title: Platelet-Derived Growth Factor and Transforming Growth Factor β1 Regulate ARDS-Associated Lung Fibrosis Through Distinct Signaling Pathways.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Emergency Medicine, the Central Hospital of Minhang District, Fudan University, Shanghai, China.
authors.forename: Xingqi
authors.initials: X
authors.lastname: Deng
authors.forename: Kun
authors.initials: K
authors.lastname: Jin
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Gu
authors.forename: Mei
authors.initials: M
authors.lastname: Liu
authors.forename: Ling
authors.initials: L
authors.lastname: Zhou
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D005333:Fetus; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D051900:Smad3 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: C508504:6,7-dimethyl-2-(2E)-3-(1-methyl-2-phenyl-1H-pyrrolo(2,3-b)pyridin-3-yl-prop-2-enoyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride; C541116:ACTA2 protein, human; D000199:Actins; D024042:Collagen Type I; D005419:Flavonoids; D007546:Isoquinolines; D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011758:Pyrroles; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; D019950:Mitogen-Activated Protein Kinase 1; D048051:p38 Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one