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Received for publication June 13, 2006.
Revised August 2, 2006.
Accepted for publication August 2, 2006.
receptor I kinase inhibitor, SD-208, in chronic allergic airway inflammation and remodeling
Transforming growth factor-
(TGF-) is a multifunctional regulator of cell growth and differentiation with both pro- and anti-inflammatory properties. We used an inhibitor of TGF- receptor I (TGF-RI) kinase, SD-208, to determine the role of TGF- in airway allergic inflammation and remodeling. Brown-Norway rats sensitized and repeatedly-exposed to ovalbumin (OVA) aerosol challenge were orally administered SD-208 twice daily, prior to each of 6 OVA exposures in order to determine the preventive effects, or only prior to each of the last 3 of 6 OVA exposures in order to investigate its reversal effects. SD-208 (60mg/kg) reversed bronchial hyperresponsiveness (BHR) induced by repeated allergen exposure, but did not prevent it. SD-208 prevented changes in serum total and OVA-specific IgE but did not reverse them. SD-208 had both a preventive and reversal of airway inflammation as measured by major basic protein-positive eosinophils and CD2+ T-cells counts in mucosal airways, cell proliferation measured by 5-Bromo-2'-deoxyuridine expression in airway smooth muscle (ASM) cells and epithelial cells, and goblet cell hyperplasia induced by repeated allergen challenges. There was a significant decrease in intracellular Smad2/3 expression. SD-208 did not significantly decrease the increased ASM thickness induced by allergen exposure. These findings support a pro-inflammatory and pro-remodeling role for TGF- in allergic airway inflammation. Inhibition of TGF-RI kinase activities by SD-208 may be a useful approach to the reversal of BHR, and to the prevention and reversal of inflammatory and remodeling features of chronic asthma.
Key words:
Airway smooth muscle, Bronchial hyperresponsiveness, SD-208, TGF-beta, TGF-beta receptor 1 kinase, smad
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