Abstract
Transforming growth factor (TGF)-β is a multifunctional regulator of cell growth and differentiation with both pro- and anti-inflammatory properties. We used an inhibitor of TGF-β receptor I (TGF-βRI) kinase, SD-208 (2,4-disubstituted pteridine, a ATP-competitive inhibitor of TGF-βRI kinase), to determine the role of TGF-β 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, before each of six OVA exposures to determine the preventive effects, or only before each of the last three of six OVA exposures to investigate its reversal effects. SD-208 (60 mg/kg) reversed bronchial hyperresponsiveness (BHR) induced by repeated allergen exposure, but it did not prevent it. SD-208 prevented changes in serum total and OVA-specific IgE, but it did not reverse them. SD-208 had both a preventive and reversal effect on airway inflammation as measured by major basic protein-positive eosinophils and CD2+ T-cell 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 proinflammatory and proremodeling role for TGF-β in allergic airway inflammation. Inhibition of TGF-βRI 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.
Footnotes
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This work was supported by The Wellcome Trust Grant 059857.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.109314.
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ABBREVIATIONS: BHR, bronchial hyperresponsiveness; TGF, transforming growth factor; ALK, activin receptor-like kinase; TGF-βRI, transforming growth factor-β receptor I; SD-208, 2,4-disubstituted pteridine; OVA, ovalbumin; BrdU, 5-bromo-2′-deoxyuridine; ASM, airway smooth muscle; MBP, major basic protein; DAPI, 4,6-diamidino-2-phenylindole; ACh, acetylcholine; RL, lung resistance PC200, provocative concentration of acetylcholine needed to increase baseline lung resistance by 200%; IL, interleukin.
- Received June 12, 2006.
- Accepted August 2, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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