title: Essential role of stem cell factor-c-Kit signalling pathway in bleomycin-induced pulmonary fibrosis.
abstract: Stem cell factor (SCF) and its receptor c-Kit have been implicated in tissue remodelling and fibrosis. Alveolar fibroblasts from patients with diffuse interstitial fibrosis secrete more SCF. However, its precise role remains unclear. In this study the potential role of the SCF-c-Kit axis in pulmonary fibrosis was examined. Fibrosis was induced by intratracheal instillation of bleomycin (BLM), which caused increased SCF levels in plasma, bronchoalveolar lavage fluid (BALF) and lung tissue, as well as increased expression by lung fibroblasts. These changes were accompanied by increased numbers of bone marrow-derived c-Kit(+) cells in the lung, with corresponding depletion in bone marrow. Both recombinant SCF and lung extracts from BLM-treated animals induced bone-marrow cell migration, which was blocked by c-Kit inhibitor. The migrated cells promoted myofibroblast differentiation when co-cultured with fibroblasts, suggesting a paracrine pathogenic role. Interestingly, lung fibroblast cultures contained a subpopulation of cells that expressed functionally active c-Kit, which were significantly greater and more responsive to SCF induction when isolated from fibrotic lungs, including those from patients with idiopathic pulmonary fibrosis (IPF). This c-Kit(+) subpopulation was αSMA-negative and expressed lower levels of collagen I but significantly higher levels of TGFβ than c-Kit-negative cells. SCF deficiency achieved by intratracheal treatment with neutralizing anti-SCF antibody or by use of Kitl(Sl)/Kitl(Sl-d) mutant mice in vivo resulted in significant reduction in pulmonary fibrosis. Taken together, the SCF-c-Kit pathway was activated in BLM-injured lung and might play a direct role in pulmonary fibrosis by the recruitment of bone marrow progenitor cells capable of promoting lung myofibroblast differentiation.
authors: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109-2200, USA.
authors: Lin
authors: L
authors: Ding
authors: Vladilsav
authors: V
authors: Dolgachev
authors: Zhuang
authors: Z
authors: Wu
authors: Tianju
authors: T
authors: Liu
authors: Taku
authors: T
authors: Nakashima
authors: Zhe
authors: Z
authors: Wu
authors: Matthew
authors: M
authors: Ullenbruch
authors: Nicholas W
authors: NW
authors: Lukacs
authors: Zidi
authors: Z
authors: Chen
authors: Sem H
authors: SH
authors: Phan
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000633:toxicity; D001854:Bone Marrow Cells / Q000187:drug effects; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002452:Cell Count; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D055370:Lung Injury / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019009:Proto-Oncogene Proteins c-kit / Q000502:physiology*; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D019089:Stem Cell Factor / Q000172:deficiency / Q000378:metabolism* / Q000494:pharmacology; D014020:Tissue Extracts / Q000494:pharmacology
chemical_list: D011994:Recombinant Proteins; D019089:Stem Cell Factor; D014020:Tissue Extracts; D001761:Bleomycin; D019009:Proto-Oncogene Proteins c-kit
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