Fig. 2.

Rigid fibrotic niche accelerates the progression of lung fibrosis. a At homeostasis, communications between alveolar cells maintain the tissue integrity. b (a) Upon mechanical stress the ATP released by AECs promote Endo-MT of endothelial cells; (b) ATP also interact with P2X7R on macrophage to induce IL-1B production; (c) mtDNA released by AECs activate local fibroblasts; (d) TGF-β produced by AECs lead to the Endo-MT of endothelial cells and transformation of fibroblasts; (e) endothelial cells transform to mesenchymal cells via Endo-MT; (f) mechanical stressed niche contracts fibroblasts to activate TGF-β stored in the ECM and release ATP as pro-fibrotic mediator; (g) When subjected to mechanical stress machrophges will release IL-8 to activate mesenchymal progenitor cells (MPCs) and IL-6 to shifts acute inflammation into a more chronic pro-fibrotic state; (h) Mast cells response to mechanical stress by degranulation which subsequently release pro-fibrotic mediators such as tryptase, chymase and TGF-β to promote fibroblasts activation; (i) Alveolar stem cells -AECIIs under sustained elevated mechanical tension could liberate TGF-β stored in the ECM to promote fibroblasts activation; (j) mechanical stress affects the lipid metabolism in endothelial cells and contribute to Endo-MT, also static mechanical stress reduce the production of surfactant phospholipids in AECIIs; (k) Epigenetic regulation including DNA methylation, histone modification, non-coding RNAs and chromatin remodeling promote lung fibrosis by activating the transcription pro-fibrotic genes and miRNAs regulation and modification