Effect of transforming growth factor-beta receptor I kinase inhibitor 2,4-disubstituted pteridine (SD-208) in chronic allergic airway inflammation and remodeling.
Transforming growth factor (TGF)-beta is a multifunctional regulator of cell growth and differentiation with both pro- and anti-inflammatory properties. We used an inhibitor of TGF-beta receptor I (TGF-betaRI) kinase, SD-208 (2,4-disubstituted pteridine, a ATP-competitive inhibitor of TGF-betaRI kinase), to determine the role of TGF-beta 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-beta in allergic airway inflammation. Inhibition of TGF-betaRI 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.
Leung
Sum Yee
SY
National Heart and Lung Institute, Dovehouse St., London SW3 6LY, UK.
Niimi
Akio
A
Noble
Alistair
A
Oates
Timothy
T
Williams
Alison S
AS
Medicherla
Satyanarayana
S
Protter
Andrew A
AA
Chung
Kian Fan
KF
D000109:Acetylcholine / Q000494:pharmacology; D030201:Activin Receptors, Type I / Q000378:metabolism; D000818:Animals; D001249:Asthma / Q000188:drug therapy*; D001973:Bromodeoxyuridine / Q000378:metabolism; D001980:Bronchi / Q000187:drug effects*; D002908:Chronic Disease; D004305:Dose-Response Relationship, Drug; D005260:Female; D007073:Immunoglobulin E / Q000097:blood; D009130:Muscle, Smooth / Q000187:drug effects; D010047:Ovalbumin / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011621:Pteridines / Q000494:pharmacology*; D051381:Rats; D011914:Rats, Inbred BN; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D051899:Smad2 Protein / Q000032:analysis; D051900:Smad3 Protein / Q000032:analysis; D016212:Transforming Growth Factor beta / Q000502:physiology
D011621:Pteridines; D018125:Receptors, Transforming Growth Factor beta; C511004:SD-208; D051899:Smad2 Protein; C497784:Smad2 protein, rat; D051900:Smad3 Protein; C497787:Smad3 protein, rat; D016212:Transforming Growth Factor beta; D007073:Immunoglobulin E; D010047:Ovalbumin; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625843:Tgfbr1 protein, rat; D001973:Bromodeoxyuridine; D000109:Acetylcholine