Diffuse pulmonary disease

classification Obstructive disease(airway disease)-characterised by limitation of airflow usually resulting from an increased resistance caused by partial or complete obstruction at any level. Restrictive lung disease characterised by reduced expansion of lung parenchyma accompanied by decreased total lung capacity

Major diffuse obstructive disorders are: 1.Emphysema 2.Chronic bronchitis 3.Bronchiectasis 4.Asthma

Restrictive defects occur in 2 general conditions:- 1.Chest wall disorders in the presence of normal lungs eg. Severe obesity,disease of pleura,neuromuscular disorders like Guillan- Barre syndrome that affects respiratory muscles 2.Acute or chronic interstitial lung disease eg. Pneumoconiosis, ARDS,etc.

Obstuctive pulmonary disease Chronic bronchitis and emphysema Usually both co-exist,have a common etiological factor i.e. chronic smoking. Both together are grouped under “COPD” Irreversible airflow obstruction unlike asthma where it is usually reversible

Emphysema Definition: Emphysema is characterised by abnormal permanent enlargement distal to the terminal bronchioles accompanied by destruction of their wall without obvious fibrosis. Overinflation—no destruction of wall eg. Compensatory overinflation of opposite lung after unilateral pneumonectomy

Types of emphysema Classified according to its anatomic distribution within the lobule(lobule – acinus-distal to terminal bronchioles and a cluster of 3-5 acini forms a lobule) 1.Centri-acinar-most common 2.Panacinar –next common 3.Distal acinar 4.Irregular

Centriacinar emphysema Respiratory bronchiole affected;distal alveoli spared Therefore,in the same lobule, normal and emphysematous change is seen Common in upper lobes,esp. apical segment In severe cases distal part of acinus also involved;hence difficult to differentiate from panacinar Commonest cause:smoking

Panacinar emphysema Uniform enlargement from respiratory bronchiole to terminal alveoli Common in lower lung zones Associated with alpha-1-anti-trypsin deficiency

Distal acinar(paraseptal) emphysema Distal part of acinus involved More common adjacent to pleura Adjacent to areas of fibrosis/scarring or atelectasis More severe in upper half of lung Multiple contiguous enlarged airspaces,that range in diameter from 0.5mm->2.0cms.,sometimes forming cyst-like structures(bullae)

Irregular emphysema Irregular involvement of acinus Usually associated with scarring eg. Healed inflammatory lesion Asymptomatic(commonest)

Pathogenesis Emphysema results as an imbalance of: 1.Protease-antiprotease 2.Oxidant-antioxidant

Protease-antiprotease imbalance hypothesis Patients with a genetic deficiency of antiprotease,alpha1-antitrypsin deficiency have a markedly enhanced tendency to develop emphysema which is compounded with smoking Incidence of alpha-1-antitrypsin deficiency – 1% of all patients with emphysema

The following sequence is postulated:- 1.Neutrophils,the principle source of cellular proteases, are normally sequestered in peripheral capillaries and in lungs and a few gain access to the alveolar spaces 2.Any stimulus that increases either the number of leukocytes(neutrophils and macrophages) in the lung or the release of their protease containing granules  increases proteolytic activity

3) With low levels of serum alpha-1- antitrypsin,elastic tissue destruction is unchecked and emphysema results

In people with normal amounts of alpha-1- antitrypsin deficiency:- In smokers,neutrophils and macrophages accumulate in alveoli due to chemoattractant effect of nicotine and effect of reactive O2 species contained in smoke

These activate the transcription factors which switches on genes thatencode TNF & chemokines including IL-8. These in turn attract and activate neutrophils 2.Accumulated neutrophils are activated and release their granules,rich in a variety of cellular proteases(neutrophil elastase,proteinase3 and cathepsin G) resulting in tissue damage

3. Smoking also enhances elastase activity in macrophages; macrophage elastase is not inhibited by alpha-1-antitrypsin and can digest this anti-protease(i.e.alpha-1- antitrypsin) Also matrix metalloproteinases derived from macrophage and neutrophils have a role in tissue destruction

Smoking also has a role in perpetuating the oxidant-antioxidant imbalancein the pathogenesis of emphysema Normally the lung contains a healthy complement of antioxidants(superoxide dismutase,glutathione) that keeps oxidative damage to a minimum

