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Am J Physiol Lung Cell Mol Physiol 284: L548-L556, 2003. First published December 6, 2002; doi:10.1152/ajplung.00091.2002
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Vol. 284, Issue 3, L548-L556, March 2003

GM-CSF increases airway smooth muscle cell connective tissue expression by inducing TGF-beta receptors

Gang Chen1, Gary Grotendorst2, Thomas Eichholtz3, and Nasreen Khalil1

1 Department of Medicine, Vancouver Hospital and Health Sciences Centre, University of British Columbia, Vancouver, British Columbia V6Z 3Z6, Canada; 2 University of Miami School of Medicine, Miami, Florida 33136; and 3 GlaxoSmithKline, Stevenage, Herts SG1 2NY, United Kingdom

Fibrosis around the smooth muscle of asthmatic airway walls leads to irreversible airway obstruction. Bronchial epithelial cells release granulocyte/macrophage colony-stimulating factor (GM-CSF) in asthmatics and are in close proximity to airway smooth muscle cells (ASMC). The findings in this study demonstrate that GM-CSF induces confluent, prolonged, serum-deprived cultures of ASMC to increase expression of collagen I and fibronectin. GM-CSF also induced ASMC to increase the expression of transforming growth factor (TGF)-beta receptors type I, II, and III (Tbeta R-I, Tbeta R-II, Tbeta R-III), but had no detectable effect on the release of TGF-beta 1 by the same ASMC. The presence of GM-CSF also induced the association of TGF-beta 1 with Tbeta R-III, which enhances binding of TGF-beta 1 to Tbeta R-II. The induction of Tbeta Rs was parallel to the increased induction of phosphorylated Smad2 (pSmad2) and connective tissue growth factor (CTGF), indicative of TGF-beta -mediated connective tissue synthesis. Dexamethasone decreased GM-CSF-induced Tbeta R-I, Tbeta R-II, Tbeta R-III, pSmad2, CTGF, collagen I, and fibronectin. In conclusion, GM-CSF increases the responsiveness of ASMC to TGF-beta 1-mediated connective tissue expression by induction of Tbeta Rs, which is inhibited by corticosteroids.

airway remodeling; corticosteroids; irreversible airway obstruction; phosphorylated Smad2; connective tissue growth factor; granulocyte/macrophage colony-stimulating factor; transforming growth factor-beta ; airway smooth muscle cells


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