title: HB-EGF-Promoted Airway Smooth Muscle Cells and Their Progenitor Migration Contribute to Airway Smooth Muscle Remodeling in Asthmatic Mouse.
abstract: The airway smooth muscle (ASM) cells' proliferation, migration, and their progenitor's migration are currently regarded as causative factors for ASM remodeling in asthma. Heparin-binding epidermal growth factor (HB-EGF), a potent mitogen and chemotactic factor, could promote ASM cell proliferation through MAPK pathways. In this study, we obtained primary ASM cells and their progenitors from C57BL/6 mice and went on to explore the role of HB-EGF in these cells migration and the underlying mechanisms. We found that recombinant HB-EGF (rHB-EGF) intratracheal instillation accelerated ASM layer thickening in an OVA-induced asthmatic mouse. Modified Boyden chamber assay revealed that rHB-EGF facilitate ASM cell migration in a dose-dependent manner and ASM cells from asthmatic mice had a greater migration ability than that from normal counterparts. rHB-EGF could stimulate the phosphorylation of ERK1/2 and p38 in ASM cells but further migration assay showed that only epidermal growth factor receptor inhibitor (AG1478) or p38 inhibitor (SB203580), but not ERK1/2 inhibitor (PD98059), could inhibit rHB-EGF-mediated ASM cells migration. Actin cytoskeleton experiments exhibited that rHB-EGF could cause actin stress fibers disassembly and focal adhesions formation of ASM cells through the activation of p38. Finally, airway instillation of rHB-EGF promoted the recruitment of bone marrow-derived smooth muscle progenitor cells, which were transferred via caudal vein, migrating into the airway from the circulation. These observations demonstrated that ASM remodeling in asthma might have resulted from HB-EGF-mediated ASM cells and their progenitor cells migration, via p38 MAPK-dependent actin cytoskeleton remodeling.
authors.affiliation: Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Zhejiang 310003, People's Republic of China;
authors.forename: Qing
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Zhejiang 310003, People's Republic of China; zjyhz@zju.edu.cn lihequan@zju.edu.cn.
authors.forename: Hequan
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Zhejiang 310003, People's Republic of China;
authors.forename: Yinan
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Zhejiang 310003, People's Republic of China;
authors.forename: Guohua
authors.initials: G
authors.lastname: Lu
authors.affiliation: Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Zhejiang 310003, People's Republic of China;
authors.forename: Yuehong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School of Public Health, Zhejiang University, Hangzhou 310027, China; and Institute of Immunology, Zhejiang University, Hangzhou 310027, China.
authors.forename: Dajing
authors.initials: D
authors.lastname: Xia
authors.affiliation: Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Zhejiang 310003, People's Republic of China; zjyhz@zju.edu.cn lihequan@zju.edu.cn.
authors.forename: Jianying
authors.initials: J
authors.lastname: Zhou
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D056151:Airway Remodeling / Q000187:drug effects; D000818:Animals; D001249:Asthma / Q000378:metabolism* / Q000473:pathology*; D015415:Biomarkers; D002454:Cell Differentiation; D002465:Cell Movement / Q000187:drug effects; D015870:Gene Expression; D066257:Heparin-binding EGF-like Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D058628:Myofibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000199:Actins; D015415:Biomarkers; D066257:Heparin-binding EGF-like Growth Factor; D048051:p38 Mitogen-Activated Protein Kinases