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INFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Effect of Transforming Growth Factor- Receptor I Kinase Inhibitor 2,4-Disubstituted Pteridine (SD-208) in Chronic Allergic Airway Inflammation and Remodeling

Experimental Studies, National Heart and Lung Institute, Imperial College, London, United Kingdom (S.Y.L., A.Ni., T.O., A.S.W., K.F.C.); Department of Immunology, King's College, London, United Kingdom (A.No.); and Scios Inc., Fremont, California (S.M., A.A.P.)

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 (2,4-disubstituted pteridine, a ATP-competitive inhibitor of TGF-RI kinase), 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, 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- 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.

Address correspondence to: Dr. Kian Fan Chung, National Heart and Lung Institute, Dovehouse St., London SW3 6LY, UK. E-mail: f.chung{at}imperial.ac.uk

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