and dilate increase mucus
- hormones (eg adrenaline)
bull Proteinases (eg neutrophil elastase)
bull Reactive gas species (eg O2- NO)
Airway disease = Loss of normal control
20
SEM showing two alveolar macrophages (MP) in the alveolar space (ALV)
Airway macrophages a collision of functions
bull Induction of
inflammation
pathogens
bull Inhibition of
inflammation
clearance of self
cells and
extracellular
matrix turnover
products
Epithelial regulation of immunity
Tolerance
level set to
high =
bacterial
escape
Tolerance levels set too low
26
Respiratory diseases with loss of airway function
bull Common conditions
Asthma ndash ~5 of population in industrialised countries
COPD ndash 4th leading cause of death in UK and USA
Cystic fibrosis ndash lethal autosomal recessive gene defect (~12000 Caucasians)
bull Airway remodelling
- goblet cell hyperplasia
- submucosal gland hypertrophy
- fibrosis
- smooth muscle hypertrophy (asthma)
- alveolar destruction (COPD)
27
Asthma
bull Symptoms cough wheeze
shortness of breath and tightness of
the chest
bull Increased airway hyper-reactivity to
a variety of stimuli (smooth muscle
sensitive to constriction)
bull Airway narrowing and airflow
obstruction - usually reversible
(spontaneously or with drugs)
bull Wide spectrum of symptoms and
different severities of disease-
different phenotypes
Normal
Asthma
28
Asthma pathophysiology
CHRONIC
INFLAMMATION
AIRWAY
REMODELLING
29
Pathological changes in the asthmatic
airway- remodelling
bull Mucus hypersecretion
bull Denuded epithelium
bull Goblet cell hyperplasia
bull Reticular thickening
bull Appearance of myofibroblasts
bull Smooth muscle cell hypertrophy
bull Angiogenesis
bull Plasma extravasation
30
Improved therapies
Current
bull Relievers ndash inhalers are usually blue or green
ndash Bronchodilators cause smooth muscle to relax
ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur
bull Preventers ndash inhalers are usually brown orange or red
ndash Inhaled corticosteroids reduce inflammation in the airways
ndash Used daily even when there are no symptoms
bull Combination ndash A bronchodilatoranti-inflammatory drug
5-10 steroid resistant - severe
31
Chronic Obstructive Pulmonary Disease ndash COPD
bull Globally 64 million people have
COPD
bull Smoking main cause
bull Consists of a number of conditions
including emphysema and chronic
bronchitis
bull Symptoms of cough shortness of
breath tight chest wheeze
bull Can lead to irreversible airway
obstruction ndash no cure
32
Effect of smoking on FEV1
(Forced expiratory volume in 1 second)
Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33
Global Initiative on Obstructive Lung
Disease (GOLD)
GOLD has classified COPD as ldquoa disease
state characterised by airflow limitation that
is not fully reversible The airflow limitation
is usually both progressive and associated
with an abnormal inflammatory response of
the lungs to noxious particles or gasesrdquo
World Health Organization The GOLD global strategy for the
management and prevention of COPD 2001wwwgoldcopdorg 34
GOLD 1-4 classification with 4 most severe
Summary
bull Airways conduct air in and out of the lung mechanical stability
bull Airways comprised of many cell types with specific functions
- control of contractionrelaxation
- mucociliary clearance of foreign particles
- reduction of surface tension
bull Structural cells may also be lsquoregulatoryrsquo- cross-talk between cells
bull Immunity must display appropriate inflammatory tone
bull Respiratory disease leads to loss of lsquocontrolrsquo
- inflammation
- remodelling
- tissue breakdown
Additional information on websites Asthma UK
British Lung Foundation
35
Basic structure of the conducting airway
Cartilage
9
Airway associated cells ndash different roles
Categoryfunction Cell type ndash over 40 different types
Lining cells Ciliated intermediate brush basal epithelium
Contractile cells Smooth muscle
Secretory cells Goblet (epithelium) mucous serous (glands)
Connective tissue Fibroblast interstitial cell produce
elastin collagen proteoglycans cartilage
Neuroendocrine Nerves ganglia neuroendocrine cells neuroepithelial
bodies
Vascular cells Endothelial smooth muscle pericyte
Immune cells Mast cell dendritic cell lymphocyte eosinophil
macrophage neutrophil
10
The epithelium is not simply a barrier
11
Functions of the conducting airway epithelium
bull Protection by secretion and movement
of mucus by cilia towards the pharynx ndash
mucociliary clearance
bull Physical barrier to pathogens ndash
junctional components between cells (tight adherens
desmosomes)
bull Production of regulatory and inflammatory mediators
ndash Chemokines (eg IL-8 and IL-6)- attract inflammatory cells
ndash Cytokines (eg GM-CSF and TGF-β) ndash cell signalling
ndash Proteases (eg plasminogen activators MMPs)- migration
degradation of ECM growth factor activation
Mucus secretion
Mucus is a hydrated gel that is a
key component of airway defence
The principal gel-forming
components are MUCINS
produced by goblet and mucous
cells
Mucociliary transport
Submucosal gland
Mucus
Goblet
cell Functions
bull Barrier to pathogens
particulates and allergens
bull Maintenance of hydration
bull Serous cells secrete
antibacterials (eg lysozyme)
bull Glands also secrete water and
salts (eg Na+ and Cl-)
13
Function of airway smooth muscle
TONE
(airway calibre)
Contraction
Relaxation
STRUCTURE
Spiral
organisation
SECRETION
Mediators
Cytokines
Chemokines
14
Tertiary bronchus
bull Reduced cartilage
more smooth muscle
bull Fewer goblet cells and
submucosal glands
bull Increase in club cells
producing surfactant
15
Bronchiole
16
bull Single layer of ciliated epithelium
bull No cartilage
bull Reduced smooth muscle
bull No goblet cells or submucosal
glands
bull More club cells producing surfactant
Distal region ndash site of gas exchange
bull Alveoli - passive gas exchange
with capillary network ndash 150
million
bull Collagen elastic fibres and
fibroblasts and macrophages
present in septal junctions
bull Several alveoli grouped into
lobules surrounded by
connective tissue
17
Lung parenchyma
bull Type I alveolar cells - simple squamous
epithelium non-ciliated and main site of gas
exchange ndash covers 90 of alveolus
bull Type II alveolar cells (septal cells) ndash produce
surfactant to reduce surface tension preventing
alveoli collapse and renew type I cells
Type II alveolar cells
Type I alveolar cells
18
Control of airflow
bull Relaxation of smooth muscle = bronchodilation = increased airflow
bull Constriction of smooth muscle = bronchoconstriction = reduced airflow
Inflammation ndash driven constriction
of airway smooth muscle
Smooth muscle tone controlled by
autonomic nervous system
adrenal medullary hormones and
local factors
Autonomic nervous system
Parasympathetic Sympathetic
Muscarinic
beta2 alpha
- Constricts smooth muscle
- Causes mucus gland secretion
- Constricts
blood vessels
- Relaxes smooth muscle
19
Regulators of airflow
bull Nerves
- parasympathetic (cholinergic - constriction)
- sympathetic (adrenergic - dilation)
bull Regulatory and inflammatory mediators
- mast cell histamine - constriction
- arachidonic acid metabolites ndashconstrict and dilate
(eg prostaglandins leukotrienes)
- cytokines ndash constrict and dilate increase mucus
- hormones (eg adrenaline)
bull Proteinases (eg neutrophil elastase)
bull Reactive gas species (eg O2- NO)
Airway disease = Loss of normal control
20
SEM showing two alveolar macrophages (MP) in the alveolar space (ALV)
Airway macrophages a collision of functions
bull Induction of
inflammation
pathogens
bull Inhibition of
inflammation
clearance of self
cells and
extracellular
matrix turnover
products
Epithelial regulation of immunity
Tolerance
level set to
high =
bacterial
escape
Tolerance levels set too low
26
Respiratory diseases with loss of airway function
bull Common conditions
Asthma ndash ~5 of population in industrialised countries
COPD ndash 4th leading cause of death in UK and USA
Cystic fibrosis ndash lethal autosomal recessive gene defect (~12000 Caucasians)
bull Airway remodelling
- goblet cell hyperplasia
- submucosal gland hypertrophy
- fibrosis
- smooth muscle hypertrophy (asthma)
- alveolar destruction (COPD)
27
Asthma
bull Symptoms cough wheeze
shortness of breath and tightness of
the chest
bull Increased airway hyper-reactivity to
a variety of stimuli (smooth muscle
sensitive to constriction)
bull Airway narrowing and airflow
obstruction - usually reversible
(spontaneously or with drugs)
bull Wide spectrum of symptoms and
different severities of disease-
different phenotypes
Normal
Asthma
28
Asthma pathophysiology
CHRONIC
INFLAMMATION
AIRWAY
REMODELLING
29
Pathological changes in the asthmatic
airway- remodelling
bull Mucus hypersecretion
bull Denuded epithelium
bull Goblet cell hyperplasia
bull Reticular thickening
bull Appearance of myofibroblasts
bull Smooth muscle cell hypertrophy
bull Angiogenesis
bull Plasma extravasation
30
Improved therapies
Current
bull Relievers ndash inhalers are usually blue or green
ndash Bronchodilators cause smooth muscle to relax
ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur
bull Preventers ndash inhalers are usually brown orange or red
ndash Inhaled corticosteroids reduce inflammation in the airways
ndash Used daily even when there are no symptoms
bull Combination ndash A bronchodilatoranti-inflammatory drug
5-10 steroid resistant - severe
31
Chronic Obstructive Pulmonary Disease ndash COPD
bull Globally 64 million people have
COPD
bull Smoking main cause
bull Consists of a number of conditions
including emphysema and chronic
bronchitis
bull Symptoms of cough shortness of
breath tight chest wheeze
bull Can lead to irreversible airway
obstruction ndash no cure
32
Effect of smoking on FEV1
(Forced expiratory volume in 1 second)
Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33
Global Initiative on Obstructive Lung
Disease (GOLD)
GOLD has classified COPD as ldquoa disease
state characterised by airflow limitation that
is not fully reversible The airflow limitation
is usually both progressive and associated
with an abnormal inflammatory response of
the lungs to noxious particles or gasesrdquo
World Health Organization The GOLD global strategy for the
management and prevention of COPD 2001wwwgoldcopdorg 34
GOLD 1-4 classification with 4 most severe
Summary
bull Airways conduct air in and out of the lung mechanical stability
bull Airways comprised of many cell types with specific functions
- control of contractionrelaxation
- mucociliary clearance of foreign particles
- reduction of surface tension
bull Structural cells may also be lsquoregulatoryrsquo- cross-talk between cells
bull Immunity must display appropriate inflammatory tone
bull Respiratory disease leads to loss of lsquocontrolrsquo
- inflammation
- remodelling
- tissue breakdown
Additional information on websites Asthma UK
British Lung Foundation
35
Airway associated cells ndash different roles
Categoryfunction Cell type ndash over 40 different types
Lining cells Ciliated intermediate brush basal epithelium
Contractile cells Smooth muscle
Secretory cells Goblet (epithelium) mucous serous (glands)
Connective tissue Fibroblast interstitial cell produce
elastin collagen proteoglycans cartilage
Neuroendocrine Nerves ganglia neuroendocrine cells neuroepithelial
bodies
Vascular cells Endothelial smooth muscle pericyte
Immune cells Mast cell dendritic cell lymphocyte eosinophil
macrophage neutrophil
10
The epithelium is not simply a barrier
11
Functions of the conducting airway epithelium
bull Protection by secretion and movement
of mucus by cilia towards the pharynx ndash
mucociliary clearance
bull Physical barrier to pathogens ndash
junctional components between cells (tight adherens
desmosomes)
bull Production of regulatory and inflammatory mediators
ndash Chemokines (eg IL-8 and IL-6)- attract inflammatory cells
ndash Cytokines (eg GM-CSF and TGF-β) ndash cell signalling
ndash Proteases (eg plasminogen activators MMPs)- migration
degradation of ECM growth factor activation
Mucus secretion
Mucus is a hydrated gel that is a
key component of airway defence
The principal gel-forming
components are MUCINS
produced by goblet and mucous
cells
Mucociliary transport
Submucosal gland
Mucus
Goblet
cell Functions
bull Barrier to pathogens
particulates and allergens
bull Maintenance of hydration
bull Serous cells secrete
antibacterials (eg lysozyme)
bull Glands also secrete water and
salts (eg Na+ and Cl-)
13
Function of airway smooth muscle
TONE
(airway calibre)
Contraction
Relaxation
STRUCTURE
Spiral
organisation
SECRETION
Mediators
Cytokines
Chemokines
14
Tertiary bronchus
bull Reduced cartilage
more smooth muscle
bull Fewer goblet cells and
submucosal glands
