copd first session
TRANSCRIPT
COPD
Gamal Rabie Agmy, MD,FCCP Professor of Chest Diseases, Assiut university
Goal of this learning modules
• To Provide a framework to make informed decisions regarding the diagnosis and treatment of Chronic obstructive pulmonary disease
Learning objectives
After completing this module you should know:
• know the definition of COPD
• Understand the burden of COPD
• know the risk factors of COPD occurrence
• Learn about the pathology, pathogenesis and Pathophysiology of COPD.
History of COPD
• A British medical textbook (1860s )→ C/P of chronic bronchitis as an advanced disease with repeated bronchial infections that ended in right-sided heart failure.
• 20th century, Ciba symposium of 1958 proposed definitions of chronic bronchitis and emphysema → concept of airflow obstruction.
• Chronic bronchitis: chronic productive cough for 3 months during each of 2 consecutive years (other causes of cough being excluded).
• Emphysema: an abnormal, permanent enlargement of the air spaces distal to the terminal bronchioles, accompanied by destruction of their walls and without obvious fibrosis
Definition & Overview
Common preventable & treatable disease
Characterized by persistent airflow limitation that is usually progressive
Associated with an enhanced chronic inflammatory response in the airways & the lung to noxious particles or gases
Exacerbations & comorbidities contribute to the overall severity in individual patients
COPD is a progressive disease The Downward Spiral in COPD
Burden of COPD
COPD is a leading cause of morbidity & mortality worldwide
The burden will increase in coming decades due to
continued exposure to risk factors & the aging of the
world’s population
COPD is associated with significant economic burden
Prevalence
Buist AS, McBurnie MA, Vollmer WM, et al. International variation in the prevalence of COPD (the BOLD Study): a population -based prevalence study. Lancet. 2007;370:741-750.
11.8% 8.5% 10.1% overall
COPD Misdiagnosis Is Common in Women
Chapman KR, Tashkin DP, Pye DJ. Gender bias in the diagnosis of COPD. Chest. 2001;119:1691-1695
Under diagnosis of COPD in the United States
• Over 12 million people in the United States have been diagnosed with COPD; another 12 million are estimated to be undiagnosed1
• Data from NHANES III indicate that approximately 24 million US adults have evidence of impaired lung function indicative of COPD2,3
• Most (70%) of patients with undiagnosed COPD are <65 years
70%
<Age 65
30%
≥Age 65
Percent With Undiagnosed COPD
1. NHLBI; available at http://www.nhlbi.nih.gov/health/public/lung/copd/index.html. 3. Mannino DM, et al. Proc Am Thorac Soc. 2007;4:502-306
2. Mannino DM, et al. MMWR Surveill Summ. 2002;51:1-16.
Mortality :
Global burden of Disease study: COPD rank
Murray and Lopez Lancet 1997
Mortality :
Global burden of Disease study: COPD rank
Mortality :
Global burden of Disease study
• Almost 90% of COPD deaths occur in low- and middle-income countries.
Economic and social burden
Economic • USA: Direct costs $ 29.5 billion & Indirect costs $ 20.4 billion
• Europe: 38.6 billion Euros
• In developing countries:
– Workplace & home productivity loss > Medical costs loss
Social • Disability-Adjusted Life year (DALY)
– 1990→ 12th leading cause of DALYs
– 2030 → 7th leading cause of DALYs
Risk factors for COPD Influence disease development & progression
Genes
• Gene-environmental interaction are the key for development of COPD.
• Susceptibility to COPD is not dichotomous variable and a range of susceptibility exits.
– Some smokers develop the disease earlier than others.
– Progression in COPD is very heterogeneous
Genes
• In patients with COPD
– emphysema represents accelerated ageing of the lung
– studies showed telomere shortening & dysfunction
• Telomerase null mice with short telomeres – increased emphysema
– double-strand DNA breaks
• after exposure to chronic cigarette smoke
• with evidence of reduced epithelial repair
• Family with a telomerase mutation
– have early-onset emphysema
Cumulative exposure to noxious particles is the key risk factor for COPD
Airway Responsiveness-Dutch Hypothesis
• Increased airways responsiveness and allergy are clinical phenotypes that predict increased susceptibility to cigarette smoke.
• Methacholine and histamine responsiveness precedes and predicts accelerated decline in lung function, thus a risk factor for COPD.*
• Increased airways responsiveness noted among 1st degree relatives of patients with early onset COPD.^
*Silva, GE et al. Asthma as a risk factor for COPD in a longitudinal study. Chest 2004; 126:59.
^Celedon JC et al. Bronchodilator responsiveness and serum total IgE levels in families of probands with severe early-onset COPD. Eur Respir J 1999; 14:1009.
