Effect of Transforming Growth Factor- Receptor I Kinase Inhibitor 2,4-Disubstituted Pteridine (SD-208) in Chronic Allergic Airway Inflammation and Remodeling Sum Yee Leung, Akio Niimi, Alistair Noble, Timothy Oates, Alison S. Williams, Satyanarayana Medicherla, Andrew A. Protter, and Kian Fan Chung 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.) Received June 12, 2006; accepted August 2, 2006 ABSTRACT Transforming growth factor (TGF)- is a multifunctional regula- tor of cell growth and differentiation with both pro- and anti- inflammatory properties. We used an inhibitor of TGF- recep- tor 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 de- termine 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 mea- sured 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 signifi- cant decrease in intracellular Smad2/3 expression. SD-208 did not significantly decrease the increased ASM thickness in- duced by allergen exposure. These findings support a proin- flammatory 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 fea- tures of chronic asthma. Asthma is a chronic inflammatory disorder of the airways characterized by bronchial hyperresponsiveness (BHR), air- flow limitation, and airway wall remodeling, which consists of goblet cell hyperplasia (Aikawa et al., 1992), subepithelial fibrosis (Roche et al., 1989), and airway smooth muscle hy- pertrophy and hyperplasia (Dunnill et al., 1969). Airway wall remodeling may result from an imbalance of tissue regener- ation and repair mechanisms. Thus, the airway epithelium may undergo repeated episodes of injury and repair in asthma (Stewart et al., 1993) and shows a high level of expression of growth factors such as transforming growth factor (TGF)- and epidermal growth factor. TGF-, which exists in three isoforms (1, 2, and 3) (Grande, 1997), is an important fibrogenic and immuno- modulatory factor. It is produced in the airways of asthmatic subjects by inflammatory cells such as eosinophils infiltrat- ing the bronchial mucosa (Balzar et al., 2005) as well as by structural cells of the airway wall, including fibroblasts, ep- ithelial, endothelial, and smooth muscle cells (Khalil et al., 1991). TGF- participates in the initiation and propagation of inflammatory and immune responses in the airways (Du- vernelle et al., 2003), but it may also function as a down- regulator of immune responses. For example, regulatory T cells expressing surface TGF-1 have suppressive functions (Nakamura et al., 2001). TGF--producing T cells have been shown to ameliorate allergen-induced BHR and airway in- flammation (Hansen et al., 2000). TGF- also regulates re- pair responses that lead to matrix deposition and tissue This work was supported by The Wellcome Trust Grant 059857. Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.106.109314. ABBREVIATIONS: BHR, bronchial hyperresponsiveness; TGF, transforming growth factor; ALK, activin receptor-like kinase; TGF-RI, transform- ing growth factor- 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; R L , lung resistance PC 200 , provocative concentration of acetylcholine needed to increase baseline lung resistance by 200%; IL, interleukin. 0022-3565/06/3192-586–594$20.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 319, No. 2 Copyright © 2006 by The American Society for Pharmacology and Experimental Therapeutics 109314/3145672 JPET 319:586–594, 2006 Printed in U.S.A. 586 at ASPET Journals on August 17, 2017 jpet.aspetjournals.org Downloaded from