pulmonary pathology copd

Two major lung diseasesTwo major lung diseases

1. Obstructive1. Obstructive – airway diseasea) limitations of airflow

i) partial or complete obstruction at any level major causes

a) asthma – obstructiveb) emphysema – loss of elastic recoilc) chronic bronchitisd) Bronchiectasise) cystic fibrosisf) bronchiolitis

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1. Obstructive (con’t)1. Obstructive (con’t)

In these diseases:• TLC and FVC are normal or slightly increased• Marked by decreased expiratory flow (FEV1)• Ratio of FEV1 to FVC is decreased


Obstructive Lung Disease

1. Asthma

• “Characterized by episodic, reversible bronchospasm resulting from broncho constriction in response to various stimuli”

a) basis of hyperactivity of bronchi is unclear

i) thought to be from persistent/chronic bronchial inflammation of the airways

- eosinophils- mast cells, epithelial cells- macrophages- neutrophils, T-lymphocytes


b) clinicallyi) dyspneaii) coughiii) wheezing (expiratory)

- triggered via bronchospasmiv) 5% adults and 10%childrenv) status asthmaticus – fatal

outcomevi) between attacks

asymptomatic


ClassificationClassificationa) extrinsic asthma – initiated by type I

hypersensitivity reaction induced by

exposure to extrinsic antigen

b) 3 types of extrinsic asthmai) atopic (most common); 1st 2

decades; increased IgE; CD4 and T cells

- type I hypersensitivityii) occupational (many forms)iii) allergic bronchopulmonary

aspergillus’s (bacterial colonization followed by IgE antibodies)


• Major etiologic factors of asthmaMajor etiologic factors of asthma a) genetic predisposition to type I hypersensitivity (“atopy”)

i) precise cellular response is unknown

b) type 2 helper T (TH2) cells are important components of bronchial inflammation

i) release cytokines (IL)- promote inflammatory

response- stimulate B-cells to IgE

and other antibodiesc) (TH1) IFN-1 and IL-2

i) kill viruses, etc by activating macrophages and cytotoxic T

cells


• Both these two T cell types regulate one another

a) imbalance between these may be the key to asthma

b) when IFN-1 is altered and fails to “check” TH2 airway

inflammationi) patients with allergic asthma

have increased TH2- etiology is unclear

ii) transcription factor T-bet is required for TH1 cell differentiation

- asthmatics are deficient in this transcription factor


• Airway remodelingAirway remodelinga) seen several years prior to onset of symptoms

i) ADAM-33 gene linkage to asthma

- found in bronchial SM- found in lung fibrobalsts

ii) ADAM-33 polymorphism causes - proliferation of bronchial SM

cells and fibrobalst, thereby contributing to:

bronchial hyperactivity subepithelial fibrosis

iii) Mast cells


iv) thickening of basement membrane

v) edemavi) size of submucosal glandsvii) muscular hypertrophyviii) inflammatory infiltrate in

bronchial walls (eosinophils and Mast cells)


• Atopic asthmaAtopic asthmaa) most common type of asthma

i) childhoodii) triggered by environmental

antigen (dust, pollen, food, etc)iii) positive family history is

commoniv) attacks usually preceded by

allergic rhinitis, utricaria or eczema


• Proposed progressionProposed progressiona) sensitization to allergen in lung

results in b) TH2 synthesis/activation c) release of cytokines (IL-4, IL-5) d) promote IgE by B-cells, growth of

Mast cells (IL-4), and eosinophils (IL-5)

e) “acute phase response” (4-8 hrs)f) initial Mast cell reactions occur on mucosal surface releasing

mediatorsi) opens mucosal tight junctions

- promotes antigen movement to mucosal Mast cells

ii) stimulation of parasympathetics- bronchoconstriction


g) acute phase begins within minutes of exposure

i) edemaii) mucus secretioniii) hypotension (rare occurrence)

h) Mast cells release other mediatorsi) other leukocytes

- neutrophils- lymphocytes- monocytes- basophils- eosinophils (mainly – IL-5)

i) these inflammatory cells set stage for “late phase reaction” (12-24 hrs)www.freelivedoctor.com

• Late phase reactionLate phase reactiona) induced by leukocyte chemotaxis induced by Mast cellsb) other cells can also produce

mediatorsi) vascular endothelial cellsii) airway epithelial cells

- produce cytokines in response to infections, drugs, gases.

