Platelet-Derived Growth Factor and Transforming Growth Factor β1 Regulate ARDS-Associated Lung Fibrosis Through Distinct Signaling Pathways

Background/Aims: Severe acute lung injury (ALI) often develops into acute respiratory distress syndrome (ARDS). Previous studies have shown that platelet-derived growth factor (PDGF) and transforming growth factor beta 1 (TGF beta 1) participate in the pathogenesis of ARDS by stimulation of fibroblast proliferation, leading to the development of pulmonary fibrosis. However, the exact pathways downstream of PDGF and TGF beta receptor signaling have not been completely elucidated. Method: We treated human lung fibroblasts (HLF) with PDGF, or TGF beta 1, or combined, and examined the activation of p38 MAPK, p42/p44 MAPK and SMAD3. We used a specific inhibitor PD98059 to antagonize phosphorylation of p42/p44 MAPK, or used a specific inhibitor SN203580 to antagonize phosphorylation of p38 MAPK, or used a specific inhibitor SIS3 to antagonize phosphorylation of SMAD3. We then examined the effects of these inhibitors on the activation of collagen I and alpha-smooth muscle actin (alpha-SMA) induced by PDGF or TGF beta 1 stimulation. Results: PDGF activated p38 MAPK and p42/p44 MAPK, but not SMAD3 in HLF cells. TGF beta 1 activated p38 MAPK and SMAD3, but not p42/p44 MAPK in HLF cells. Activation of p38 MAPK by either PDGF or TGF beta 1 induced alpha-SMA but not collagen I in HLF cells, while activation of p42/p44 MAPK by PDGF induced collagen I but not alpha-SMA in HLF cells. Activation of SMAD3 by TGF beta 1 did not affect either collagen I or alpha-SMA in HLF cells. Conclusion: PDGF and TGF beta 1 regulate ARDS-associated lung fibrosis through distinct signaling pathway-mediated activation of fibrosis-related proteins. Treatments with both PDGF and TGF beta 1 antagonists may result in a better anti-fibrotic outcome for ALI-induced lung fibrosis. Copyright (C) 2015 S. Karger AG, Basel