Pathogenesis
Noxious agents
Biomass particles Occupational agents Pollutants
Genetic factors Resp. infection
These data are communicated for scientific purpose only. Confidential slide set 23
Apoptotic Pathways in COPD
Demedts IK, et al. Respir Res. 2006;7:53. Reproduced with permission from Biomed Central.
Survival factor Granzyme B Perforin
TNF-α sFasL
cytoplasm
nucleus
ER Stress
Apoptosome
Apaf 1 Procasp-9
Procasp-9 Casp-9
Casp-8 CAD CAD
ICAD
Casp-8
Procasp-8 Procasp-8
FADD Bid tBid
Bax
Bak
Cyt C
ER stress
DNA fragmentation
1 2
4
3
5
?
Fas
COPD Pathogenesis
These data are communicated for scientific purpose only. Confidential slide set
These data are communicated for scientific purpose only. Confidential slide set 25
Angiogenesis in COPD
Reprinted f rom International Journal of COPD, 2, Siafakas NM, et al., Role of angiogenesis and vascular remodeling in
chronic obstructive pulmonary disease, 453-462, Copyright 2007, with permission f rom Dove Medical Press Ltd.
extravasated
plasma proteins
Inflammatory cells (Mac, Neu, Epith, Lymph)
Release of angiogenic
mediators
Fibrinogen products
Inflammation Tissue
hypoxia
Airway
fibrosis
Mechanical
Injury
Increased
blood flow
Vessel growth
Angiogenesis
Vascular remodeling
Up-regulation of
Angiogenic factors
Shear stress
on the endothelium
COPD Pathogenesis
These data are communicated for scientific purpose only. Confidential slide set
Angiogenic and Angiostatic Factors in COPD
• Angiogenic CXC Chemokines, CC Chemokines, and Growth Factors:
– CXCL1
– CXCL5
– CXCL8
– CCL2
– VEGF
– bFGF
– Angiopoietin-1
– HGF
– EGF
• Angiostatic CXC Chemokines, CC Chemokines, and Growth Factors:
– CXCL10
– CXCL11
Siafakas NM, et al. Int J Chron Obstruct Pulmon Dis. 2007;2:453-462.
COPD Pathogenesis
Pathogenesis
Obstructive Bronchiolitis Emphysema
These data are communicated for scientific purpose only. Confidential slide set
Inflammatory Cells in Stable
COPD
Gamal Agmy 2-5-2014
Inflammation in COPD
These data are communicated for scientific purpose only. Confidential slide set 29
Neutrophils in COPD
Mucous hypersecretion
Serine proteases Neutrophil Elastase
Cathepsin G
Proteinase-3
O2-
MPO
LTB4, IL-8, GRO-
LTB4, IL-8
Adapted f rom Barnes PJ. N Engl J Med. 2000; 343: 269-280
Adapted f rom Barnes PJ, et al. Eur Respir J. 2003; 22: 672-688
Emphysema
Severe emphysema
Images courtesy R Buhl.
Inflammation in COPD
These data are communicated for scientific purpose only. Confidential slide set 30
Sputum Neutrophil Count Correlates With Declining Lung Function
Reproduced with permission of Thorax f rom “Airways obstruction, chronic expectoration and rapid decline of FEV1 in smokers are
associated with increased levels of sputum neutrophils,” Stanescu et al, Vol 51, Copyright © 1996; permission conveyed through
Copyright Clearance Center, Inc.
> 30 < 20
100
0
Ne
utr
op
hils in
iIn
du
ce
d s
pu
tum
(%
)
90
20 – 30
80
60
70
50
40
FEV1 decline (mL/year)
P<0.01
Inflammation in COPD
These data are communicated for scientific purpose only. Confidential slide set 31
Neutrophils Infiltrating Bronchial Glands in COPD
Saetta M, et al. Am J Respir Crit Care Med. 1997;156:1633-1639. Reproduced with permission f rom American Thoracic Society.
Copyright © 1997
Inflammation in COPD
These data are communicated for scientific purpose only. Confidential slide set 32
Reduction in Neutrophil Apoptosis in COPD
Adapted f rom Brown V, et al. Respir Res. 2009;10:24.
Apoptotic neutrophils
(arrows)
*P<0.05
*P<0.01
Morphology Tunel
NS
HS
COPD
60
50
40
30
20
10
0
Apoptotic
neutrophils [%]
Image courtesy of R Buhl.