- eotaxin chemoattractant and activator of eosinophils

- basic protein of eosinophils causes epithelial

damage bronchoconstriction


• MediatorsMediatorsa) leukotrienes C4 D4 E4

bronchoconstriction, vascular permeability, mucus

secretionb) Ach SM constriction (via

muscarinic)c) histamine PGD2 PAF (serotonin)

bronchoconstrictiond) IL-1, TNF, IL-6, eotaxin, NO,

endothelin

• Nonatopic (i.e., intrinsic) asthmaNonatopic (i.e., intrinsic) asthmaa) usually triggered by respiratory viral infection (rhino-, parainfluenza)b) family history uncommon


c) serum IgE are normald) no associated allergiese) exercisef) cold

• Theory Theory hyperirritability of hyperirritability of airwaysairways

a) virus lowers threshold of vagal receptors to irritants bronchoconstriction•Occupational induced asthmaOccupational induced asthma

a) fumes (epoxy resins, plastic)b) gases (toluene) c) dust (wool, wood, platinum)d) penicillin productse) formaldehyde


• Drug induced asthmaDrug induced asthmaa) aspirin

• Since so many patients have overlapping characteristics and IgE, this classification is no longer clinically applicable.

• Asthma developing early in life has strong allergic (i.e., extrinsic) component, whereas developing late in life more often intrinsic (i.e., nonatopic)


• Clinical Coursea) labors to get air in and can’t exhale

wellb) Bronchodilators and corticosteroids

• Status asthmaticus – last days to weeks and does not respond to therapy

a) hypercapniai) acidosis may be fatal


COPDCOPD

• Affects more than 10% of US adultAffects more than 10% of US adult population and is 4th leading cause population and is 4th leading cause ofof death in USdeath in US

• Irreversible airflow obstruction of Irreversible airflow obstruction of COPDCOPD distinguishes it from asthma (largelydistinguishes it from asthma (largely reversible)reversible)

• Refer to emphysema and chronic Refer to emphysema and chronic bronchitis (smoking common to bronchitis (smoking common to both)both)


2. Emphysema2. Emphysema• Permanent enlargement of Permanent enlargement of airspacesairspaces distal to terminal bronchioles and is distal to terminal bronchioles and is accompanied by destruction of theiraccompanied by destruction of their wallswalls• Overinflation Overinflation enlargement of enlargement of airspacesairspaces w/no destructionw/no destruction

a) compensated overinflation due to contralateral pneumonectomy

• Morphological definition (based on Morphological definition (based on areaarea w/in lobule)w/in lobule)


Types of emphysemaTypes of emphysemaa) Panacinar (panlobular) emphysema

i) uniformly enlarged aciniii) lower lung zonesiii) 1-antitrypsin definciency

b) Centrilacinar emphysemai) dilation upstream with normal

distal portionsii) more common than panacinar

(~ 95% of cases)iii)more common/severe in upper

lobes- contain black pigmentwww.freelivedoctor.com

Centriacinar (con’t)Centriacinar (con’t)

iv) in severe disease distal acini may be involved differentialte from panacinar difficult

v) seen in heavy smokers, often in association with chronic

bronchitis

c) Distal Acinar (paraseptal) emphysema

i) proximal acini normal and distal part most involvedii) upper half of lungs/near pleuraiii) associated with spontaneous

pneumothorax in the young


d) irregulari) acini irregularly involvedii) airspace enlargement with

fibrosisiii) may be the most common

- most autopsies show some scarring from healed

inflammationiv) most are asymptomatic and

not clinically significant

• Centriacinar and panacinar are the Centriacinar and panacinar are the onesones that cause clinical airflow that cause clinical airflow obstructionobstruction


IncidenceIncidence• Common disease (~50% of patients on autopsy) – asymptomatic• Centrilobular – most common and severe in men• Clear association with cigarette smoking• 5th and 8th decade becomes disabling• Chronic mild inflammation of lung architecture

a) mediators• Centriacinar and panacinar

a) genesis not completely understoodb) 2 Theories

i) protease-antiprotease imbalance

ii) oxidant-antioxidant imbalance


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• Protease-antiprotease HypothesisProtease-antiprotease Hypothesis a) patients with deficiency of

antiprotease, 1-antitrypsin (AAT) have increased tendency to develop emphysema

b) about 1% of all patients have this defect

c) 1-antitrypsin major inhibitor of proteases, particularly elastase

d) homozygous patients w/genetic AAT deficiency develop emphysema

e) PiMM normal phenotype for 1- antitrypsin

f) PiZZ common phenotype for AAT deficiency


• Sequence:Sequence:a) neutrophils (primary source of

proteases) sequestered in pulmonary capillaries (lower zones primarily)

i) smoking neutrophils & macrophages

ii) CD8+ T cells cause direct damage and/or recruit

macrophagesb) few gain access to alveolar spacec) release of proteolytic enzymes +

ROSd) low levels of 1-antitrypsin

damage to elastin (via elastase)e) emphysema ensues


• Oxidant-antioxidant hypothesisOxidant-antioxidant hypothesis Lung has antioxidants

a) superoxide dismutaseb) glutathione

• Smoke has many oxidant species Smoke has many oxidant species whichwhich deplete these normal scavengersdeplete these normal scavengers

a) activated neutrophils also has ROS• Oxidative injury depletes or Oxidative injury depletes or destroysdestroys native antiproteasesnative antiproteases

a) ”Functional” 1- antitrypsin definciency even though blood enzyme is not deficient


• Smoking (ROS) and Smoking (ROS) and 11- antitrypsin - antitrypsin deficiency SEVERE DAMAGE!!!deficiency SEVERE DAMAGE!!!