bull Increase in club cells
producing surfactant
15
Bronchiole
16
bull Single layer of ciliated epithelium
bull No cartilage
bull Reduced smooth muscle
bull No goblet cells or submucosal
glands
bull More club cells producing surfactant
Distal region ndash site of gas exchange
bull Alveoli - passive gas exchange
with capillary network ndash 150
million
bull Collagen elastic fibres and
fibroblasts and macrophages
present in septal junctions
bull Several alveoli grouped into
lobules surrounded by
connective tissue
17
Lung parenchyma
bull Type I alveolar cells - simple squamous
epithelium non-ciliated and main site of gas
exchange ndash covers 90 of alveolus
bull Type II alveolar cells (septal cells) ndash produce
surfactant to reduce surface tension preventing
alveoli collapse and renew type I cells
Type II alveolar cells
Type I alveolar cells
18
Control of airflow
bull Relaxation of smooth muscle = bronchodilation = increased airflow
bull Constriction of smooth muscle = bronchoconstriction = reduced airflow
Inflammation ndash driven constriction
of airway smooth muscle
Smooth muscle tone controlled by
autonomic nervous system
adrenal medullary hormones and
local factors
Autonomic nervous system
Parasympathetic Sympathetic
Muscarinic
beta2 alpha
- Constricts smooth muscle
- Causes mucus gland secretion
- Constricts
blood vessels
- Relaxes smooth muscle
19
Regulators of airflow
bull Nerves
- parasympathetic (cholinergic - constriction)
- sympathetic (adrenergic - dilation)
bull Regulatory and inflammatory mediators
- mast cell histamine - constriction
- arachidonic acid metabolites ndashconstrict and dilate
(eg prostaglandins leukotrienes)
- cytokines ndash constrict and dilate increase mucus
- hormones (eg adrenaline)
bull Proteinases (eg neutrophil elastase)
bull Reactive gas species (eg O2- NO)
Airway disease = Loss of normal control
20
SEM showing two alveolar macrophages (MP) in the alveolar space (ALV)
Airway macrophages a collision of functions
bull Induction of
inflammation
pathogens
bull Inhibition of
inflammation
clearance of self
cells and
extracellular
matrix turnover
products
Epithelial regulation of immunity
Tolerance
level set to
high =
bacterial
escape
Tolerance levels set too low
26
Respiratory diseases with loss of airway function
bull Common conditions
Asthma ndash ~5 of population in industrialised countries
COPD ndash 4th leading cause of death in UK and USA
Cystic fibrosis ndash lethal autosomal recessive gene defect (~12000 Caucasians)
bull Airway remodelling
- goblet cell hyperplasia
- submucosal gland hypertrophy
- fibrosis
- smooth muscle hypertrophy (asthma)
- alveolar destruction (COPD)
27
Asthma
bull Symptoms cough wheeze
shortness of breath and tightness of
the chest
bull Increased airway hyper-reactivity to
a variety of stimuli (smooth muscle
sensitive to constriction)
bull Airway narrowing and airflow
obstruction - usually reversible
(spontaneously or with drugs)
bull Wide spectrum of symptoms and
different severities of disease-
different phenotypes
Normal
Asthma
28
Asthma pathophysiology
CHRONIC
INFLAMMATION
AIRWAY
REMODELLING
29
Pathological changes in the asthmatic
airway- remodelling
bull Mucus hypersecretion
bull Denuded epithelium
bull Goblet cell hyperplasia
bull Reticular thickening
bull Appearance of myofibroblasts
bull Smooth muscle cell hypertrophy
bull Angiogenesis
bull Plasma extravasation
30
Improved therapies
Current
bull Relievers ndash inhalers are usually blue or green
ndash Bronchodilators cause smooth muscle to relax
ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur
bull Preventers ndash inhalers are usually brown orange or red
ndash Inhaled corticosteroids reduce inflammation in the airways
ndash Used daily even when there are no symptoms
bull Combination ndash A bronchodilatoranti-inflammatory drug
5-10 steroid resistant - severe
31
Chronic Obstructive Pulmonary Disease ndash COPD
bull Globally 64 million people have
COPD
bull Smoking main cause
bull Consists of a number of conditions
including emphysema and chronic
bronchitis
bull Symptoms of cough shortness of
breath tight chest wheeze
bull Can lead to irreversible airway
obstruction ndash no cure
32
Effect of smoking on FEV1
(Forced expiratory volume in 1 second)
Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33
Global Initiative on Obstructive Lung
Disease (GOLD)
GOLD has classified COPD as ldquoa disease
state characterised by airflow limitation that
is not fully reversible The airflow limitation
is usually both progressive and associated
with an abnormal inflammatory response of
the lungs to noxious particles or gasesrdquo
World Health Organization The GOLD global strategy for the
management and prevention of COPD 2001wwwgoldcopdorg 34
GOLD 1-4 classification with 4 most severe
Summary
bull Airways conduct air in and out of the lung mechanical stability
bull Airways comprised of many cell types with specific functions
- control of contractionrelaxation
- mucociliary clearance of foreign particles
- reduction of surface tension
bull Structural cells may also be lsquoregulatoryrsquo- cross-talk between cells
bull Immunity must display appropriate inflammatory tone
bull Respiratory disease leads to loss of lsquocontrolrsquo
- inflammation
- remodelling
- tissue breakdown
Additional information on websites Asthma UK
British Lung Foundation
35
The epithelium is not simply a barrier
11
Functions of the conducting airway epithelium
bull Protection by secretion and movement
of mucus by cilia towards the pharynx ndash
mucociliary clearance
bull Physical barrier to pathogens ndash
junctional components between cells (tight adherens
desmosomes)
bull Production of regulatory and inflammatory mediators
ndash Chemokines (eg IL-8 and IL-6)- attract inflammatory cells
ndash Cytokines (eg GM-CSF and TGF-β) ndash cell signalling
ndash Proteases (eg plasminogen activators MMPs)- migration
degradation of ECM growth factor activation
Mucus secretion
Mucus is a hydrated gel that is a
key component of airway defence
The principal gel-forming
components are MUCINS
produced by goblet and mucous
cells
Mucociliary transport
Submucosal gland
Mucus
Goblet
cell Functions
bull Barrier to pathogens
particulates and allergens
bull Maintenance of hydration
bull Serous cells secrete
antibacterials (eg lysozyme)
bull Glands also secrete water and
salts (eg Na+ and Cl-)
13
Function of airway smooth muscle
TONE
(airway calibre)
Contraction
Relaxation
STRUCTURE
Spiral
organisation
SECRETION
Mediators
Cytokines
Chemokines
14
Tertiary bronchus
bull Reduced cartilage
more smooth muscle
bull Fewer goblet cells and
submucosal glands
bull Increase in club cells
producing surfactant
15
Bronchiole
16
bull Single layer of ciliated epithelium
bull No cartilage
bull Reduced smooth muscle
bull No goblet cells or submucosal
glands
bull More club cells producing surfactant
Distal region ndash site of gas exchange
bull Alveoli - passive gas exchange
with capillary network ndash 150
million
bull Collagen elastic fibres and
fibroblasts and macrophages
present in septal junctions
bull Several alveoli grouped into
lobules surrounded by
connective tissue
17
Lung parenchyma
bull Type I alveolar cells - simple squamous
epithelium non-ciliated and main site of gas
exchange ndash covers 90 of alveolus
bull Type II alveolar cells (septal cells) ndash produce
surfactant to reduce surface tension preventing
alveoli collapse and renew type I cells
Type II alveolar cells
Type I alveolar cells
18
Control of airflow
bull Relaxation of smooth muscle = bronchodilation = increased airflow
bull Constriction of smooth muscle = bronchoconstriction = reduced airflow
Inflammation ndash driven constriction
of airway smooth muscle
Smooth muscle tone controlled by
autonomic nervous system
adrenal medullary hormones and
local factors
Autonomic nervous system
Parasympathetic Sympathetic
Muscarinic
beta2 alpha
- Constricts smooth muscle
- Causes mucus gland secretion
- Constricts
blood vessels
- Relaxes smooth muscle
19
Regulators of airflow
bull Nerves
- parasympathetic (cholinergic - constriction)
- sympathetic (adrenergic - dilation)
bull Regulatory and inflammatory mediators
- mast cell histamine - constriction
- arachidonic acid metabolites ndashconstrict and dilate
(eg prostaglandins leukotrienes)
- cytokines ndash constrict and dilate increase mucus
- hormones (eg adrenaline)
bull Proteinases (eg neutrophil elastase)
bull Reactive gas species (eg O2- NO)
Airway disease = Loss of normal control
20
SEM showing two alveolar macrophages (MP) in the alveolar space (ALV)
Airway macrophages a collision of functions
bull Induction of
inflammation
pathogens
bull Inhibition of
inflammation
clearance of self
cells and
extracellular
matrix turnover
products
Epithelial regulation of immunity
Tolerance
level set to
high =
bacterial
escape
Tolerance levels set too low
26
Respiratory diseases with loss of airway function
bull Common conditions
Asthma ndash ~5 of population in industrialised countries
COPD ndash 4th leading cause of death in UK and USA
Cystic fibrosis ndash lethal autosomal recessive gene defect (~12000 Caucasians)
bull Airway remodelling
- goblet cell hyperplasia
- submucosal gland hypertrophy
- fibrosis
- smooth muscle hypertrophy (asthma)
- alveolar destruction (COPD)
27
Asthma
bull Symptoms cough wheeze
shortness of breath and tightness of
the chest
bull Increased airway hyper-reactivity to
a variety of stimuli (smooth muscle
sensitive to constriction)
bull Airway narrowing and airflow
obstruction - usually reversible
(spontaneously or with drugs)
bull Wide spectrum of symptoms and
different severities of disease-
different phenotypes
Normal
Asthma
28
Asthma pathophysiology
CHRONIC
INFLAMMATION
AIRWAY
REMODELLING
29
Pathological changes in the asthmatic
airway- remodelling
bull Mucus hypersecretion
bull Denuded epithelium
bull Goblet cell hyperplasia
bull Reticular thickening
bull Appearance of myofibroblasts
bull Smooth muscle cell hypertrophy
bull Angiogenesis
bull Plasma extravasation
30
Improved therapies
Current
bull Relievers ndash inhalers are usually blue or green
ndash Bronchodilators cause smooth muscle to relax
ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur
bull Preventers ndash inhalers are usually brown orange or red
ndash Inhaled corticosteroids reduce inflammation in the airways
ndash Used daily even when there are no symptoms
bull Combination ndash A bronchodilatoranti-inflammatory drug
5-10 steroid resistant - severe
31
Chronic Obstructive Pulmonary Disease ndash COPD
bull Globally 64 million people have
COPD
bull Smoking main cause
bull Consists of a number of conditions
including emphysema and chronic
bronchitis
bull Symptoms of cough shortness of
breath tight chest wheeze
bull Can lead to irreversible airway
obstruction ndash no cure
32
Effect of smoking on FEV1
(Forced expiratory volume in 1 second)
Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33
Global Initiative on Obstructive Lung
Disease (GOLD)
GOLD has classified COPD as ldquoa disease
state characterised by airflow limitation that
is not fully reversible The airflow limitation
is usually both progressive and associated
with an abnormal inflammatory response of
the lungs to noxious particles or gasesrdquo
World Health Organization The GOLD global strategy for the
management and prevention of COPD 2001wwwgoldcopdorg 34
GOLD 1-4 classification with 4 most severe
Summary
bull Airways conduct air in and out of the lung mechanical stability
bull Airways comprised of many cell types with specific functions
- control of contractionrelaxation
- mucociliary clearance of foreign particles
- reduction of surface tension
bull Structural cells may also be lsquoregulatoryrsquo- cross-talk between cells
bull Immunity must display appropriate inflammatory tone
bull Respiratory disease leads to loss of lsquocontrolrsquo
- inflammation
- remodelling
- tissue breakdown
Additional information on websites Asthma UK
British Lung Foundation
35
Functions of the conducting airway epithelium
bull Protection by secretion and movement
of mucus by cilia towards the pharynx ndash
mucociliary clearance
bull Physical barrier to pathogens ndash
junctional components between cells (tight adherens
desmosomes)
bull Production of regulatory and inflammatory mediators
ndash Chemokines (eg IL-8 and IL-6)- attract inflammatory cells
ndash Cytokines (eg GM-CSF and TGF-β) ndash cell signalling
ndash Proteases (eg plasminogen activators MMPs)- migration
degradation of ECM growth factor activation
Mucus secretion
Mucus is a hydrated gel that is a
key component of airway defence
The principal gel-forming
components are MUCINS
produced by goblet and mucous
cells
Mucociliary transport
Submucosal gland
Mucus
