Etiology
The cause of idiopathic pulmonary fibrosis (IPF) is not known. One theory is that an unidentified insult causes damage to the alveolar epithelium, endothelium, and basement membrane and leads to the formation of scar tissue. Cigarette smoke, organic or metal dust, and pine wood dust have been implicated.[3] Gastroesophageal reflux disease, diabetes, infection, and genetic factors (e.g., familial pulmonary fibrosis) may increase risk.[3][4][5]
There is evidence to suggest an etiological role for genes associated with telomere length (25% to 30% cases), surfactant homeostasis (3% to 5%), and complex syndromes (3% to 5%) in the development of IPF.[16][19][20] Most cases (60%) have no known genetic cause.
Pathophysiology
Insults to the lung trigger a proinflammatory and profibrotic response that leads to an influx of macrophages, fibroblasts, and other inflammatory cells. However, fibroblasts and myofibroblasts show dysregulated and persistent activity, resulting in alveolar destruction, infiltration of the interstitial space with fibrosis, and architectural distortion of the lung parenchyma. The clinical features of IPF follow, with patients developing symptoms of progressive dyspnea and hypoxemia, pulmonary function testing with a pattern of restriction and impaired diffusion, and radiographic findings of honeycombing and traction bronchiectasis.
The formation of fibroblastic foci is a pathologic hallmark of IPF associated with continued extracellular matrix (ECM) deposition and progressive fibrosis.[21][22] Biopsy typically reveals fibroblastic foci in various stages of development adjacent to normal parenchyma, suggesting that disease results from repeated injury.[22] ECM deposition by fibroblasts also explains the relative paucity of active inflammatory infiltrates at surgical lung biopsy and the presence of ground-glass opacities on high-resolution computed tomography. It may also explain why anti-inflammatory therapies (e.g.,corticosteroids) have been ineffective in slowing the progression of IPF.
Most patients experience a steady decline, but a subset experience acute intermittent exacerbations (also of unknown cause) with diffuse alveolar damage superimposed on a background of usual interstitial pneumonia.[15] Whether these represent separate events or an accelerated form of the underlying process is unknown, but they are usually associated with abrupt and permanent declines in pulmonary function.
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