• Signs: a) “Barrel” chested and dyspneic b) Hyperventilation c) Normal blood gases (- “pink puffers”)• Some patients have other pulmonary disease

a) do not hyperventilate and become cyanotic

i) “blue-bloaters” (chronic bronchitis)b) death from Right CHF, coma, acidosis, pulmonary fatiguewww.freelivedoctor.com

• OtherOthera) Obstructive overinflation

i) “ball valve” affectii) sub total obstruction by tumor,

etciii) classic example:

- congenital lobar overinflation

- - hypoplasia?b) Bullous

i) large subpleural blebs (> 1-2 cm dia)

ii) apical regionsiii) may cause pneumothorax

c) interstitiali) air

- alveolar tears, etc.


Chronic BronchitisChronic Bronchitis• Common in smokers (> 90%), passive inhalation of smoke and smog-ridden cities• Definition: Based on clinical grounds. “persistent productive cough for at least 3 consecutive months and at least 2 consecutive years”• Occurrence: (Increased mucus production)

a) simple chronic bronchitisi) raises mucoid sputumii) airflow not obstructed

b) chronic mucopurulent bronchitisi) mucus and pusii) from secondary infection


c) chronic asthmatic bronchitisi) bronchitis with intermittent

hypersensitivity and asthmatic constriction (difficult to diagnose from atopic asthma)

d) chronic obstructive bronchitisi) difficult outflow as measured by

pulmonary function test• Involves large bronchiolesInvolves large bronchioles• Small airway disease (bronchiolitis)Small airway disease (bronchiolitis) resulting from fibroses and resulting from fibroses and inflammation inflammation may lead to (chronic bronchitis)may lead to (chronic bronchitis)

a) increase goblet cells in small bronchi and bronchioles (i.e., bronchiolitis obliterans)


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PathogenesisPathogenesis• Hypersecretion of mucusHypersecretion of mucus

a) beginning in large airwaysb) smoking single most important

causative factor• Eosinophils are lackingEosinophils are lacking• Increased transcription of mucin Increased transcription of mucin genegene (MUC5AC) by cigarette smoke(MUC5AC) by cigarette smoke

a) enlargement of mucus secreting glands (major consequence)

b) hyperplasia and hypertrophy of mucus secreting cells and increase proportion of mucus to serous secretions.

i) Reid index – size of mucus glands


• Cough with sputum may last Cough with sputum may last indefinitelyindefinitely without respiratory obstructionwithout respiratory obstruction• usually accompanies emphysema usually accompanies emphysema • Some patients develop COPD withSome patients develop COPD with outflow obstructionoutflow obstruction

a) hypercapniab) hypoxemiac) exertional dyspnead) cyanosis – “blue-bloaters”

• Progression of diseaseProgression of diseasea) pulmonary hypertension (Cor

Pulmonale)b) cardiac failure

• Metaplasia of bronchial epitheliumMetaplasia of bronchial epithelium


BronchiectasisBronchiectasis• Permanent dilation of bronchi and Permanent dilation of bronchi and bronchioles caused by destruction bronchioles caused by destruction of theof the muscle and elastic supporting muscle and elastic supporting tissuetissue resulting or associated withresulting or associated with chronic necrotizing infection.chronic necrotizing infection.• Is Is notnot primary disease but primary disease but secondary tosecondary to persisting infection or obstruction persisting infection or obstruction causedcaused by variety of conditions.by variety of conditions.• Cough and purulent sputumCough and purulent sputum• Irreversible Bronchial dilationIrreversible Bronchial dilation


• Most often caused by:Most often caused by:a) bronchial obstruction

i) tumorsii) foreign bodiesiii) localized to obstructed lung

segmentb) congenital or hereditary condition

i) cystic fibrosisii) immunodeficiency states (IgE

deficiency) – repeated infections

iii) Kartagener syndrome (Structural abnormalities of cilia (decreased mucocilliary clearance)

- Sterility in males/females


c) necrotizing pneumonia (S. aureus, K. pneumoniae)

i) post tubercular bronchiectasis significant cause of morbidity