NS: nonsmoking controls (n=9) HS:
healthy smoking controls (n=9)
TUNEL: the terminal transferase-
mediated dUTP nick end-labeling method
Inflammation in COPD
These data are communicated for scientific purpose only. Confidential slide set 33
Alveolar Macrophages in COPD
Phagocytosis
Cigarette smoke
Wood smoke
Elastolysis MMP-9, MMP-12
Cathepsins K, L, S
Emphysema
Steroid resistance
NO
ROS ONOO-
HDAC Steroid
response
Monocytes
MCP-1
GRO-
Neutrophils
LTB4
IL-8 GRO-
CD8+ Cells
IP-10 Mig I-TAC
Adapted f rom Barnes PJ. J COPD. 2004;1:59-70. Copyright © 2004 f rom "Alveolar Macrophages as Orchestrators of COPD" by
Barnes. Reproduced by permission of Taylor & Francis Group, LLC., www.taylorandfrancis.com
Emphysema
Severe emphysema
Images courtesy of R Buhl.
Numbers
Secretion
Inflammation in COPD
These data are communicated for scientific purpose only. Confidential slide set 34
Inflammatory Mediators in COPD – Summary
Cell
Neutrophils
Macrophages
T-cell
Epithelial cell
IL-8, TGF- 1, IP-10, Mig, I-TAC, LTB4, GRO- , MCP-1, MMP-9
Granzyme B, perforins, IFN-, TNF-
IL-8, IL-6, TGF-1 TGF-, IP-10, Mig, I-TAC, LTB4, GRO-, MCP-1, ROS, MMP-9
Serine proteases, TNF-, ROS, IL-8, MPO, LTB4
Selected Mediators
Barnes PJ, et al. Eur Respir J. 2003;22:672-888.
Inflammation in COPD
These data are communicated for scientific purpose only. Confidential slide set 35
Examples of Chemotactic Factors in COPD
Barnes PJ. Curr Opin Pharmacol. 2004;4:263-272.
Hill AT, et al. Am J Respir Crit Care Med. 1999;160: 893-898.
Montuschi P, et al. Thorax. 2003;58:585-588.
MCP-1
GRO-
Elastin
fragments
LTB4
IL-8
GRO-
Elastin
fragments
IP-10
Mig
I-TAC
Neutrophil Monocyte T-cell
Inflammation in COPD
These data are communicated for scientific purpose only. Confidential slide set 36
TNF- Has Pro-inflammatory Actions in COPD
Mukhopadhyay S, et al. Respir Res. 2006;7:125. Reproduced with permission f rom Biomed Central.
Oxidative stress
Activation of NF-B and AP-1
Activation of proinflammatory molecules e.g. VCAM-1, ICAM-1 and RAGE
Subcellular ROS production
TNF-
Antioxidants
e.g. GSH, Catalase
Scavenge free radicals,
detoxify cellular hydrogen peroxide and inhibit ROS generation
Proinflammation
+
+ +
+
+
+
+
-
-
Inflammation in COPD
These data are communicated for scientific purpose only. Confidential slide set
Modulation of Inflammation by
Histone Deacetylase (HDAC)
Inflammation in COPD
Gamal Agmy 2-5-2014
These data are communicated for scientific purpose only. Confidential slide set 38
Decreased HDAC Expression May Promote
Inflammation and Decrease Response to
ICS in COPD
Normal
Histone acetylation
Stimuli
Steroid sensitive
Histone hyperacetylation
nitration ubiquitination
oxidation
↑TNF
↑IL-8
↑GM-CSF
Stimuli
Steroid resistant
HAT
TF
HAT
TF
TNF IL-8 GM-CSF
Glucocorticoid
receptor
COPD
HDAC2
HDAC2
Glucocorticoid
peroxynitrite
Reproduced f rom Pharmacol Ther, Vol 116, Ito et al, “Impact of protein acetylation in inf lammatory lung diseases,” pp249-265.
Copyright © 2007, with permission f rom Elsevier.
Inflammation in COPD
These data are communicated for scientific purpose only. Confidential slide set 39
Pulmonary HDAC Levels Decrease With COPD Severity
Adapted f rom Ito K, et al. N Engl J Med. 2005;352:1967-1976.
S = COPD Stage
0
.5
1.0
1.5
2.0
Non-
smoker
N=11
P<0.001
HD
AC
2 e
xp
ressio
n (vs. la
min
A/C
)
P=0.04
P<0.001
P<0.001
S4
N=6
S0
N=9
S1
N=10 S2
N=10
■ ■
■
■
■
Inflammation in COPD
These data are communicated for scientific purpose only. Confidential slide set
Inflammation Leads to Small Airway Narrowing
• Acute and chronic inflammation suspected to contribute to COPD-
related small airway narrowing
• Airway narrowing leads to airway obstruction
• Narrowing results from several factors:
– Collagen deposition and increased lymphoid follicles in outer
airway wall
– Mucosal thickening of airway lumen
– Inflammatory exudate in airway lumen
Barnes PJ, et al. Eur Respir J. 2003;22: 672-688.
