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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.
AuthorsLin Ding, Vladilsav Dolgachev, Zhuang Wu, Tianju Liu, Taku Nakashima, Zhe Wu, Matthew Ullenbruch, Nicholas W Lukacs, Zidi Chen, Sem H Phan
JournalThe Journal of pathology (J Pathol) Vol. 230 Issue 2 Pg. 205-14 (Jun 2013) ISSN: 1096-9896 [Electronic] England
PMID23401096 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
CopyrightCopyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Chemical References
  • Recombinant Proteins
  • Stem Cell Factor
  • Tissue Extracts
  • Bleomycin
  • Proto-Oncogene Proteins c-kit
Topics
  • Animals
  • Bleomycin (toxicity)
  • Bone Marrow Cells (drug effects)
  • Bronchoalveolar Lavage Fluid (chemistry)
  • Cell Count
  • Cell Movement (drug effects)
  • Cells, Cultured
  • Female
  • Fibroblasts (drug effects, metabolism)
  • Hematopoietic Stem Cells (drug effects, metabolism, pathology)
  • Humans
  • Lung (drug effects, metabolism, pathology)
  • Lung Injury (chemically induced, metabolism, pathology)
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Proto-Oncogene Proteins c-kit (physiology)
  • Pulmonary Fibrosis (chemically induced, metabolism, pathology)
  • Recombinant Proteins (pharmacology)
  • Signal Transduction (physiology)
  • Stem Cell Factor (deficiency, metabolism, pharmacology)
  • Tissue Extracts (pharmacology)

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