title: Triggering the induction of myofibroblast and fibrogenesis by airway epithelial shedding.
abstract: Myofibroblasts have been thought to participate in subepithelial fibrosis in asthma, but the mechanism of myofibroblast induction has not been fully understood. In this study we investigated injury-related myofibroblast induction in a coculture system of guinea-pig epithelial cells and fibroblasts cocultured in a human amnion chamber. After pseudostratified epithelial cells were mechanically scraped, migrated flat epithelial cells differentiated into cuboidal appearances on Day 4 and then returned to their original shapes on Day 8. During the course of the epithelial redifferentiation, it was found by Northern blot analysis, immunohistochemistry for alpha-smooth muscle actin, and electron microscopic observation that the myofibroblasts were transiently induced on Day 4. The myofibroblast induction was inhibited by the blocking of transforming growth factor (TGF)-beta1 and thrombospondin (TSP)-1, indicating that the activation of TGF-beta1 by TSP-1 would induce myofibroblasts. This finding was also supported by a transient upregulation of TSP immunoreactivity and TSP-1 messenger RNA (mRNA) in fibroblasts. Interestingly, epithelial injury reduced TGF-beta1 immunoreactivity in the amnion membrane but did not affect TGF-beta1 mRNA in epithelial cells and fibroblasts, indicating that TGF-beta1 supplied from the extracellular matrix can participate in myofibroblast induction. Concurrently with myofibroblast induction, procollagen type I and III mRNAs were upregulated in fibroblasts, and obvious collagen deposition was observed ultrastructurally around the myofibroblasts compared with the fibroblasts. These results indicate that induced myofibroblasts can be functionally more active in producing collagen than are resting fibroblasts. The present study suggests that epithelial injury stimulates TGF-beta1 release from the extracellular matrix and its activation via TSP-1 production, causing collagen synthesis through myofibroblast induction.
authors.affiliation: Department of Pulmonary Medicine, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Morishima
authors.forename: A
authors.initials: A
authors.lastname: Nomura
authors.forename: Y
authors.initials: Y
authors.lastname: Uchida
authors.forename: Y
authors.initials: Y
authors.lastname: Noguchi
authors.forename: T
authors.initials: T
authors.lastname: Sakamoto
authors.forename: Y
authors.initials: Y
authors.lastname: Ishii
authors.forename: Y
authors.initials: Y
authors.lastname: Goto
authors.forename: K
authors.initials: K
authors.lastname: Masuyama
authors.forename: M J
authors.initials: MJ
authors.lastname: Zhang
authors.forename: K
authors.initials: K
authors.lastname: Hirano
authors.forename: M
authors.initials: M
authors.lastname: Mochizuki
authors.forename: M
authors.initials: M
authors.lastname: Ohtsuka
authors.forename: K
authors.initials: K
authors.lastname: Sekizawa
mesh_terms: D000199:Actins / Q000378:metabolism; D000650:Amnion / Q000166:cytology; D000818:Animals; D000951:Antigens, Neoplasm; D015152:Blotting, Northern; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D003094:Collagen / Q000096:biosynthesis / Q000235:genetics; D015194:Diffusion Chambers, Culture; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure*; D006168:Guinea Pigs; D006801:Humans; D007150:Immunohistochemistry; D016023:Integrins / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D020545:Respiratory Mucosa / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D019700:Thrombospondin 1 / Q000096:biosynthesis / Q000494:pharmacology; D014132:Trachea / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000494:pharmacology; D053773:Transforming Growth Factor beta1; D014945:Wound Healing / Q000187:drug effects / Q000502:physiology
chemical_list: D000199:Actins; D000951:Antigens, Neoplasm; D016023:Integrins; D012333:RNA, Messenger; C508960:TGFB1 protein, human; D019700:Thrombospondin 1; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C073878:integrin alphavbeta6; D003094:Collagen