Inflammation in COPD
These data are communicated for scientific purpose only. Confidential slide set 41
Inflammation and Airway Destruction
Normal COPD
Reproduced f rom The Lancet, Vol 364, Hogg JC. "Pathophysiology of airf low limitation in chronic obstructive pulmonary
disease," pp709-721. Copyright © 2004, with permission f rom Elsevier.
Inflammation in COPD
These data are communicated for scientific purpose only. Confidential slide set 42
Exacerbations of Chronic Bronchitis and Inflammatory Cell Types
Saetta M, et al. Am J Respir Crit Care Med. 1994;150:1646-1652.
Maestrelli P, et al. Am J Respir Crit Care Med. 1995;152:1926-1931.
Barnes PJ. N Engl J Med. 2000;343:269-280.
COPD Exacerbation
Eosinophils
Eosinophils
T-Cells
Neutrophils
Cells Predominant in:
Induced sputum
Biopsy
Neutrophils
Inflammation in
COPD
These data are communicated for scientific purpose only. Confidential slide set 43
Clinical Impact of Inflammation in COPD
Tsoumakidou M, et al. Respir Res. 2006;7:80. Reproduced with permission f rom Biomed Central.
Increased Airway Inflammation
Increased mucous production
Airway wall thickening
Airway wall oedema
Bronchoconstriction
Airway narrowing
V’/Q’ Mismatching Hyperinflation
Worsening of gas exchange
Increased work of breathing
Increased oxygen consumption –
Decreased mixed venous oxygen
Cough, sputum, dyspnoea, Respiratory failure
Inflammation in COPD
These data are communicated for scientific purpose only. Confidential slide set 44
Inflammation: Clinical Consequences
Systemic
• Nutritional abnormalities and weight loss
• Hypoxaemia
• Skeletal muscle dysfunction
• Cardiovascular disease
• Depression
• Osteoporosis
• Anaemia
Agusti AG, et al. Eur Respir J. 2003;21:347-360.
Agusti AG. Proc Am Thorac. 2006;3:478-483.
Barnes PJ, Cell BR. Eur Respir J. 2009;33:1165-1185.
Pulmonary
Dyspnoea
Cough
Sputum production
Exacerbations
Inflammation in COPD
Inflammatory cells and mediators in COPD
Pathogenesis
The site of pathology in COPD
Mucus gland hyperplasia
Goblet cellhyperplasia
Mucus hypersecretion Neutrophils in sputum
Squamous metaplasia of epithelium
↑ Macrophages
No basement membrane thickening
Little increase in
airway smooth muscle
↑ CD8+ lymphocytes
Changes in Large Airways of COPD PatientsChanges in Large Airways of COPD Patients
Source: Peter J. Barnes, MD
Chronic bronchitis
Hyperplasia of mucous glands and infiltration of the airway wall with inflammatory cells
The site of pathology in COPD
Disrupted alveolar attachments
Inflammatory exudate in lumen
Peribronchial fibrosisLymphoid follicle
Thickened wall with inflammatory cells
- macrophages, CD8+ cells, fibroblasts
Changes in Small Airways in COPD Patients
Source: Peter J. Barnes, MD
The site of pathology in COPD
Endothelial dysfunction
Intimal hyperplasia
Smooth muscle hyperplasia
↑ Inflammatory cells
(macrophages, CD8+ lymphocytes)
Changes in Pulmonary Arteries in COPD Patients
Source: Peter J. Barnes, MD
The site of pathology in COPD
Emphysema
Emphysema
• Centriacinar – Focal destruction limited to the respiratory
bronchioles and the central portions of the acini.
– associated with cigarette smoking
– most severe in the upper lobes
• Panacinar
– involves the entire alveolus distal to the terminal bronchiole.
– most severe in the lower lung zones
– AAT deficiency
• Distal acinar or paraseptal – least common form and involves distal airway
structures, alveolar ducts, and sacs.
loss of alveolar walls and dilatation
of airspaces in emphysema
Natural History of Emphysema
• In non-smokers, maximal lung function
– attained at age 15 - 25 years
– after a variable plateau phase, declines ~ 20 -25 mL/year
• Lung Health Study (large longitudinal study)
– smoking is associated with an accelerated decline in lung function
• Females are at higher risk of lung damage
– related to smoke exposure than males
Fletcher C et al. 1977
FEV
1 (%
of v
alu
e at
age
25
)
100
25 50 75
Never smoked or not susceptible to smoke
Age (years)
Disability
Smoked regularly and susceptible to its effects
Death
0
25
50
75
Stopped at 65
Stopped at 45
Classical View of “Disease Progression” & “Disease Modification”
Pathogenic mechanisms
Pathological changes in COPD
Physiological abnormalities: Mucous hypersecretion & ciliary dysfunction
Airflow obstruction & hyperinflation
Gas exchange abnormalities
Pulmonary hypertension & systemic effects
Pathophysiology
Spectrum of COPD
Thank you