Tobacco smoke contains abundant reactive O2 species(free radicals) which deplete this antioxidant mechanism thereby inciting tissue damage. Activated neutrophils also add to the pool of reactive O2 species in the alveoli A secondary consequence of oxidative injury is inactivation of native antiproteases,resulting in functional alpha-1- antitrypsin deficiency even in patients without enzyme deficiency

Oxidant –antioxidant imbalance Smoking also has a role in perpetuatingthe oxidant antioxidant imbalance in the pathogenesis of emphysema Normally the lung contains a healthy complement of antioxidants(superoxide dismutase,glutathione)that keeps oxidative damage to a minimum

Tobacco smoke contains abundant reactive O2 species(free radicals)which deplete this antioxidant mechanism,thereby inciting tissue damage. Activated neutrophils also add to the pool of rective O2 species in the alveoli A secondary consequence of oxidative injury is inactivation of native antiproteases, resulting in functional alpha1antitrypsin deficiency even in patients without enzyme deficiency

Morphology Gross: 1)Panacinar:- pale voluminous lungs that obscure the heart when anterior chest wall is opened at autopsy. 2)Centriacinar:-less impressive;less voluminous;upper two-third of lung affected

Microscopy Thinning and destruction of alveolar walls In advanced disease,adjacent alveoli become confluent creating large air spaces

Clinical course Dyspnoea-steadily progressive Weight loss Pulmonary function tests show decreased FEV with normal or near normal FVC Barrel-chest Pink –puffers,if associated with chronis bronchitis—”blue-bloaters”

In all secondary pulmonary hypertension develops gradually because of hypoxia- induced pulmonary vascular spasm andloss of pulmonary capillary surface from alveolar destruction Death due to either pulmonary failurewith respiratory acidosis,hypoxia and coma OR right heart failure(cor pulmonale)

Chronic bronchitis Common among cigarette smokersand urban dwellers in smog ridden cities Incidence: % of individual in the age group of years Diagnosis on clinical grounds i.e person with persistent productive coughfor at least 3 consecutive months in at least 2 consecutive years

It occurs in several forms 1.Most patients have simple chronic bronchitis: productive cough with mucoid sputum; no air flow obstruction 2.Chronic asthmatic bronchitis- some patients withchronic bronchitis will have hyper-responsiveairwayswith intermittent bronchospasm and wheezing

3)a few bronchitic patients,esp. heavy smokers, develop chronic outflow obstruction,usually with emphysema and these are said to have chronic obstructive bronchitis

Pathogenesis The distinctive feature of chronic bronchitis is hypersecretion of mucus,beginning in the large airways Cause :-cigarette smoking & inhalation of sulfur dioxide and nitrogen dioxide These irritants cause hypertrophy of mucous glands in the trachea and main bronchi and goblet cell metaplasia in the surface epithelium lining smaller bronchi and bronchioles

Also irritants cause inflammation with infiltration of CD8+ T-cells,macrophages and neutrophils(no eosinophils are seen unlike as in asthma) The morphological basis of airflow obstruction is more peripheral and results from:-1)so-called “small airway disease” induced by goblet cell metaplasia with mucus plugging of the bronchiolar lumen,inflammation & bronchiolar wall fibrosis and 2) co-existent emphysema

It is postulated that many of the respiratory effects of environmental irritants are mediated by T-cell cytokines such as IL-3 There has been some experiment donein which some genetic changes has been implicated as a result of exposure to tobacco smoke

Morphology Gross:mucosal lining hyperaemic and edematous/swollen.The mucosa is covered by mucinous and mucopurulent secretions. Micro:In larger bronchi and trachea-hypertrophy of the mucous glands.(Reid index-normally 0.4) Chronic inflammatory cells in the wall of the bronchi Chronic bronchiolitis:goblet cell metaplasia,mucus plugging,inflammation and peribronchiolar fibrosis  obstruction to airway.

Clinical course Chronic cough with expectoration May develop COPD – patient will then have hypercapnia, hypoxemia and in severe cases cyanosis(blue bloaters) With progressive disease –pulmonary hypertension and cardiac failure