Goblet
cell Functions
bull Barrier to pathogens
particulates and allergens
bull Maintenance of hydration
bull Serous cells secrete
antibacterials (eg lysozyme)
bull Glands also secrete water and
salts (eg Na+ and Cl-)
13
Function of airway smooth muscle
TONE
(airway calibre)
Contraction
Relaxation
STRUCTURE
Spiral
organisation
SECRETION
Mediators
Cytokines
Chemokines
14
Tertiary bronchus
bull Reduced cartilage
more smooth muscle
bull Fewer goblet cells and
submucosal glands
bull Increase in club cells
producing surfactant
15
Bronchiole
16
bull Single layer of ciliated epithelium
bull No cartilage
bull Reduced smooth muscle
bull No goblet cells or submucosal
glands
bull More club cells producing surfactant
Distal region ndash site of gas exchange
bull Alveoli - passive gas exchange
with capillary network ndash 150
million
bull Collagen elastic fibres and
fibroblasts and macrophages
present in septal junctions
bull Several alveoli grouped into
lobules surrounded by
connective tissue
17
Lung parenchyma
bull Type I alveolar cells - simple squamous
epithelium non-ciliated and main site of gas
exchange ndash covers 90 of alveolus
bull Type II alveolar cells (septal cells) ndash produce
surfactant to reduce surface tension preventing
alveoli collapse and renew type I cells
Type II alveolar cells
Type I alveolar cells
18
Control of airflow
bull Relaxation of smooth muscle = bronchodilation = increased airflow
bull Constriction of smooth muscle = bronchoconstriction = reduced airflow
Inflammation ndash driven constriction
of airway smooth muscle
Smooth muscle tone controlled by
autonomic nervous system
adrenal medullary hormones and
local factors
Autonomic nervous system
Parasympathetic Sympathetic
Muscarinic
beta2 alpha
- Constricts smooth muscle
- Causes mucus gland secretion
- Constricts
blood vessels
- Relaxes smooth muscle
19
Regulators of airflow
bull Nerves
- parasympathetic (cholinergic - constriction)
- sympathetic (adrenergic - dilation)
bull Regulatory and inflammatory mediators
- mast cell histamine - constriction
- arachidonic acid metabolites ndashconstrict and dilate
(eg prostaglandins leukotrienes)
- cytokines ndash constrict and dilate increase mucus
- hormones (eg adrenaline)
bull Proteinases (eg neutrophil elastase)
bull Reactive gas species (eg O2- NO)
Airway disease = Loss of normal control
20
SEM showing two alveolar macrophages (MP) in the alveolar space (ALV)
Airway macrophages a collision of functions
bull Induction of
inflammation
pathogens
bull Inhibition of
inflammation
clearance of self
cells and
extracellular
matrix turnover
products
Epithelial regulation of immunity
Tolerance
level set to
high =
bacterial
escape
Tolerance levels set too low
26
Respiratory diseases with loss of airway function
bull Common conditions
Asthma ndash ~5 of population in industrialised countries
COPD ndash 4th leading cause of death in UK and USA
Cystic fibrosis ndash lethal autosomal recessive gene defect (~12000 Caucasians)
bull Airway remodelling
- goblet cell hyperplasia
- submucosal gland hypertrophy
- fibrosis
- smooth muscle hypertrophy (asthma)
- alveolar destruction (COPD)
27
Asthma
bull Symptoms cough wheeze
shortness of breath and tightness of
the chest
bull Increased airway hyper-reactivity to
a variety of stimuli (smooth muscle
sensitive to constriction)
bull Airway narrowing and airflow
obstruction - usually reversible
(spontaneously or with drugs)
bull Wide spectrum of symptoms and
different severities of disease-
different phenotypes
Normal
Asthma
28
Asthma pathophysiology
CHRONIC
INFLAMMATION
AIRWAY
REMODELLING
29
Pathological changes in the asthmatic
airway- remodelling
bull Mucus hypersecretion
bull Denuded epithelium
bull Goblet cell hyperplasia
bull Reticular thickening
bull Appearance of myofibroblasts
bull Smooth muscle cell hypertrophy
bull Angiogenesis
bull Plasma extravasation
30
Improved therapies
Current
bull Relievers ndash inhalers are usually blue or green
ndash Bronchodilators cause smooth muscle to relax
ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur
bull Preventers ndash inhalers are usually brown orange or red
ndash Inhaled corticosteroids reduce inflammation in the airways
ndash Used daily even when there are no symptoms
bull Combination ndash A bronchodilatoranti-inflammatory drug
5-10 steroid resistant - severe
31
Chronic Obstructive Pulmonary Disease ndash COPD
bull Globally 64 million people have
COPD
bull Smoking main cause
bull Consists of a number of conditions
including emphysema and chronic
bronchitis
bull Symptoms of cough shortness of
breath tight chest wheeze
bull Can lead to irreversible airway
obstruction ndash no cure
32
Effect of smoking on FEV1
(Forced expiratory volume in 1 second)
Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33
Global Initiative on Obstructive Lung
Disease (GOLD)
GOLD has classified COPD as ldquoa disease
state characterised by airflow limitation that
is not fully reversible The airflow limitation
is usually both progressive and associated
with an abnormal inflammatory response of
the lungs to noxious particles or gasesrdquo
World Health Organization The GOLD global strategy for the
management and prevention of COPD 2001wwwgoldcopdorg 34
GOLD 1-4 classification with 4 most severe
Summary
bull Airways conduct air in and out of the lung mechanical stability
bull Airways comprised of many cell types with specific functions
- control of contractionrelaxation
- mucociliary clearance of foreign particles
- reduction of surface tension
bull Structural cells may also be lsquoregulatoryrsquo- cross-talk between cells
bull Immunity must display appropriate inflammatory tone
bull Respiratory disease leads to loss of lsquocontrolrsquo
- inflammation
- remodelling
- tissue breakdown
Additional information on websites Asthma UK
British Lung Foundation
35
Mucus secretion
Mucus is a hydrated gel that is a
key component of airway defence
The principal gel-forming
components are MUCINS
produced by goblet and mucous
cells
Mucociliary transport
Submucosal gland
Mucus
Goblet
cell Functions
bull Barrier to pathogens
particulates and allergens
bull Maintenance of hydration
bull Serous cells secrete
antibacterials (eg lysozyme)
bull Glands also secrete water and
salts (eg Na+ and Cl-)
13
Function of airway smooth muscle
TONE
(airway calibre)
Contraction
Relaxation
STRUCTURE
Spiral
organisation
SECRETION
Mediators
Cytokines
Chemokines
14
Tertiary bronchus
bull Reduced cartilage
more smooth muscle
bull Fewer goblet cells and
submucosal glands
bull Increase in club cells
producing surfactant
15
Bronchiole
16
bull Single layer of ciliated epithelium
bull No cartilage
bull Reduced smooth muscle
bull No goblet cells or submucosal
glands
bull More club cells producing surfactant
Distal region ndash site of gas exchange
bull Alveoli - passive gas exchange
with capillary network ndash 150
million
bull Collagen elastic fibres and
fibroblasts and macrophages
present in septal junctions
bull Several alveoli grouped into
lobules surrounded by
connective tissue
17
Lung parenchyma
bull Type I alveolar cells - simple squamous
epithelium non-ciliated and main site of gas
exchange ndash covers 90 of alveolus
bull Type II alveolar cells (septal cells) ndash produce
surfactant to reduce surface tension preventing
alveoli collapse and renew type I cells
Type II alveolar cells
Type I alveolar cells
18
Control of airflow
bull Relaxation of smooth muscle = bronchodilation = increased airflow
bull Constriction of smooth muscle = bronchoconstriction = reduced airflow
Inflammation ndash driven constriction
of airway smooth muscle
Smooth muscle tone controlled by
autonomic nervous system
adrenal medullary hormones and
local factors
Autonomic nervous system
Parasympathetic Sympathetic
Muscarinic
beta2 alpha
- Constricts smooth muscle
- Causes mucus gland secretion
- Constricts
blood vessels
- Relaxes smooth muscle
19
Regulators of airflow
bull Nerves
- parasympathetic (cholinergic - constriction)
- sympathetic (adrenergic - dilation)
bull Regulatory and inflammatory mediators
- mast cell histamine - constriction
- arachidonic acid metabolites ndashconstrict and dilate
(eg prostaglandins leukotrienes)
- cytokines ndash constrict and dilate increase mucus
- hormones (eg adrenaline)
bull Proteinases (eg neutrophil elastase)
bull Reactive gas species (eg O2- NO)
Airway disease = Loss of normal control
20
SEM showing two alveolar macrophages (MP) in the alveolar space (ALV)
Airway macrophages a collision of functions
bull Induction of
inflammation
pathogens
bull Inhibition of
inflammation
clearance of self
cells and
extracellular
matrix turnover
products
Epithelial regulation of immunity
Tolerance
level set to
high =
bacterial
escape
Tolerance levels set too low
26
Respiratory diseases with loss of airway function
bull Common conditions
Asthma ndash ~5 of population in industrialised countries
COPD ndash 4th leading cause of death in UK and USA
Cystic fibrosis ndash lethal autosomal recessive gene defect (~12000 Caucasians)
bull Airway remodelling
- goblet cell hyperplasia
- submucosal gland hypertrophy
- fibrosis
- smooth muscle hypertrophy (asthma)
- alveolar destruction (COPD)
27
Asthma
bull Symptoms cough wheeze
shortness of breath and tightness of
the chest
bull Increased airway hyper-reactivity to
a variety of stimuli (smooth muscle
sensitive to constriction)
bull Airway narrowing and airflow
obstruction - usually reversible
(spontaneously or with drugs)
bull Wide spectrum of symptoms and
different severities of disease-
different phenotypes
Normal
Asthma
28
Asthma pathophysiology
CHRONIC
INFLAMMATION
AIRWAY
REMODELLING
29
Pathological changes in the asthmatic
airway- remodelling
bull Mucus hypersecretion
bull Denuded epithelium
bull Goblet cell hyperplasia
bull Reticular thickening
bull Appearance of myofibroblasts
bull Smooth muscle cell hypertrophy
bull Angiogenesis
bull Plasma extravasation
30
Improved therapies
Current
bull Relievers ndash inhalers are usually blue or green
ndash Bronchodilators cause smooth muscle to relax
ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur
bull Preventers ndash inhalers are usually brown orange or red
ndash Inhaled corticosteroids reduce inflammation in the airways
ndash Used daily even when there are no symptoms
bull Combination ndash A bronchodilatoranti-inflammatory drug
5-10 steroid resistant - severe
31
Chronic Obstructive Pulmonary Disease ndash COPD
bull Globally 64 million people have
COPD
bull Smoking main cause
bull Consists of a number of conditions
including emphysema and chronic
bronchitis
bull Symptoms of cough shortness of
breath tight chest wheeze
bull Can lead to irreversible airway
obstruction ndash no cure
32
Effect of smoking on FEV1
(Forced expiratory volume in 1 second)
Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33
Global Initiative on Obstructive Lung
Disease (GOLD)
GOLD has classified COPD as ldquoa disease
state characterised by airflow limitation that
is not fully reversible The airflow limitation
is usually both progressive and associated
with an abnormal inflammatory response of
the lungs to noxious particles or gasesrdquo
World Health Organization The GOLD global strategy for the
management and prevention of COPD 2001wwwgoldcopdorg 34
GOLD 1-4 classification with 4 most severe
Summary
bull Airways conduct air in and out of the lung mechanical stability
bull Airways comprised of many cell types with specific functions
- control of contractionrelaxation
- mucociliary clearance of foreign particles
- reduction of surface tension
bull Structural cells may also be lsquoregulatoryrsquo- cross-talk between cells
bull Immunity must display appropriate inflammatory tone
bull Respiratory disease leads to loss of lsquocontrolrsquo
- inflammation
- remodelling
- tissue breakdown
Additional information on websites Asthma UK
British Lung Foundation
35
Function of airway smooth muscle
TONE
(airway calibre)
Contraction
Relaxation
STRUCTURE
Spiral
organisation
SECRETION
Mediators
Cytokines
Chemokines
14
Tertiary bronchus
bull Reduced cartilage
more smooth muscle
bull Fewer goblet cells and
submucosal glands
bull Increase in club cells
producing surfactant
15
Bronchiole
16
bull Single layer of ciliated epithelium
bull No cartilage
bull Reduced smooth muscle
bull No goblet cells or submucosal
glands
bull More club cells producing surfactant
Distal region ndash site of gas exchange
bull Alveoli - passive gas exchange
with capillary network ndash 150
million
bull Collagen elastic fibres and
fibroblasts and macrophages
present in septal junctions
bull Several alveoli grouped into
lobules surrounded by
connective tissue
17
Lung parenchyma
bull Type I alveolar cells - simple squamous
epithelium non-ciliated and main site of gas
