Toll-like receptor 4 mediates lipopolysaccharide-induced collagen secretion by phosphoinositide3-kinase-Akt pathway in fibroblasts during acute lung injury.
Gram-negative bacillus infection is an important risk factor of acute lung injury (ALI). Previous experiments have revealed that lipopolysaccharide (LPS), a primary component of endotoxin of gram-negative bacilli, stimulated the inflammatory reactions that contribute to ALI and pulmonary interstitial fibrosis, but the mechanisms were not well understood. We reported that LPS was able to directly induce secretion of collagen in mouse lung fibroblasts via activation of phosphoinositide3-kinase-Akt (PI3K-Akt) pathway through toll-like receptor 4 (TLR4) in vitro. We found that overexpression of TLR4, type I procollagen, alpha smooth muscle actin (alpha-SMA), and p-AKT in primary cultured mouse lung fibroblast stimulated by LPS were detected by real-time PCR or Western blots, and the contents of C-terminal propeptide of type I procollagen (PICP) in cell culture supernatants were increased simultaneously. The activation of TLR4 stimulated by LPS could also up-regulate the expression of integrin beta1 and TLR4 in mouse lung fibroblast, which could accelerate ALI and pulmonary interstitial fibrosis processes. All these changes could be inhabited by transfection of Lentivirus-TLR4-siRNA or application of PI3K inhibitor LY294002. Therefore, we infer that besides pulmonary macrophage, lung fibroblasts are also important target cells directly influenced by LPS, which may play an important role in ALI and pulmonary interstitial fibrosis.
He
ZhengYu
Z
Department of Anesthesiology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Zhu
YeSen
Y
Jiang
Hong
H
D055371:Acute Lung Injury / Q000276:immunology* / Q000382:microbiology; D000818:Animals; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D024042:Collagen Type I / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000276:immunology; D019012:Integrin beta1 / Q000187:drug effects / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000276:immunology; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D002867:Chromones; D024042:Collagen Type I; D004791:Enzyme Inhibitors; D019012:Integrin beta1; D008070:Lipopolysaccharides; D009025:Morpholines; D051197:Toll-Like Receptor 4; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt