Asthma is a chronic inflammatory disorder of the airway. Recent studies have demonstrated that CD4+ Th2 cells play a critical role in allergen-induced asthma and that the Th2 cytokine, interleukin (IL)-13, plays a key role in the generation of the asthmatic phenotype. We have established constitutive, inducible and inducible/suppressible (""""""""on/off"""""""") overexpression (OE) transgenic systems in which IL-13 is targeted to the lung/airway. Using these systems, we have demonstrated that IL-13 causes inflammation, eosinophilic infiltration, mucus metaplasia, subepithelial fibrosis and physiologic alterations in the murine airway that mimic, in many ways, those seen in asthma. Recent studies have also demonstrated that IL-13 receptor subunits, CC chemokines, transforming growth factor-beta (TGF-beta) family proteins and fibroblast growth factor-2 (FGF-2) are strikingly induced in the IL-13 treated lung and that the CCR2 chemokine receptor (and its ligands) plays a critical role(s) in the pathogenesis of selected aspects of the IL-13 phenotype. We contend that the airway effects of IL-13 are the result of complex IL-13-IL-13 receptor subunit interactions and the induction of a downstream target gene cascade that mediates specific effects of the IL-13 phenotype. We propose to: (1) characterize the expression of the different IL-13 receptor subunits and their roles in mediating the effects of IL-13 in vivo, (2) characterize the CC chemokine response mediating the inflammatory and remodeling effects of IL-13, (3) characterize the roles of TGF-beta family proteins and FGF-2 in IL-13- induced inflammatory and remodeling responses; and (4) determine if IL-13-induced inflammation and remodeling are reversible.
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