title: Csk/Src/EGFR signaling regulates migration of myofibroblasts and alveolarization.
abstract: Bronchopulmonary dysplasia (BPD) is characterized by premature alveolar developmental arrest. Antenatal exposure to inflammation inhibits lung morphogenesis, thus increasing the risk of developing BPD. Alveolar myofibroblasts are thought to migrate into the septal tips and elongate secondary septa during alveolarization. Here we found lipopolysaccharide (LPS) disrupted the directional migration of myofibroblasts and increased actin stress fiber expression and focal adhesion formation. In addition, COOH-terminal Src kinase (Csk) activity was downregulated in myofibroblasts treated with LPS, while activation of Src or epidermal growth factor receptor (EGFR) was upregulated by LPS treatment. Specifically, decreased Csk activity and increased activation of Src or EGFR was also observed in primary myofibroblasts isolated from newborn rat lungs with intra-amniotic LPS exposure, a model for BPD. Further investigation revealed that EGFR was involved in cell migration impairment induced by LPS, and Src inhibition blocked LPS-induced activation of EGFR or cell migration impairment. Csk silencing also resulted in EGFR activation and cell migration impairment. Besides, we found the effect of EGFR on myofibroblast migration was mediated through RhoA activation. EGFR inhibition alleviated the abnormal localization of myofibroblasts and improved alveolar development in antenatal LPS-treated rats. Taken together, our data suggest that the Csk/Src/EGFR signaling pathway is critically involved in regulating directional migration of myofibroblasts and may contribute to arrested alveolar development in BPD.
authors.affiliation: Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; and.
authors.forename: Jianhui
authors.initials: J
authors.lastname: Li
authors.affiliation: Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; and.
authors.forename: Yahui
authors.initials: Y
authors.lastname: Li
authors.affiliation: Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; and.
authors.forename: Hua
authors.initials: H
authors.lastname: He
authors.affiliation: Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; and.
authors.forename: Chengbo
authors.initials: C
authors.lastname: Liu
authors.affiliation: Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; and.
authors.forename: Wen
authors.initials: W
authors.lastname: Li
authors.affiliation: Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; and.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Xie
authors.affiliation: Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; and MOE and Shanghai Key Laboratory of Children's Environmental Health, Shanghai, China zhangyongjun@sjtu.edu.cn.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001997:Bronchopulmonary Dysplasia / Q000276:immunology / Q000378:metabolism; D000081247:CSK Tyrosine-Protein Kinase; D002465:Cell Movement; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology; D005260:Female; D008070:Lipopolysaccharides / Q000494:pharmacology; D058628:Myofibroblasts / Q000502:physiology*; D011650:Pulmonary Alveoli / Q000254:growth & development / Q000276:immunology / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000276:immunology*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D000069347:Erlotinib Hydrochloride; C483803:Egfr protein, rat; D066246:ErbB Receptors; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; D020742:rhoA GTP-Binding Protein
keywords: bronchopulmonary dysplasia; carboxy-terminal Src kinase; cell migration; epidermal growth factor receptor; lipopolysaccharide; myofibroblasts