Journal
RESPIRATORY RESEARCH
Volume 12, Issue -, Pages -Publisher
BMC
DOI: 10.1186/1465-9921-12-113
Keywords
airway fibroblasts; airway remodeling; asthma; fibronectin; geranylgeranyl transferase; statins
Categories
Funding
- Canadian Institutes of Health Research (CIHR)
- GlaxoSmithKline
- Manitoba Institute of Child Health
- Canada Foundation for Innovation
- CIHR/HSFC IMPACT
- Parker B. Francis postdoctoral fellowship
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Background: Bronchial fibroblasts contribute to airway remodelling, including airway wall fibrosis. Transforming growth factor (TGF)-beta 1 plays a major role in this process. We previously revealed the importance of the mevalonate cascade in the fibrotic response of human airway smooth muscle cells. We now investigate mevalonate cascade-associated signaling in TGF beta 1-induced fibronectin expression by bronchial fibroblasts from non-asthmatic and asthmatic subjects. Methods: We used simvastatin (1-15 mu M) to inhibit 3-hydroxy-3-methlyglutaryl-coenzyme A (HMG-CoA) reductase which converts HMG-CoA to mevalonate. Selective inhibitors of geranylgeranyl transferase-1 (GGT1; GGTI-286, 10 mu M) and farnesyl transferase (FT; FTI-277, 10 mu M) were used to determine whether GGT1 and FT contribute to TGF beta 1-induced fibronectin expression. In addition, we studied the effects of co-incubation with simvastatin and mevalonate (1 mM), geranylgeranylpyrophosphate (30 mu M) or farnesylpyrophosphate (30 mu M). Results: Immunoblotting revealed concentration-dependent simvastatin inhibition of TGF beta 1 (2.5 ng/ml, 48 h)induced fibronectin. This was prevented by exogenous mevalonate, or isoprenoids (geranylgeranylpyrophosphate or farnesylpyrophosphate). The effects of simvastatin were mimicked by GGTI-286, but not FTI-277, suggesting fundamental involvement of GGT1 in TGF beta 1-induced signaling. Asthmatic fibroblasts exhibited greater TGF beta 1-induced fibronectin expression compared to non-asthmatic cells; this enhanced response was effectively reduced by simvastatin. Conclusions: We conclude that TGF beta 1-induced fibronectin expression in airway fibroblasts relies on activity of GGT1 and availability of isoprenoids. Our results suggest that targeting regulators of isoprenoid-dependent signaling holds promise for treating airway wall fibrosis.
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