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.