The Lung Part 4 Flashcards
Restrictive lung disorder occur in what two general conditions?
1) chronic interstitial and infiltrative disease like pneumoconiosis and interstital fibrosis of unknown etiology
2) chest wall disorders (neuromuscular diseases like poliomyelitis, severe obesity, pleural diseases and kyphoscoliosis)
Chronic interstitial pulmonary diseases are a heterogenous group of disorders characterized by
- inflammation and fibrosis of the pulmonary interstitium!
- Many entities are of unknown cause/pathogenesis
- some have intra-alveolar and interstitial component
- RESTRICTIVE LUNG DISEASE
Symptoms/abnrmalities of chronic interstitial pulmonary diseases
- Dyspnea, tachypnea, end-inspiratory crackles and eventual cyanosis without wheezing or airway obst.
- reductions in diffusion capacity, lung voilume and lung compliance
- Chest Xray: small nodules bilaterally, irregular lines or GROUND-GLASS shadows
- eventually will have pulm HTN and RHF associated with cor pulmonale
- can distinguish entities early but later cannot bc all result in scarring and gross destruction of lung (end stage lung or honey comb lung)
Idiopathic pulmonary fibrosis (IPF)
- Refers to clinicopathologic syndrome marked by progressive interstitial pulmonary fibrosis and respiratory failure (cryptogenic fibrosisng alveolitis)
- also called usual interstitial pneumonia (histo pattern) which is also seen in connective tissue diseases, chronic HS pneumonia, and asbestosis
Fibrosing interstitial lung disease
- Usual interstitial pneumonia (idiopathic pulm fibrosis)
- Nonspecific interstitial pneumonia
- Cryptogenic organizing pneumonia
- Connective tissue disease-associated
- Pneumoconiosis
- Drug reactions
- Radiation pneumonitis
Granulomatous interstitial lung disease
- Sarcoidosis
- HS pneumonitis
Smoking related interstitial lung diseases
- Desquamative interstitial pneumonia
- Respiratory bronchiolitis-associated interstitial lung disease
Other Interstitial lung diseases
- Eiosinophilic (own category)
- Langerhans cell histiocytosis
- Pulmonary alveolar prteinosis
- Lymphoid interstitial pneumonia
Pathogenesis of Idiopathic Pulmonary fibrosis (IPF)
-cause unknown but think that fibrosis arises in genetically predisposed patients prone to aberrant repair of recurrent alveolar epithelial cell injuries caused by env exposures
Implicated factors in the pathogenesis of Idiopathic pulmonary fibrosis
-Environmental factors
-Genetic factors
Age
Environmental factors and pathogenesis of IPF
- cigarette smoking increases IPF risk by several folds!
- metal fumues, wood dust or certain occupations like farming, hair-dressers and stone-polishing
- toxins causes recurrent alveolar epithelial cell damage
- Also associated with gastric reflux
Genetic factors and pathogenesis of Interstitial pulmonary fibrosis (IPF)
- many smokers or people exposed to other toxins don’t develop IPF– means genetic factors at play
- Germline loss of function mutations in the TERT and TERC genes which encode components of TELOMERASE
- 15% familial IPF and 25% sporadic IPF associated with abnormal telomerase shortening in peripheral blood lymphocytes
- cause of shortening unknown and unknown if these people have shortening in their alveolar epithelial cells
- Other rare forms of IPF associated with gene mutations encoding surfactant leading to unfolded protein response in type II pneumocytes–makes pneumocytes more sensitive to env insults leading to cellular dysfunction and injury
- 1/3 of IPF associated with common genetic variant that increases secretion of MUC5B (mucin that makes alveolar epithelial cells susceptible to injury or exaggerate events that lead to fibrosis)
Age and pathogenesis of IPF
- Older individuals>50
- Maybe due to age related telomere shortening but unknown if this is true
Pathogenesis of IPF summary (from figure)
- Env factors are potentially injurious to alveolar epithelium interact with genetic or aging factors that place epithelium at risk to create persistent epithelial injury
- Factors released from injured/activated epithelium and factors released from innate and adaptive immune cells activate interstitial fibroblasts
- Interstitial fibroblasts exhibit signaling abnormalities that lead to increased signaling through PI3K/AKT pathway
- Activated fibroblasts synthesize and deposit collagen leading to interstitial fibrosis and resp failure
How does alveolar epithelial cell damage translate into interstitial fibrosis in IPF?
- unknown but proposed theory 1: Injured epithelial cells are source of profibrogenic factors like TGF-B
- theory 2: innate and adaptive immune cells produce factors as part of host response to epithelial cell damage
- theory 3: abnormalities in fibroblasts themselves involve changes in intracellular signaling and features reminiscent of epithelial mesenchymal transition; causal link to fibrosis not established
Interstitial pulmonary fibrosis Gross morphology
pleural surface of lung cobblestones bc of retraction of scars along interlobular septa; firm, rubbery white areas of fibrosis especially in LOWER lobes, SUBPLEURAL regions and INTERLOBULAR SEPTA
Interstitial pulmonary fibrosis Microscopic morphology
- PATCHY INTERSTITIAL FIBROSIS
- early lesions: fibroblastic proliferation (FIBROBLASTIC FOCI)–with time become collagenous and less cellular
- dense fibrosis causes destruction of alveoli and forms cystic spaces lined by hyper plastic type II pneumocytes or bronchiolar epithelium (HONEYCOMB FIBROSIS)
- mild/moderate inflammation in fibrotic areas with mostly lymphocytes with few plasma cells, neutrophils, eosinophils and mast cells
- Foci of squamous metaplasia and smooth muscle hyperplasia may be present along with pulmonary arterial hypertensive changes (intimal fibrosis and medial thickening)
- may have diffuse alveolar damage superimposed in acute exacerbations on these chronic changes
Clinical course of of IPF
- starts w/ gradually increasing DYSPNEA ON EXERTION and dry cough
- 55-75 yrs at presentation
- Hypoxemia, CYANOSIS, clubbing late in course
- unpredictable course
- Usually gradual deterioration in pulm status despite treatment with immunosuppressive drugs like corticosteroids, cyclophosphamide, azathioprine
- Other IPF patients have acute exacerbations of underlying disease and follow rapid downhill clinical course
- median survival only 3 yrs after Dx! Lung transplant only definitive tx!
