Interactive model of TGF-β, IGF, PAPP-A and cellular senescence in IPF
(A) TGF-β-induced IGF signaling in early stages of fibrosis through increases in IGF-I and PAPP-A expression promotes proliferation and survival of myofibroblasts, the major producer of ECM.
(B) Senescence markedly augments PAPP-A expression and activity in lung SASP while TGF-β-induced expression of IGF-I is retained. Thus, TGF-β, IGF, PAPP-A and senescence appear to interact to promote a pro-fibrotic, anti-apoptotic environment, which could contribute to unresolved pulmonary fibrosis in IPF. In addition, active PAPP-A associated with EVs that are produced by senescent lung fibroblasts and released into the surrounding environment has the potential to participate in crosstalk with other cells in the lung.