exchange ndash covers 90 of alveolus
bull Type II alveolar cells (septal cells) ndash produce
surfactant to reduce surface tension preventing
alveoli collapse and renew type I cells
Type II alveolar cells
Type I alveolar cells
18
Control of airflow
bull Relaxation of smooth muscle = bronchodilation = increased airflow
bull Constriction of smooth muscle = bronchoconstriction = reduced airflow
Inflammation ndash driven constriction
of airway smooth muscle
Smooth muscle tone controlled by
autonomic nervous system
adrenal medullary hormones and
local factors
Autonomic nervous system
Parasympathetic Sympathetic
Muscarinic
beta2 alpha
- Constricts smooth muscle
- Causes mucus gland secretion
- Constricts
blood vessels
- Relaxes smooth muscle
19
Regulators of airflow
bull Nerves
- parasympathetic (cholinergic - constriction)
- sympathetic (adrenergic - dilation)
bull Regulatory and inflammatory mediators
- mast cell histamine - constriction
- arachidonic acid metabolites ndashconstrict and dilate
(eg prostaglandins leukotrienes)
- cytokines ndash constrict and dilate increase mucus
- hormones (eg adrenaline)
bull Proteinases (eg neutrophil elastase)
bull Reactive gas species (eg O2- NO)
Airway disease = Loss of normal control
20
SEM showing two alveolar macrophages (MP) in the alveolar space (ALV)
Airway macrophages a collision of functions
bull Induction of
inflammation
pathogens
bull Inhibition of
inflammation
clearance of self
cells and
extracellular
matrix turnover
products
Epithelial regulation of immunity
Tolerance
level set to
high =
bacterial
escape
Tolerance levels set too low
26
Respiratory diseases with loss of airway function
bull Common conditions
Asthma ndash ~5 of population in industrialised countries
COPD ndash 4th leading cause of death in UK and USA
Cystic fibrosis ndash lethal autosomal recessive gene defect (~12000 Caucasians)
bull Airway remodelling
- goblet cell hyperplasia
- submucosal gland hypertrophy
- fibrosis
- smooth muscle hypertrophy (asthma)
- alveolar destruction (COPD)
27
Asthma
bull Symptoms cough wheeze
shortness of breath and tightness of
the chest
bull Increased airway hyper-reactivity to
a variety of stimuli (smooth muscle
sensitive to constriction)
bull Airway narrowing and airflow
obstruction - usually reversible
(spontaneously or with drugs)
bull Wide spectrum of symptoms and
different severities of disease-
different phenotypes
Normal
Asthma
28
Asthma pathophysiology
CHRONIC
INFLAMMATION
AIRWAY
REMODELLING
29
Pathological changes in the asthmatic
airway- remodelling
bull Mucus hypersecretion
bull Denuded epithelium
bull Goblet cell hyperplasia
bull Reticular thickening
bull Appearance of myofibroblasts
bull Smooth muscle cell hypertrophy
bull Angiogenesis
bull Plasma extravasation
30
Improved therapies
Current
bull Relievers ndash inhalers are usually blue or green
ndash Bronchodilators cause smooth muscle to relax
ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur
bull Preventers ndash inhalers are usually brown orange or red
ndash Inhaled corticosteroids reduce inflammation in the airways
ndash Used daily even when there are no symptoms
bull Combination ndash A bronchodilatoranti-inflammatory drug
5-10 steroid resistant - severe
31
Chronic Obstructive Pulmonary Disease ndash COPD
bull Globally 64 million people have
COPD
bull Smoking main cause
bull Consists of a number of conditions
including emphysema and chronic
bronchitis
bull Symptoms of cough shortness of
breath tight chest wheeze
bull Can lead to irreversible airway
obstruction ndash no cure
32
Effect of smoking on FEV1
(Forced expiratory volume in 1 second)
Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33
Global Initiative on Obstructive Lung
Disease (GOLD)
GOLD has classified COPD as ldquoa disease
state characterised by airflow limitation that
is not fully reversible The airflow limitation
is usually both progressive and associated
with an abnormal inflammatory response of
the lungs to noxious particles or gasesrdquo
World Health Organization The GOLD global strategy for the
management and prevention of COPD 2001wwwgoldcopdorg 34
GOLD 1-4 classification with 4 most severe
Summary
bull Airways conduct air in and out of the lung mechanical stability
bull Airways comprised of many cell types with specific functions
- control of contractionrelaxation
- mucociliary clearance of foreign particles
- reduction of surface tension
bull Structural cells may also be lsquoregulatoryrsquo- cross-talk between cells
bull Immunity must display appropriate inflammatory tone
bull Respiratory disease leads to loss of lsquocontrolrsquo
- inflammation
- remodelling
- tissue breakdown
Additional information on websites Asthma UK
British Lung Foundation
35
Tertiary bronchus
bull Reduced cartilage
more smooth muscle
bull Fewer goblet cells and
submucosal glands
bull Increase in club cells
producing surfactant
15
Bronchiole
16
bull Single layer of ciliated epithelium
bull No cartilage
bull Reduced smooth muscle
bull No goblet cells or submucosal
glands
bull More club cells producing surfactant
Distal region ndash site of gas exchange
bull Alveoli - passive gas exchange
with capillary network ndash 150
million
bull Collagen elastic fibres and
fibroblasts and macrophages
present in septal junctions
bull Several alveoli grouped into
lobules surrounded by
connective tissue
17
Lung parenchyma
bull Type I alveolar cells - simple squamous
epithelium non-ciliated and main site of gas
exchange ndash covers 90 of alveolus
bull Type II alveolar cells (septal cells) ndash produce
surfactant to reduce surface tension preventing
alveoli collapse and renew type I cells
Type II alveolar cells
Type I alveolar cells
18
Control of airflow
bull Relaxation of smooth muscle = bronchodilation = increased airflow
bull Constriction of smooth muscle = bronchoconstriction = reduced airflow
Inflammation ndash driven constriction
of airway smooth muscle
Smooth muscle tone controlled by
autonomic nervous system
adrenal medullary hormones and
local factors
Autonomic nervous system
Parasympathetic Sympathetic
Muscarinic
beta2 alpha
- Constricts smooth muscle
- Causes mucus gland secretion
- Constricts
blood vessels
- Relaxes smooth muscle
19
Regulators of airflow
bull Nerves
- parasympathetic (cholinergic - constriction)
- sympathetic (adrenergic - dilation)
bull Regulatory and inflammatory mediators
- mast cell histamine - constriction
- arachidonic acid metabolites ndashconstrict and dilate
(eg prostaglandins leukotrienes)
- cytokines ndash constrict and dilate increase mucus
- hormones (eg adrenaline)
bull Proteinases (eg neutrophil elastase)
bull Reactive gas species (eg O2- NO)
Airway disease = Loss of normal control
20
SEM showing two alveolar macrophages (MP) in the alveolar space (ALV)
Airway macrophages a collision of functions
bull Induction of
inflammation
pathogens
bull Inhibition of
inflammation
clearance of self
cells and
extracellular
matrix turnover
products
Epithelial regulation of immunity
Tolerance
level set to
high =
bacterial
escape
Tolerance levels set too low
26
Respiratory diseases with loss of airway function
bull Common conditions
Asthma ndash ~5 of population in industrialised countries
COPD ndash 4th leading cause of death in UK and USA
Cystic fibrosis ndash lethal autosomal recessive gene defect (~12000 Caucasians)
bull Airway remodelling
- goblet cell hyperplasia
- submucosal gland hypertrophy
- fibrosis
- smooth muscle hypertrophy (asthma)
- alveolar destruction (COPD)
27
Asthma
bull Symptoms cough wheeze
shortness of breath and tightness of
the chest
bull Increased airway hyper-reactivity to
a variety of stimuli (smooth muscle
sensitive to constriction)
bull Airway narrowing and airflow
obstruction - usually reversible
(spontaneously or with drugs)
bull Wide spectrum of symptoms and
different severities of disease-
different phenotypes
Normal
Asthma
28
Asthma pathophysiology
CHRONIC
INFLAMMATION
AIRWAY
REMODELLING
29
Pathological changes in the asthmatic
airway- remodelling
bull Mucus hypersecretion
bull Denuded epithelium
bull Goblet cell hyperplasia
bull Reticular thickening
bull Appearance of myofibroblasts
bull Smooth muscle cell hypertrophy
bull Angiogenesis
bull Plasma extravasation
30
Improved therapies
Current
bull Relievers ndash inhalers are usually blue or green
ndash Bronchodilators cause smooth muscle to relax
ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur
bull Preventers ndash inhalers are usually brown orange or red
ndash Inhaled corticosteroids reduce inflammation in the airways
ndash Used daily even when there are no symptoms
bull Combination ndash A bronchodilatoranti-inflammatory drug
5-10 steroid resistant - severe
31
Chronic Obstructive Pulmonary Disease ndash COPD
bull Globally 64 million people have
COPD
bull Smoking main cause
bull Consists of a number of conditions
including emphysema and chronic
bronchitis
bull Symptoms of cough shortness of
breath tight chest wheeze
bull Can lead to irreversible airway
obstruction ndash no cure
32
Effect of smoking on FEV1
(Forced expiratory volume in 1 second)
Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33
Global Initiative on Obstructive Lung
Disease (GOLD)
GOLD has classified COPD as ldquoa disease
state characterised by airflow limitation that
is not fully reversible The airflow limitation
is usually both progressive and associated
with an abnormal inflammatory response of
the lungs to noxious particles or gasesrdquo
World Health Organization The GOLD global strategy for the
management and prevention of COPD 2001wwwgoldcopdorg 34
GOLD 1-4 classification with 4 most severe
Summary
bull Airways conduct air in and out of the lung mechanical stability
bull Airways comprised of many cell types with specific functions
- control of contractionrelaxation
- mucociliary clearance of foreign particles
- reduction of surface tension
bull Structural cells may also be lsquoregulatoryrsquo- cross-talk between cells
bull Immunity must display appropriate inflammatory tone
bull Respiratory disease leads to loss of lsquocontrolrsquo
- inflammation
- remodelling
- tissue breakdown
Additional information on websites Asthma UK
British Lung Foundation
35
Bronchiole
16
bull Single layer of ciliated epithelium
bull No cartilage
bull Reduced smooth muscle
bull No goblet cells or submucosal
glands
bull More club cells producing surfactant
Distal region ndash site of gas exchange
bull Alveoli - passive gas exchange
with capillary network ndash 150
million
bull Collagen elastic fibres and
fibroblasts and macrophages
present in septal junctions
bull Several alveoli grouped into
lobules surrounded by
connective tissue
17
Lung parenchyma
bull Type I alveolar cells - simple squamous
epithelium non-ciliated and main site of gas
exchange ndash covers 90 of alveolus
bull Type II alveolar cells (septal cells) ndash produce
surfactant to reduce surface tension preventing
alveoli collapse and renew type I cells
Type II alveolar cells
Type I alveolar cells
18
Control of airflow
bull Relaxation of smooth muscle = bronchodilation = increased airflow
bull Constriction of smooth muscle = bronchoconstriction = reduced airflow
Inflammation ndash driven constriction
of airway smooth muscle
Smooth muscle tone controlled by
autonomic nervous system
adrenal medullary hormones and
local factors
Autonomic nervous system
Parasympathetic Sympathetic
Muscarinic
beta2 alpha
- Constricts smooth muscle
- Causes mucus gland secretion
- Constricts
blood vessels
- Relaxes smooth muscle
19
Regulators of airflow
bull Nerves
- parasympathetic (cholinergic - constriction)
- sympathetic (adrenergic - dilation)
bull Regulatory and inflammatory mediators
- mast cell histamine - constriction
- arachidonic acid metabolites ndashconstrict and dilate
(eg prostaglandins leukotrienes)
- cytokines ndash constrict and dilate increase mucus
- hormones (eg adrenaline)
bull Proteinases (eg neutrophil elastase)
bull Reactive gas species (eg O2- NO)
Airway disease = Loss of normal control
20
SEM showing two alveolar macrophages (MP) in the alveolar space (ALV)
Airway macrophages a collision of functions
bull Induction of
inflammation
pathogens
bull Inhibition of
inflammation
clearance of self
cells and
extracellular
matrix turnover
products
Epithelial regulation of immunity
Tolerance
level set to
high =
bacterial
escape
Tolerance levels set too low
26
Respiratory diseases with loss of airway function
bull Common conditions
Asthma ndash ~5 of population in industrialised countries
COPD ndash 4th leading cause of death in UK and USA
Cystic fibrosis ndash lethal autosomal recessive gene defect (~12000 Caucasians)
bull Airway remodelling
- goblet cell hyperplasia
- submucosal gland hypertrophy
