Figure. Three-stage description of the pathogenesis of idiopathic pulmonary fibrosis.

In the predisposition stage, recurrent environmental insults lead, in genetically predisposed individuals, to increased turnover of alveolar type II cells, ER-stress-mediated activation of UPR, apoptosis, and progressive telomere attrition. In the activation stage, accumulation of a lifetime insults leads to pathological alterations of the lung epithelium, such as senescence reprogramming, and release of profibrotic mediators (eg, TGFβ, Wnts, and PDGFβ) by the alveolar epithelium. These mediators, either directly or indirectly via leucocytes, activate fibroblasts to deposit pathological matrix. In the progression stage, the pathological matrix promotes additional differentiation of fibroblasts to myofibroblasts, which deposit more matrix and further activate fibroblasts in a feed-forward loop of lung remodelling. ER=endoplasmic reticulum. UPR=unfolded protein response. PDGF=platelet-derived growth factor. TGF=transforming growth factor.