Transforming growth factor-β-Induced differentiation of airway smooth muscle cells is inhibited by fibroblast growth factor-2

Michael Schuliga, Aqeel Javeed, Trudi Harris, Yuxiu Xia, Chengxue Qin, Zhexing Wang, Xuehua Zhang, Peter V.S. Lee, Blanca Camoretti-Mercado, Alastair G. Stewart

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Abstract

In asthma, basic fibroblast growth factor (FGF-2) plays an important (patho)physiological role. This study examines the effects of FGF-2 on the transforming growth factor-b (TGF-b)-stimulated differentiation of airway smooth muscle (ASM) cells in vitro. The differentiation of humanASMcells after incubation with TGF-b(100 pM)and/ or FGF-2 (300 pM) for 48 hours was assessed by increases in contractile protein expression, actin-cytoskeleton reorganization, enhancements in cell stiffness, and collagen remodeling. FGF-2 inhibited TGF-β-stimulated increases in transgelin (SM22) and calponin gene expression (n = 15, P < 0.01) in an extracellular signal-regulated kinase 1/2 (ERK1/2) signal transduction-dependent manner. The abundance of ordered a-smooth muscle actin (a-SMA) filaments formed in the presence of TGF-b were also reduced by FGF-2, as was the ratio of F-actin to G-actin (n = 8, P < 0.01). Furthermore, FGF-2 attenuated TGF-β-stimulated increases in ASM cell stiffness andtheASM-mediatedcontraction of lattices,composed of collagen fibrils (n = 5, P < 0.01). However, the TGF-β-stimulated production of IL-6 was not influenced by FGF-2 (n=4, P.>.05), suggesting that FGF-2 antagonism is selective for the regulation of ASM cell contractile protein expression, organization, and function. Another mitogen, thrombin (0.3 U ml21), exerted no effect on TGF-β-regulated contractile protein expression (n=8, P.>.05),a-SMA organization, or the ratio of F-actin to G-actin (n=4, P.>.05), suggesting that the inhibitory effect of FGF-2 is dissociated from its mitogenic actions. The addition of FGF-2, 24 hours after TGF-b treatment, still reduced contractile protein expression, even when the TGF-β-receptor kinase inhibitor, SB431542 (10 mM), was added 1 hour before FGF-2. Weconclude that the ASM cell differentiation promoted by TGF-b is antagonized by FGF-2. A better understanding of the mechanism of action for FGF-2 is necessary to develop a strategy for therapeutic exploitation in the treatment of asthma.

Original languageEnglish
Pages (from-to)346-353
Number of pages8
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume48
Issue number3
DOIs
Publication statusPublished - Mar 2013
Externally publishedYes

Keywords

  • Airway wall remodeling
  • Asthma
  • Cytoskeleton
  • Transgelin
  • α-smooth muscle actin

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