- fibrosis
- smooth muscle hypertrophy (asthma)
- alveolar destruction (COPD)
27
Asthma
bull Symptoms cough wheeze
shortness of breath and tightness of
the chest
bull Increased airway hyper-reactivity to
a variety of stimuli (smooth muscle
sensitive to constriction)
bull Airway narrowing and airflow
obstruction - usually reversible
(spontaneously or with drugs)
bull Wide spectrum of symptoms and
different severities of disease-
different phenotypes
Normal
Asthma
28
Asthma pathophysiology
CHRONIC
INFLAMMATION
AIRWAY
REMODELLING
29
Pathological changes in the asthmatic
airway- remodelling
bull Mucus hypersecretion
bull Denuded epithelium
bull Goblet cell hyperplasia
bull Reticular thickening
bull Appearance of myofibroblasts
bull Smooth muscle cell hypertrophy
bull Angiogenesis
bull Plasma extravasation
30
Improved therapies
Current
bull Relievers ndash inhalers are usually blue or green
ndash Bronchodilators cause smooth muscle to relax
ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur
bull Preventers ndash inhalers are usually brown orange or red
ndash Inhaled corticosteroids reduce inflammation in the airways
ndash Used daily even when there are no symptoms
bull Combination ndash A bronchodilatoranti-inflammatory drug
5-10 steroid resistant - severe
31
Chronic Obstructive Pulmonary Disease ndash COPD
bull Globally 64 million people have
COPD
bull Smoking main cause
bull Consists of a number of conditions
including emphysema and chronic
bronchitis
bull Symptoms of cough shortness of
breath tight chest wheeze
bull Can lead to irreversible airway
obstruction ndash no cure
32
Effect of smoking on FEV1
(Forced expiratory volume in 1 second)
Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33
Global Initiative on Obstructive Lung
Disease (GOLD)
GOLD has classified COPD as ldquoa disease
state characterised by airflow limitation that
is not fully reversible The airflow limitation
is usually both progressive and associated
with an abnormal inflammatory response of
the lungs to noxious particles or gasesrdquo
World Health Organization The GOLD global strategy for the
management and prevention of COPD 2001wwwgoldcopdorg 34
GOLD 1-4 classification with 4 most severe
Summary
bull Airways conduct air in and out of the lung mechanical stability
bull Airways comprised of many cell types with specific functions
- control of contractionrelaxation
- mucociliary clearance of foreign particles
- reduction of surface tension
bull Structural cells may also be lsquoregulatoryrsquo- cross-talk between cells
bull Immunity must display appropriate inflammatory tone
bull Respiratory disease leads to loss of lsquocontrolrsquo
- inflammation
- remodelling
- tissue breakdown
Additional information on websites Asthma UK
British Lung Foundation
35
Distal region ndash site of gas exchange
bull Alveoli - passive gas exchange
with capillary network ndash 150
million
bull Collagen elastic fibres and
fibroblasts and macrophages
present in septal junctions
bull Several alveoli grouped into
lobules surrounded by
connective tissue
17
Lung parenchyma
bull Type I alveolar cells - simple squamous
epithelium non-ciliated and main site of gas
exchange ndash covers 90 of alveolus
bull Type II alveolar cells (septal cells) ndash produce
surfactant to reduce surface tension preventing
alveoli collapse and renew type I cells
Type II alveolar cells
Type I alveolar cells
18
Control of airflow
bull Relaxation of smooth muscle = bronchodilation = increased airflow
bull Constriction of smooth muscle = bronchoconstriction = reduced airflow
Inflammation ndash driven constriction
of airway smooth muscle
Smooth muscle tone controlled by
autonomic nervous system
adrenal medullary hormones and
local factors
Autonomic nervous system
Parasympathetic Sympathetic
Muscarinic
beta2 alpha
- Constricts smooth muscle
- Causes mucus gland secretion
- Constricts
blood vessels
- Relaxes smooth muscle
19
Regulators of airflow
bull Nerves
- parasympathetic (cholinergic - constriction)
- sympathetic (adrenergic - dilation)
bull Regulatory and inflammatory mediators
- mast cell histamine - constriction
- arachidonic acid metabolites ndashconstrict and dilate
(eg prostaglandins leukotrienes)
- cytokines ndash constrict and dilate increase mucus
- hormones (eg adrenaline)
bull Proteinases (eg neutrophil elastase)
bull Reactive gas species (eg O2- NO)
Airway disease = Loss of normal control
20
SEM showing two alveolar macrophages (MP) in the alveolar space (ALV)
Airway macrophages a collision of functions
bull Induction of
inflammation
pathogens
bull Inhibition of
inflammation
clearance of self
cells and
extracellular
matrix turnover
products
Epithelial regulation of immunity
Tolerance
level set to
high =
bacterial
escape
Tolerance levels set too low
26
Respiratory diseases with loss of airway function
bull Common conditions
Asthma ndash ~5 of population in industrialised countries
COPD ndash 4th leading cause of death in UK and USA
Cystic fibrosis ndash lethal autosomal recessive gene defect (~12000 Caucasians)
bull Airway remodelling
- goblet cell hyperplasia
- submucosal gland hypertrophy
- fibrosis
- smooth muscle hypertrophy (asthma)
- alveolar destruction (COPD)
27
Asthma
bull Symptoms cough wheeze
shortness of breath and tightness of
the chest
bull Increased airway hyper-reactivity to
a variety of stimuli (smooth muscle
sensitive to constriction)
bull Airway narrowing and airflow
obstruction - usually reversible
(spontaneously or with drugs)
bull Wide spectrum of symptoms and
different severities of disease-
different phenotypes
Normal
Asthma
28
Asthma pathophysiology
CHRONIC
INFLAMMATION
AIRWAY
REMODELLING
29
Pathological changes in the asthmatic
airway- remodelling
bull Mucus hypersecretion
bull Denuded epithelium
bull Goblet cell hyperplasia
bull Reticular thickening
bull Appearance of myofibroblasts
bull Smooth muscle cell hypertrophy
bull Angiogenesis
bull Plasma extravasation
30
Improved therapies
Current
bull Relievers ndash inhalers are usually blue or green
ndash Bronchodilators cause smooth muscle to relax
ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur
bull Preventers ndash inhalers are usually brown orange or red
ndash Inhaled corticosteroids reduce inflammation in the airways
ndash Used daily even when there are no symptoms
bull Combination ndash A bronchodilatoranti-inflammatory drug
5-10 steroid resistant - severe
31
Chronic Obstructive Pulmonary Disease ndash COPD
bull Globally 64 million people have
COPD
bull Smoking main cause
bull Consists of a number of conditions
including emphysema and chronic
bronchitis
bull Symptoms of cough shortness of
breath tight chest wheeze
bull Can lead to irreversible airway
obstruction ndash no cure
32
Effect of smoking on FEV1
(Forced expiratory volume in 1 second)
Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33
Global Initiative on Obstructive Lung
Disease (GOLD)
GOLD has classified COPD as ldquoa disease
state characterised by airflow limitation that
is not fully reversible The airflow limitation
is usually both progressive and associated
with an abnormal inflammatory response of
the lungs to noxious particles or gasesrdquo
World Health Organization The GOLD global strategy for the
management and prevention of COPD 2001wwwgoldcopdorg 34
GOLD 1-4 classification with 4 most severe
Summary
bull Airways conduct air in and out of the lung mechanical stability
bull Airways comprised of many cell types with specific functions
- control of contractionrelaxation
- mucociliary clearance of foreign particles
- reduction of surface tension
bull Structural cells may also be lsquoregulatoryrsquo- cross-talk between cells
bull Immunity must display appropriate inflammatory tone
bull Respiratory disease leads to loss of lsquocontrolrsquo
- inflammation
- remodelling
- tissue breakdown
Additional information on websites Asthma UK
British Lung Foundation
35
Lung parenchyma
bull Type I alveolar cells - simple squamous
epithelium non-ciliated and main site of gas
exchange ndash covers 90 of alveolus
bull Type II alveolar cells (septal cells) ndash produce
surfactant to reduce surface tension preventing
alveoli collapse and renew type I cells
Type II alveolar cells
Type I alveolar cells
18
Control of airflow
bull Relaxation of smooth muscle = bronchodilation = increased airflow
bull Constriction of smooth muscle = bronchoconstriction = reduced airflow
Inflammation ndash driven constriction
of airway smooth muscle
Smooth muscle tone controlled by
autonomic nervous system
adrenal medullary hormones and
local factors
Autonomic nervous system
Parasympathetic Sympathetic
Muscarinic
beta2 alpha
- Constricts smooth muscle
- Causes mucus gland secretion
- Constricts
blood vessels
- Relaxes smooth muscle
19
Regulators of airflow
bull Nerves
- parasympathetic (cholinergic - constriction)
- sympathetic (adrenergic - dilation)
bull Regulatory and inflammatory mediators
- mast cell histamine - constriction
- arachidonic acid metabolites ndashconstrict and dilate
(eg prostaglandins leukotrienes)
- cytokines ndash constrict and dilate increase mucus
- hormones (eg adrenaline)
bull Proteinases (eg neutrophil elastase)
bull Reactive gas species (eg O2- NO)
Airway disease = Loss of normal control
20
SEM showing two alveolar macrophages (MP) in the alveolar space (ALV)
Airway macrophages a collision of functions
bull Induction of
inflammation
pathogens
bull Inhibition of
inflammation
clearance of self
cells and
extracellular
matrix turnover
products
Epithelial regulation of immunity
Tolerance
level set to
high =
bacterial
escape
Tolerance levels set too low
26
Respiratory diseases with loss of airway function
bull Common conditions
Asthma ndash ~5 of population in industrialised countries
COPD ndash 4th leading cause of death in UK and USA
Cystic fibrosis ndash lethal autosomal recessive gene defect (~12000 Caucasians)
bull Airway remodelling
- goblet cell hyperplasia
- submucosal gland hypertrophy
- fibrosis
- smooth muscle hypertrophy (asthma)
- alveolar destruction (COPD)
27
Asthma
bull Symptoms cough wheeze
shortness of breath and tightness of
the chest
bull Increased airway hyper-reactivity to
a variety of stimuli (smooth muscle
sensitive to constriction)
bull Airway narrowing and airflow
obstruction - usually reversible
(spontaneously or with drugs)
bull Wide spectrum of symptoms and
different severities of disease-
different phenotypes
Normal
Asthma
28
Asthma pathophysiology
CHRONIC
INFLAMMATION
AIRWAY
REMODELLING
29
Pathological changes in the asthmatic
airway- remodelling
bull Mucus hypersecretion
bull Denuded epithelium
bull Goblet cell hyperplasia
bull Reticular thickening
bull Appearance of myofibroblasts
bull Smooth muscle cell hypertrophy
bull Angiogenesis
bull Plasma extravasation
30
Improved therapies
Current
bull Relievers ndash inhalers are usually blue or green
ndash Bronchodilators cause smooth muscle to relax
ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur
bull Preventers ndash inhalers are usually brown orange or red
ndash Inhaled corticosteroids reduce inflammation in the airways
ndash Used daily even when there are no symptoms
bull Combination ndash A bronchodilatoranti-inflammatory drug
5-10 steroid resistant - severe
31
Chronic Obstructive Pulmonary Disease ndash COPD
bull Globally 64 million people have
COPD
bull Smoking main cause
bull Consists of a number of conditions
including emphysema and chronic
bronchitis
bull Symptoms of cough shortness of
breath tight chest wheeze
bull Can lead to irreversible airway
obstruction ndash no cure
32
Effect of smoking on FEV1
(Forced expiratory volume in 1 second)
Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33
Global Initiative on Obstructive Lung
Disease (GOLD)
GOLD has classified COPD as ldquoa disease
state characterised by airflow limitation that
is not fully reversible The airflow limitation
is usually both progressive and associated
with an abnormal inflammatory response of
the lungs to noxious particles or gasesrdquo
World Health Organization The GOLD global strategy for the
management and prevention of COPD 2001wwwgoldcopdorg 34
GOLD 1-4 classification with 4 most severe
Summary
bull Airways conduct air in and out of the lung mechanical stability
bull Airways comprised of many cell types with specific functions
- control of contractionrelaxation
- mucociliary clearance of foreign particles
- reduction of surface tension
bull Structural cells may also be lsquoregulatoryrsquo- cross-talk between cells
bull Immunity must display appropriate inflammatory tone
bull Respiratory disease leads to loss of lsquocontrolrsquo
- inflammation
- remodelling
- tissue breakdown
Additional information on websites Asthma UK
British Lung Foundation
35
