The pathogenesis of idiopathic pulmonary fibrosis. 1 – In an initiating phase, there is lung alveolar epithelial damage with loss of the normal lung architecture and disruption of the basement membrane across which gas exchange takes place. With further epithelial damage and apoptosis, comes upregulation of epithelial integrins, such as αvβ6, and a phase of fibroproliferative repair dominates – driven by high levels of TGF-β. Released in an inactive form, this cytokine requires an activation step facilitated by integrins that bind the Arg-Gly-Asp (arginine-glycine-aspartic acid; RGD) motif of pro-TGFβ and promote its cleavage and activation. 2 – Locally activated TGF-β drives the recruitment of fibroblasts and a feed-forward cycle of further TGF-β production. 3 – Under these conditions, fibroblasts differentiate into myofibroblasts that express high levels of integrin αvβ6, are resistant to apoptosis and lay down a collagen matrix. 4 – Once collagen has been laid down in a lung, the architecture of which is already distorted, gas exchange is no longer efficient. There is a change in the vasculature of the lung parenchyma with both fall-out of blood vessels and neo-angiogenesis driven by local production of vascular endothelial and platelet derived growth factors (VEGF and PDGF). At this final phase, the lung is irreversibly scarred. AEC = alveolar epithelial cell; PDGF = platelet-derived growth factor; TGF-β = transforming growth factor beta; TNF-α = tumour necrosis factor alpha; VEGF = vascular endothelial growth factor.



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