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

Abstract

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 β1 (TGFβ1) 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 TGFβ receptor signaling have not been completely elucidated. Method: We treated human lung fibroblasts (HLF) with PDGF, or TGFβ1, 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 α-smooth muscle actin (α-SMA) induced by PDGF or TGFβ1 stimulation. Results: PDGF activated p38 MAPK and p42/p44 MAPK, but not SMAD3 in HLF cells. TGFβ1 activated p38 MAPK and SMAD3, but not p42/p44 MAPK in HLF cells. Activation of p38 MAPK by either PDGF or TGFβ1 induced α-SMA but not collagen I in HLF cells, while activation of p42/p44 MAPK by PDGF induced collagen I but not α-SMA in HLF cells. Activation of SMAD3 by TGFβ1 did not affect either collagen I or α-SMA in HLF cells. Conclusion: PDGF and TGFβ1 regulate ARDS-associated lung fibrosis through distinct signaling pathway-mediated activation of fibrosis-related proteins. Treatments with both PDGF and TGFβ1 antagonists may result in a better anti-fibrotic outcome for ALI-induced lung fibrosis.

Fibrocytes Ameliorate Acute Lung Injury by Decreasing Inflammatory Cytokine and Chemokine Levels and Reducing Neutrophil Accumulation in the Lung

“…Fibrocytes are a type of cell that is related to inflammation and wound healing [15, 16]. Fibrocytes are closely associated with lung diseases and inflammation [14, 16, 28, 41, 42]. Whether fibrocytes directly participate in ALI has not been studied previously.…”

Mesenchymal Stem Cells Alleviate LPS-Induced Acute Lung Injury in Mice by MiR-142a-5p-Controlled Pulmonary Endothelial Cell Autophagy

“…The cellular pathology of ALI includes breakdown of alveolar-capillary membrane integrity, excessive neutrophil migration and production and secretion of pro-inflammatory cytokines, e.g. CXCL1, CXCL2, interleukin (IL)-6 and tumor necrosis factor (TNF)-α [5][6][7]. Injuries occur to both pulmonary endothelial cells (PECs) and alveolar epithelial cells after ALI, in which the recovery of the disease could also result in loss of parts of the lung function [1][2][3][4].…”

Alleviation of Lipopolysaccharides-Induced Acute Lung Injury by MiR-454

“…interleukin (IL)-6 and tumor necrosis factor (TNF)-α, C-X-C motif chemokine 1 (CXCL1) and CXCL2. Injuries of lung epithelial and endothelial cells may finally result in loss of respiratory capacity [5][6][7].…”