Control of airflow
bull Relaxation of smooth muscle = bronchodilation = increased airflow
bull Constriction of smooth muscle = bronchoconstriction = reduced airflow
Inflammation ndash driven constriction
of airway smooth muscle
Smooth muscle tone controlled by
autonomic nervous system
adrenal medullary hormones and
local factors
Autonomic nervous system
Parasympathetic Sympathetic
Muscarinic
beta2 alpha
- Constricts smooth muscle
- Causes mucus gland secretion
- Constricts
blood vessels
- Relaxes smooth muscle
19
Regulators of airflow
bull Nerves
- parasympathetic (cholinergic - constriction)
- sympathetic (adrenergic - dilation)
bull Regulatory and inflammatory mediators
- mast cell histamine - constriction
- arachidonic acid metabolites ndashconstrict and dilate
(eg prostaglandins leukotrienes)
- cytokines ndash constrict and dilate increase mucus
- hormones (eg adrenaline)
bull Proteinases (eg neutrophil elastase)
bull Reactive gas species (eg O2- NO)
Airway disease = Loss of normal control
20
SEM showing two alveolar macrophages (MP) in the alveolar space (ALV)
Airway macrophages a collision of functions
bull Induction of
inflammation
pathogens
bull Inhibition of
inflammation
clearance of self
cells and
extracellular
matrix turnover
products
Epithelial regulation of immunity
Tolerance
level set to
high =
bacterial
escape
Tolerance levels set too low
26
Respiratory diseases with loss of airway function
bull Common conditions
Asthma ndash ~5 of population in industrialised countries
COPD ndash 4th leading cause of death in UK and USA
Cystic fibrosis ndash lethal autosomal recessive gene defect (~12000 Caucasians)
bull Airway remodelling
- goblet cell hyperplasia
- submucosal gland hypertrophy
- fibrosis
- smooth muscle hypertrophy (asthma)
- alveolar destruction (COPD)
27
Asthma
bull Symptoms cough wheeze
shortness of breath and tightness of
the chest
bull Increased airway hyper-reactivity to
a variety of stimuli (smooth muscle
sensitive to constriction)
bull Airway narrowing and airflow
obstruction - usually reversible
(spontaneously or with drugs)
bull Wide spectrum of symptoms and
different severities of disease-
different phenotypes
Normal
Asthma
28
Asthma pathophysiology
CHRONIC
INFLAMMATION
AIRWAY
REMODELLING
29
Pathological changes in the asthmatic
airway- remodelling
bull Mucus hypersecretion
bull Denuded epithelium
bull Goblet cell hyperplasia
bull Reticular thickening
bull Appearance of myofibroblasts
bull Smooth muscle cell hypertrophy
bull Angiogenesis
bull Plasma extravasation
30
Improved therapies
Current
bull Relievers ndash inhalers are usually blue or green
ndash Bronchodilators cause smooth muscle to relax
ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur
bull Preventers ndash inhalers are usually brown orange or red
ndash Inhaled corticosteroids reduce inflammation in the airways
ndash Used daily even when there are no symptoms
bull Combination ndash A bronchodilatoranti-inflammatory drug
5-10 steroid resistant - severe
31
Chronic Obstructive Pulmonary Disease ndash COPD
bull Globally 64 million people have
COPD
bull Smoking main cause
bull Consists of a number of conditions
including emphysema and chronic
bronchitis
bull Symptoms of cough shortness of
breath tight chest wheeze
bull Can lead to irreversible airway
obstruction ndash no cure
32
Effect of smoking on FEV1
(Forced expiratory volume in 1 second)
Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33
Global Initiative on Obstructive Lung
Disease (GOLD)
GOLD has classified COPD as ldquoa disease
state characterised by airflow limitation that
is not fully reversible The airflow limitation
is usually both progressive and associated
with an abnormal inflammatory response of
the lungs to noxious particles or gasesrdquo
World Health Organization The GOLD global strategy for the
management and prevention of COPD 2001wwwgoldcopdorg 34
GOLD 1-4 classification with 4 most severe
Summary
bull Airways conduct air in and out of the lung mechanical stability
bull Airways comprised of many cell types with specific functions
- control of contractionrelaxation
- mucociliary clearance of foreign particles
- reduction of surface tension
bull Structural cells may also be lsquoregulatoryrsquo- cross-talk between cells
bull Immunity must display appropriate inflammatory tone
bull Respiratory disease leads to loss of lsquocontrolrsquo
- inflammation
- remodelling
- tissue breakdown
Additional information on websites Asthma UK
British Lung Foundation
35
Regulators of airflow
bull Nerves
- parasympathetic (cholinergic - constriction)
- sympathetic (adrenergic - dilation)
bull Regulatory and inflammatory mediators
- mast cell histamine - constriction
- arachidonic acid metabolites ndashconstrict and dilate
(eg prostaglandins leukotrienes)
- cytokines ndash constrict and dilate increase mucus
- hormones (eg adrenaline)
bull Proteinases (eg neutrophil elastase)
bull Reactive gas species (eg O2- NO)
Airway disease = Loss of normal control
20
SEM showing two alveolar macrophages (MP) in the alveolar space (ALV)
Airway macrophages a collision of functions
bull Induction of
inflammation
pathogens
bull Inhibition of
inflammation
clearance of self
cells and
extracellular
matrix turnover
products
Epithelial regulation of immunity
Tolerance
level set to
high =
bacterial
escape
Tolerance levels set too low
26
Respiratory diseases with loss of airway function
bull Common conditions
Asthma ndash ~5 of population in industrialised countries
COPD ndash 4th leading cause of death in UK and USA
Cystic fibrosis ndash lethal autosomal recessive gene defect (~12000 Caucasians)
bull Airway remodelling
- goblet cell hyperplasia
- submucosal gland hypertrophy
- fibrosis
- smooth muscle hypertrophy (asthma)
- alveolar destruction (COPD)
27
Asthma
bull Symptoms cough wheeze
shortness of breath and tightness of
the chest
bull Increased airway hyper-reactivity to
a variety of stimuli (smooth muscle
sensitive to constriction)
bull Airway narrowing and airflow
obstruction - usually reversible
(spontaneously or with drugs)
bull Wide spectrum of symptoms and
different severities of disease-
different phenotypes
Normal
Asthma
28
Asthma pathophysiology
CHRONIC
INFLAMMATION
AIRWAY
REMODELLING
29
Pathological changes in the asthmatic
airway- remodelling
bull Mucus hypersecretion
bull Denuded epithelium
bull Goblet cell hyperplasia
bull Reticular thickening
bull Appearance of myofibroblasts
bull Smooth muscle cell hypertrophy
bull Angiogenesis
bull Plasma extravasation
30
Improved therapies
Current
bull Relievers ndash inhalers are usually blue or green
ndash Bronchodilators cause smooth muscle to relax
ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur
bull Preventers ndash inhalers are usually brown orange or red
ndash Inhaled corticosteroids reduce inflammation in the airways
ndash Used daily even when there are no symptoms
bull Combination ndash A bronchodilatoranti-inflammatory drug
5-10 steroid resistant - severe
31
Chronic Obstructive Pulmonary Disease ndash COPD
bull Globally 64 million people have
COPD
bull Smoking main cause
bull Consists of a number of conditions
including emphysema and chronic
bronchitis
bull Symptoms of cough shortness of
breath tight chest wheeze
bull Can lead to irreversible airway
obstruction ndash no cure
32
Effect of smoking on FEV1
(Forced expiratory volume in 1 second)
Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33
Global Initiative on Obstructive Lung
Disease (GOLD)
GOLD has classified COPD as ldquoa disease
state characterised by airflow limitation that
is not fully reversible The airflow limitation
is usually both progressive and associated
with an abnormal inflammatory response of
the lungs to noxious particles or gasesrdquo
World Health Organization The GOLD global strategy for the
management and prevention of COPD 2001wwwgoldcopdorg 34
GOLD 1-4 classification with 4 most severe
Summary
bull Airways conduct air in and out of the lung mechanical stability
bull Airways comprised of many cell types with specific functions
- control of contractionrelaxation
- mucociliary clearance of foreign particles
- reduction of surface tension
bull Structural cells may also be lsquoregulatoryrsquo- cross-talk between cells
bull Immunity must display appropriate inflammatory tone
bull Respiratory disease leads to loss of lsquocontrolrsquo
- inflammation
- remodelling
- tissue breakdown
Additional information on websites Asthma UK
British Lung Foundation
35
SEM showing two alveolar macrophages (MP) in the alveolar space (ALV)
Airway macrophages a collision of functions
bull Induction of
inflammation
pathogens
bull Inhibition of
inflammation
clearance of self
cells and
extracellular
matrix turnover
products
Epithelial regulation of immunity
Tolerance
level set to
high =
bacterial
escape
Tolerance levels set too low
26
Respiratory diseases with loss of airway function
bull Common conditions
Asthma ndash ~5 of population in industrialised countries
COPD ndash 4th leading cause of death in UK and USA
Cystic fibrosis ndash lethal autosomal recessive gene defect (~12000 Caucasians)
bull Airway remodelling
- goblet cell hyperplasia
- submucosal gland hypertrophy
- fibrosis
- smooth muscle hypertrophy (asthma)
- alveolar destruction (COPD)
27
Asthma
bull Symptoms cough wheeze
shortness of breath and tightness of
the chest
bull Increased airway hyper-reactivity to
a variety of stimuli (smooth muscle
sensitive to constriction)
bull Airway narrowing and airflow
obstruction - usually reversible
(spontaneously or with drugs)
bull Wide spectrum of symptoms and
different severities of disease-
different phenotypes
Normal
Asthma
28
Asthma pathophysiology
CHRONIC
INFLAMMATION
AIRWAY
REMODELLING
29
Pathological changes in the asthmatic
airway- remodelling
bull Mucus hypersecretion
bull Denuded epithelium
bull Goblet cell hyperplasia
bull Reticular thickening
bull Appearance of myofibroblasts
bull Smooth muscle cell hypertrophy
bull Angiogenesis
bull Plasma extravasation
30
Improved therapies
Current
bull Relievers ndash inhalers are usually blue or green
ndash Bronchodilators cause smooth muscle to relax
ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur
bull Preventers ndash inhalers are usually brown orange or red
ndash Inhaled corticosteroids reduce inflammation in the airways
ndash Used daily even when there are no symptoms
bull Combination ndash A bronchodilatoranti-inflammatory drug
5-10 steroid resistant - severe
31
Chronic Obstructive Pulmonary Disease ndash COPD
bull Globally 64 million people have
COPD
bull Smoking main cause
bull Consists of a number of conditions
including emphysema and chronic
bronchitis
bull Symptoms of cough shortness of
breath tight chest wheeze
bull Can lead to irreversible airway
obstruction ndash no cure
32
Effect of smoking on FEV1
(Forced expiratory volume in 1 second)
Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33
Global Initiative on Obstructive Lung
Disease (GOLD)
GOLD has classified COPD as ldquoa disease
state characterised by airflow limitation that
is not fully reversible The airflow limitation
is usually both progressive and associated
with an abnormal inflammatory response of
the lungs to noxious particles or gasesrdquo
World Health Organization The GOLD global strategy for the
management and prevention of COPD 2001wwwgoldcopdorg 34
GOLD 1-4 classification with 4 most severe
Summary
bull Airways conduct air in and out of the lung mechanical stability
bull Airways comprised of many cell types with specific functions
- control of contractionrelaxation
- mucociliary clearance of foreign particles
- reduction of surface tension
bull Structural cells may also be lsquoregulatoryrsquo- cross-talk between cells
bull Immunity must display appropriate inflammatory tone
bull Respiratory disease leads to loss of lsquocontrolrsquo
- inflammation
- remodelling
- tissue breakdown
Additional information on websites Asthma UK
British Lung Foundation
35
Epithelial regulation of immunity
Tolerance
level set to
high =
bacterial
escape
Tolerance levels set too low
26
Respiratory diseases with loss of airway function
bull Common conditions
Asthma ndash ~5 of population in industrialised countries
COPD ndash 4th leading cause of death in UK and USA
Cystic fibrosis ndash lethal autosomal recessive gene defect (~12000 Caucasians)
bull Airway remodelling
- goblet cell hyperplasia
- submucosal gland hypertrophy
- fibrosis
- smooth muscle hypertrophy (asthma)
- alveolar destruction (COPD)
27
Asthma
bull Symptoms cough wheeze
shortness of breath and tightness of
the chest
bull Increased airway hyper-reactivity to
a variety of stimuli (smooth muscle
sensitive to constriction)
bull Airway narrowing and airflow
obstruction - usually reversible
(spontaneously or with drugs)
bull Wide spectrum of symptoms and
different severities of disease-
different phenotypes
Normal
Asthma
28
Asthma pathophysiology
CHRONIC
INFLAMMATION
AIRWAY
REMODELLING
29
Pathological changes in the asthmatic
airway- remodelling
bull Mucus hypersecretion
bull Denuded epithelium
bull Goblet cell hyperplasia
bull Reticular thickening
bull Appearance of myofibroblasts
bull Smooth muscle cell hypertrophy
bull Angiogenesis
bull Plasma extravasation
30
Improved therapies
Current
bull Relievers ndash inhalers are usually blue or green
ndash Bronchodilators cause smooth muscle to relax
ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur
bull Preventers ndash inhalers are usually brown orange or red
ndash Inhaled corticosteroids reduce inflammation in the airways
ndash Used daily even when there are no symptoms
bull Combination ndash A bronchodilatoranti-inflammatory drug
5-10 steroid resistant - severe
31
Chronic Obstructive Pulmonary Disease ndash COPD
bull Globally 64 million people have
COPD
bull Smoking main cause
bull Consists of a number of conditions
including emphysema and chronic
bronchitis
bull Symptoms of cough shortness of
breath tight chest wheeze
bull Can lead to irreversible airway
obstruction ndash no cure
32
Effect of smoking on FEV1
(Forced expiratory volume in 1 second)
Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33
Global Initiative on Obstructive Lung
Disease (GOLD)
GOLD has classified COPD as ldquoa disease
state characterised by airflow limitation that
is not fully reversible The airflow limitation
is usually both progressive and associated
with an abnormal inflammatory response of
the lungs to noxious particles or gasesrdquo
World Health Organization The GOLD global strategy for the
management and prevention of COPD 2001wwwgoldcopdorg 34
GOLD 1-4 classification with 4 most severe
Summary
bull Airways conduct air in and out of the lung mechanical stability
bull Airways comprised of many cell types with specific functions
- control of contractionrelaxation
- mucociliary clearance of foreign particles
- reduction of surface tension
bull Structural cells may also be lsquoregulatoryrsquo- cross-talk between cells
bull Immunity must display appropriate inflammatory tone
bull Respiratory disease leads to loss of lsquocontrolrsquo
- inflammation
- remodelling
- tissue breakdown
Additional information on websites Asthma UK
British Lung Foundation
35
Tolerance
level set to
high =
bacterial
escape
Tolerance levels set too low
26
Respiratory diseases with loss of airway function
bull Common conditions
Asthma ndash ~5 of population in industrialised countries
COPD ndash 4th leading cause of death in UK and USA
Cystic fibrosis ndash lethal autosomal recessive gene defect (~12000 Caucasians)
bull Airway remodelling
- goblet cell hyperplasia
- submucosal gland hypertrophy
- fibrosis
- smooth muscle hypertrophy (asthma)
- alveolar destruction (COPD)
27
Asthma
bull Symptoms cough wheeze
shortness of breath and tightness of
the chest
bull Increased airway hyper-reactivity to
a variety of stimuli (smooth muscle
sensitive to constriction)
bull Airway narrowing and airflow
obstruction - usually reversible
(spontaneously or with drugs)
bull Wide spectrum of symptoms and
different severities of disease-
different phenotypes
Normal
Asthma
28
Asthma pathophysiology
CHRONIC
INFLAMMATION
AIRWAY
REMODELLING
29
Pathological changes in the asthmatic
airway- remodelling
bull Mucus hypersecretion
bull Denuded epithelium
bull Goblet cell hyperplasia
bull Reticular thickening
bull Appearance of myofibroblasts
bull Smooth muscle cell hypertrophy
bull Angiogenesis
bull Plasma extravasation
30
Improved therapies
Current
bull Relievers ndash inhalers are usually blue or green
ndash Bronchodilators cause smooth muscle to relax
ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur
bull Preventers ndash inhalers are usually brown orange or red
ndash Inhaled corticosteroids reduce inflammation in the airways
ndash Used daily even when there are no symptoms
bull Combination ndash A bronchodilatoranti-inflammatory drug
5-10 steroid resistant - severe
31
Chronic Obstructive Pulmonary Disease ndash COPD
bull Globally 64 million people have
COPD
bull Smoking main cause
bull Consists of a number of conditions
including emphysema and chronic
bronchitis
bull Symptoms of cough shortness of
breath tight chest wheeze
bull Can lead to irreversible airway
obstruction ndash no cure
32
Effect of smoking on FEV1
(Forced expiratory volume in 1 second)
Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33
Global Initiative on Obstructive Lung
Disease (GOLD)
GOLD has classified COPD as ldquoa disease
state characterised by airflow limitation that
is not fully reversible The airflow limitation
is usually both progressive and associated
with an abnormal inflammatory response of
the lungs to noxious particles or gasesrdquo
World Health Organization The GOLD global strategy for the
management and prevention of COPD 2001wwwgoldcopdorg 34
GOLD 1-4 classification with 4 most severe
Summary
bull Airways conduct air in and out of the lung mechanical stability
bull Airways comprised of many cell types with specific functions
- control of contractionrelaxation
- mucociliary clearance of foreign particles
- reduction of surface tension
bull Structural cells may also be lsquoregulatoryrsquo- cross-talk between cells
bull Immunity must display appropriate inflammatory tone
bull Respiratory disease leads to loss of lsquocontrolrsquo
- inflammation
- remodelling
- tissue breakdown
Additional information on websites Asthma UK
British Lung Foundation
35
Tolerance levels set too low
26
Respiratory diseases with loss of airway function
bull Common conditions
Asthma ndash ~5 of population in industrialised countries
COPD ndash 4th leading cause of death in UK and USA
Cystic fibrosis ndash lethal autosomal recessive gene defect (~12000 Caucasians)
bull Airway remodelling
- goblet cell hyperplasia
- submucosal gland hypertrophy
- fibrosis
- smooth muscle hypertrophy (asthma)
- alveolar destruction (COPD)
27
Asthma
bull Symptoms cough wheeze
shortness of breath and tightness of
the chest
bull Increased airway hyper-reactivity to
a variety of stimuli (smooth muscle
sensitive to constriction)
bull Airway narrowing and airflow
obstruction - usually reversible
(spontaneously or with drugs)
bull Wide spectrum of symptoms and
different severities of disease-
different phenotypes
Normal
Asthma
28
Asthma pathophysiology
CHRONIC
INFLAMMATION
AIRWAY
REMODELLING
29
Pathological changes in the asthmatic
airway- remodelling
bull Mucus hypersecretion
bull Denuded epithelium
bull Goblet cell hyperplasia
bull Reticular thickening
bull Appearance of myofibroblasts
bull Smooth muscle cell hypertrophy
bull Angiogenesis
bull Plasma extravasation
30
Improved therapies
Current
bull Relievers ndash inhalers are usually blue or green
ndash Bronchodilators cause smooth muscle to relax
ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur
bull Preventers ndash inhalers are usually brown orange or red
ndash Inhaled corticosteroids reduce inflammation in the airways
ndash Used daily even when there are no symptoms
bull Combination ndash A bronchodilatoranti-inflammatory drug
5-10 steroid resistant - severe
31
Chronic Obstructive Pulmonary Disease ndash COPD
bull Globally 64 million people have
COPD
bull Smoking main cause
bull Consists of a number of conditions
including emphysema and chronic
bronchitis
bull Symptoms of cough shortness of
breath tight chest wheeze
bull Can lead to irreversible airway
obstruction ndash no cure
32
Effect of smoking on FEV1
(Forced expiratory volume in 1 second)
Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33
Global Initiative on Obstructive Lung
Disease (GOLD)
GOLD has classified COPD as ldquoa disease
state characterised by airflow limitation that
is not fully reversible The airflow limitation
is usually both progressive and associated
with an abnormal inflammatory response of
the lungs to noxious particles or gasesrdquo
World Health Organization The GOLD global strategy for the
management and prevention of COPD 2001wwwgoldcopdorg 34
GOLD 1-4 classification with 4 most severe
Summary
bull Airways conduct air in and out of the lung mechanical stability
bull Airways comprised of many cell types with specific functions
- control of contractionrelaxation
- mucociliary clearance of foreign particles
- reduction of surface tension
bull Structural cells may also be lsquoregulatoryrsquo- cross-talk between cells
bull Immunity must display appropriate inflammatory tone
bull Respiratory disease leads to loss of lsquocontrolrsquo
- inflammation
- remodelling
- tissue breakdown
Additional information on websites Asthma UK
British Lung Foundation
35
Respiratory diseases with loss of airway function
bull Common conditions
Asthma ndash ~5 of population in industrialised countries
COPD ndash 4th leading cause of death in UK and USA
Cystic fibrosis ndash lethal autosomal recessive gene defect (~12000 Caucasians)
bull Airway remodelling
- goblet cell hyperplasia
- submucosal gland hypertrophy
- fibrosis
- smooth muscle hypertrophy (asthma)
- alveolar destruction (COPD)
27
Asthma
bull Symptoms cough wheeze
shortness of breath and tightness of
the chest
bull Increased airway hyper-reactivity to
a variety of stimuli (smooth muscle
sensitive to constriction)
bull Airway narrowing and airflow
obstruction - usually reversible
(spontaneously or with drugs)
bull Wide spectrum of symptoms and
different severities of disease-
different phenotypes
Normal
Asthma
28
Asthma pathophysiology
CHRONIC
INFLAMMATION
AIRWAY
REMODELLING
29
Pathological changes in the asthmatic
airway- remodelling
bull Mucus hypersecretion
bull Denuded epithelium
bull Goblet cell hyperplasia
bull Reticular thickening
bull Appearance of myofibroblasts
bull Smooth muscle cell hypertrophy
bull Angiogenesis
bull Plasma extravasation
30
Improved therapies
Current
bull Relievers ndash inhalers are usually blue or green
ndash Bronchodilators cause smooth muscle to relax
ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur
bull Preventers ndash inhalers are usually brown orange or red
ndash Inhaled corticosteroids reduce inflammation in the airways
ndash Used daily even when there are no symptoms
bull Combination ndash A bronchodilatoranti-inflammatory drug
5-10 steroid resistant - severe
31
Chronic Obstructive Pulmonary Disease ndash COPD
bull Globally 64 million people have
COPD
bull Smoking main cause
bull Consists of a number of conditions
including emphysema and chronic
bronchitis
bull Symptoms of cough shortness of
breath tight chest wheeze
bull Can lead to irreversible airway
obstruction ndash no cure
32
Effect of smoking on FEV1
(Forced expiratory volume in 1 second)
Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33
Global Initiative on Obstructive Lung
Disease (GOLD)
GOLD has classified COPD as ldquoa disease
state characterised by airflow limitation that
is not fully reversible The airflow limitation
is usually both progressive and associated
with an abnormal inflammatory response of
the lungs to noxious particles or gasesrdquo
World Health Organization The GOLD global strategy for the
management and prevention of COPD 2001wwwgoldcopdorg 34
GOLD 1-4 classification with 4 most severe
Summary
bull Airways conduct air in and out of the lung mechanical stability
bull Airways comprised of many cell types with specific functions
- control of contractionrelaxation
- mucociliary clearance of foreign particles
- reduction of surface tension
bull Structural cells may also be lsquoregulatoryrsquo- cross-talk between cells
bull Immunity must display appropriate inflammatory tone
bull Respiratory disease leads to loss of lsquocontrolrsquo
- inflammation
- remodelling
- tissue breakdown
Additional information on websites Asthma UK
British Lung Foundation
35
Asthma
bull Symptoms cough wheeze
shortness of breath and tightness of
the chest
bull Increased airway hyper-reactivity to
a variety of stimuli (smooth muscle
sensitive to constriction)
bull Airway narrowing and airflow
obstruction - usually reversible
(spontaneously or with drugs)
bull Wide spectrum of symptoms and
different severities of disease-
different phenotypes
Normal
Asthma
28
Asthma pathophysiology
CHRONIC
INFLAMMATION
AIRWAY
REMODELLING
29
Pathological changes in the asthmatic
airway- remodelling
bull Mucus hypersecretion
bull Denuded epithelium
bull Goblet cell hyperplasia
bull Reticular thickening
bull Appearance of myofibroblasts
bull Smooth muscle cell hypertrophy
bull Angiogenesis
bull Plasma extravasation
30
Improved therapies
Current
bull Relievers ndash inhalers are usually blue or green
ndash Bronchodilators cause smooth muscle to relax
ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur
bull Preventers ndash inhalers are usually brown orange or red
ndash Inhaled corticosteroids reduce inflammation in the airways
ndash Used daily even when there are no symptoms
bull Combination ndash A bronchodilatoranti-inflammatory drug
5-10 steroid resistant - severe
31
Chronic Obstructive Pulmonary Disease ndash COPD
bull Globally 64 million people have
COPD
bull Smoking main cause
bull Consists of a number of conditions
including emphysema and chronic
bronchitis
bull Symptoms of cough shortness of
breath tight chest wheeze
bull Can lead to irreversible airway
obstruction ndash no cure
32
Effect of smoking on FEV1
(Forced expiratory volume in 1 second)
Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33
Global Initiative on Obstructive Lung
Disease (GOLD)
GOLD has classified COPD as ldquoa disease
state characterised by airflow limitation that
is not fully reversible The airflow limitation
is usually both progressive and associated
with an abnormal inflammatory response of
the lungs to noxious particles or gasesrdquo
World Health Organization The GOLD global strategy for the
management and prevention of COPD 2001wwwgoldcopdorg 34
GOLD 1-4 classification with 4 most severe
Summary
bull Airways conduct air in and out of the lung mechanical stability
bull Airways comprised of many cell types with specific functions
- control of contractionrelaxation
- mucociliary clearance of foreign particles
- reduction of surface tension
bull Structural cells may also be lsquoregulatoryrsquo- cross-talk between cells
bull Immunity must display appropriate inflammatory tone
bull Respiratory disease leads to loss of lsquocontrolrsquo
- inflammation
- remodelling
- tissue breakdown
Additional information on websites Asthma UK
British Lung Foundation
35
Asthma pathophysiology
CHRONIC
INFLAMMATION
AIRWAY
REMODELLING
29
Pathological changes in the asthmatic
airway- remodelling
bull Mucus hypersecretion
bull Denuded epithelium
bull Goblet cell hyperplasia
bull Reticular thickening
bull Appearance of myofibroblasts
bull Smooth muscle cell hypertrophy
bull Angiogenesis
bull Plasma extravasation
30
Improved therapies
Current
bull Relievers ndash inhalers are usually blue or green
ndash Bronchodilators cause smooth muscle to relax
ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur
bull Preventers ndash inhalers are usually brown orange or red
ndash Inhaled corticosteroids reduce inflammation in the airways
ndash Used daily even when there are no symptoms
bull Combination ndash A bronchodilatoranti-inflammatory drug
5-10 steroid resistant - severe
31
Chronic Obstructive Pulmonary Disease ndash COPD
bull Globally 64 million people have
COPD
bull Smoking main cause
bull Consists of a number of conditions
including emphysema and chronic
bronchitis
bull Symptoms of cough shortness of
breath tight chest wheeze
bull Can lead to irreversible airway
obstruction ndash no cure
32
Effect of smoking on FEV1
(Forced expiratory volume in 1 second)
Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33
Global Initiative on Obstructive Lung
Disease (GOLD)
GOLD has classified COPD as ldquoa disease
state characterised by airflow limitation that
is not fully reversible The airflow limitation
is usually both progressive and associated
with an abnormal inflammatory response of
the lungs to noxious particles or gasesrdquo
World Health Organization The GOLD global strategy for the
management and prevention of COPD 2001wwwgoldcopdorg 34
GOLD 1-4 classification with 4 most severe
Summary
bull Airways conduct air in and out of the lung mechanical stability
bull Airways comprised of many cell types with specific functions
- control of contractionrelaxation
- mucociliary clearance of foreign particles
- reduction of surface tension
bull Structural cells may also be lsquoregulatoryrsquo- cross-talk between cells
bull Immunity must display appropriate inflammatory tone
bull Respiratory disease leads to loss of lsquocontrolrsquo
- inflammation
- remodelling
- tissue breakdown
Additional information on websites Asthma UK
British Lung Foundation
35
Pathological changes in the asthmatic
airway- remodelling
bull Mucus hypersecretion
bull Denuded epithelium
bull Goblet cell hyperplasia
bull Reticular thickening
bull Appearance of myofibroblasts
bull Smooth muscle cell hypertrophy
bull Angiogenesis
bull Plasma extravasation
30
Improved therapies
Current
bull Relievers ndash inhalers are usually blue or green
ndash Bronchodilators cause smooth muscle to relax
ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur
bull Preventers ndash inhalers are usually brown orange or red
ndash Inhaled corticosteroids reduce inflammation in the airways
ndash Used daily even when there are no symptoms
bull Combination ndash A bronchodilatoranti-inflammatory drug
5-10 steroid resistant - severe
31
Chronic Obstructive Pulmonary Disease ndash COPD
bull Globally 64 million people have
COPD
bull Smoking main cause
bull Consists of a number of conditions
including emphysema and chronic
bronchitis
bull Symptoms of cough shortness of
breath tight chest wheeze
bull Can lead to irreversible airway
obstruction ndash no cure
32
Effect of smoking on FEV1
(Forced expiratory volume in 1 second)
Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33
Global Initiative on Obstructive Lung
Disease (GOLD)
GOLD has classified COPD as ldquoa disease
state characterised by airflow limitation that
is not fully reversible The airflow limitation
is usually both progressive and associated
with an abnormal inflammatory response of
the lungs to noxious particles or gasesrdquo
World Health Organization The GOLD global strategy for the
management and prevention of COPD 2001wwwgoldcopdorg 34
GOLD 1-4 classification with 4 most severe
Summary
bull Airways conduct air in and out of the lung mechanical stability
bull Airways comprised of many cell types with specific functions
- control of contractionrelaxation
- mucociliary clearance of foreign particles
- reduction of surface tension
bull Structural cells may also be lsquoregulatoryrsquo- cross-talk between cells
bull Immunity must display appropriate inflammatory tone
bull Respiratory disease leads to loss of lsquocontrolrsquo
- inflammation
- remodelling
- tissue breakdown
Additional information on websites Asthma UK
British Lung Foundation
35
Improved therapies
Current
bull Relievers ndash inhalers are usually blue or green
ndash Bronchodilators cause smooth muscle to relax
ndash Short-acting (1-2 hours) or long-acting (up to 12 hours) and usually used when asthma symptoms occur
bull Preventers ndash inhalers are usually brown orange or red
ndash Inhaled corticosteroids reduce inflammation in the airways
ndash Used daily even when there are no symptoms
bull Combination ndash A bronchodilatoranti-inflammatory drug
5-10 steroid resistant - severe
31
Chronic Obstructive Pulmonary Disease ndash COPD
bull Globally 64 million people have
COPD
bull Smoking main cause
bull Consists of a number of conditions
including emphysema and chronic
bronchitis
bull Symptoms of cough shortness of
breath tight chest wheeze
bull Can lead to irreversible airway
obstruction ndash no cure
32
Effect of smoking on FEV1
(Forced expiratory volume in 1 second)
Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33
Global Initiative on Obstructive Lung
Disease (GOLD)
GOLD has classified COPD as ldquoa disease
state characterised by airflow limitation that
is not fully reversible The airflow limitation
is usually both progressive and associated
with an abnormal inflammatory response of
the lungs to noxious particles or gasesrdquo
World Health Organization The GOLD global strategy for the
management and prevention of COPD 2001wwwgoldcopdorg 34
GOLD 1-4 classification with 4 most severe
Summary
bull Airways conduct air in and out of the lung mechanical stability
bull Airways comprised of many cell types with specific functions
- control of contractionrelaxation
- mucociliary clearance of foreign particles
- reduction of surface tension
bull Structural cells may also be lsquoregulatoryrsquo- cross-talk between cells
bull Immunity must display appropriate inflammatory tone
bull Respiratory disease leads to loss of lsquocontrolrsquo
- inflammation
- remodelling
- tissue breakdown
Additional information on websites Asthma UK
British Lung Foundation
35
Chronic Obstructive Pulmonary Disease ndash COPD
bull Globally 64 million people have
COPD
bull Smoking main cause
bull Consists of a number of conditions
including emphysema and chronic
bronchitis
bull Symptoms of cough shortness of
breath tight chest wheeze
bull Can lead to irreversible airway
obstruction ndash no cure
32
Effect of smoking on FEV1
(Forced expiratory volume in 1 second)
Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33
Global Initiative on Obstructive Lung
Disease (GOLD)
GOLD has classified COPD as ldquoa disease
state characterised by airflow limitation that
is not fully reversible The airflow limitation
is usually both progressive and associated
with an abnormal inflammatory response of
the lungs to noxious particles or gasesrdquo
World Health Organization The GOLD global strategy for the
management and prevention of COPD 2001wwwgoldcopdorg 34
GOLD 1-4 classification with 4 most severe
Summary
bull Airways conduct air in and out of the lung mechanical stability
bull Airways comprised of many cell types with specific functions
- control of contractionrelaxation
- mucociliary clearance of foreign particles
- reduction of surface tension
bull Structural cells may also be lsquoregulatoryrsquo- cross-talk between cells
bull Immunity must display appropriate inflammatory tone
bull Respiratory disease leads to loss of lsquocontrolrsquo
- inflammation
- remodelling
- tissue breakdown
Additional information on websites Asthma UK
British Lung Foundation
35
Effect of smoking on FEV1
(Forced expiratory volume in 1 second)
Fletcher C and Peto R British Medical Journal 1977 1 1645-1648 33
Global Initiative on Obstructive Lung
Disease (GOLD)
GOLD has classified COPD as ldquoa disease
state characterised by airflow limitation that
is not fully reversible The airflow limitation
is usually both progressive and associated
with an abnormal inflammatory response of
the lungs to noxious particles or gasesrdquo
World Health Organization The GOLD global strategy for the
management and prevention of COPD 2001wwwgoldcopdorg 34
GOLD 1-4 classification with 4 most severe
Summary
bull Airways conduct air in and out of the lung mechanical stability
bull Airways comprised of many cell types with specific functions
- control of contractionrelaxation
- mucociliary clearance of foreign particles
- reduction of surface tension
bull Structural cells may also be lsquoregulatoryrsquo- cross-talk between cells
bull Immunity must display appropriate inflammatory tone
bull Respiratory disease leads to loss of lsquocontrolrsquo
- inflammation
- remodelling
- tissue breakdown
Additional information on websites Asthma UK
British Lung Foundation
35
Global Initiative on Obstructive Lung
Disease (GOLD)
GOLD has classified COPD as ldquoa disease
state characterised by airflow limitation that
is not fully reversible The airflow limitation
is usually both progressive and associated
with an abnormal inflammatory response of
the lungs to noxious particles or gasesrdquo
World Health Organization The GOLD global strategy for the
management and prevention of COPD 2001wwwgoldcopdorg 34
GOLD 1-4 classification with 4 most severe
Summary
bull Airways conduct air in and out of the lung mechanical stability
bull Airways comprised of many cell types with specific functions
- control of contractionrelaxation
- mucociliary clearance of foreign particles
- reduction of surface tension
bull Structural cells may also be lsquoregulatoryrsquo- cross-talk between cells
bull Immunity must display appropriate inflammatory tone
bull Respiratory disease leads to loss of lsquocontrolrsquo
- inflammation
- remodelling
- tissue breakdown
Additional information on websites Asthma UK
British Lung Foundation
35
Summary
bull Airways conduct air in and out of the lung mechanical stability
bull Airways comprised of many cell types with specific functions
- control of contractionrelaxation
- mucociliary clearance of foreign particles
- reduction of surface tension
bull Structural cells may also be lsquoregulatoryrsquo- cross-talk between cells
bull Immunity must display appropriate inflammatory tone
bull Respiratory disease leads to loss of lsquocontrolrsquo
- inflammation
- remodelling
- tissue breakdown
Additional information on websites Asthma UK
British Lung Foundation
35