It is increasingly appreciated that the chronic inflammation underlying the asthmatic diathesis can cause impressive end organ alterations. These tissue effects, variously termed airway remodeling, include subepithelial fibrosis, mucus metaplasia, myocyte hypertrophy and hyperplasia and myofibroblast hyperplasia. However, our knowledge of the pathogenetic mechanisms and mediators that are responsible for these alterations, their degree of reversibility and their physiologic consequences have not been adequately investigated. To define the processes that mediate airway remodeling, we developed lung-specific constitutive and inducible / suppressive overexpression transgenic modeling systems and used these systems to characterize the in vivo effector profiles induced by asthma-relevant mediators. These studies demonstrated that interleukin-6-type cytokines and Th2-type cytokines induce remodeling responses that are similar in some ways and different in others. The IL-6-type cytokines caused impressive subepithelial fibrosis, hyaluronic acid (HA) deposition and myocyte and myofibroblast hyperplasia in the absence of eosinophilia or mucus metaplasia. The Th2-type cytokines also caused subepithelial fibrosis with HA deposition. This response, however, was associated with eosinophilic inflammation and mucus metaplasia. HYPOTHESIS: The IL-6-type cytokines and Th2-type cytokines are important mediators of airway remodeling responses with overlapping and distinct effector properties. To test this hypothesis we propose to use constitutive and externally regulatable overexpression transgenic modeling systems. We will: (1) Characterize. the remodeling responses in transgenic mice that overexpress IL-6-type cytokines (IL-6, IL- 11, cardiotrophin-1) and Th2-type cytokines (IL-13, IL-9, IL-4). (2) Characterize the reversibility of the remodeling responses in transgenic mice that overexpress IL-6-type cytokines (IL-6, IL-11) and/or Th2-type cytokines (IL-13, IL-9). (3) Characterize the parameters of collagen metabolism in representative transgenic models and after chronic aeroallergen exposure. (4) Characterize the parameters of HA metabolism in representative transgenic models and after chronic aeroallergen exposure. (5) Characterize the role of the IL-6-type cytokines (IL-6, IL-11) and IL-13 in the induction of the collagen and HA responses in transgenic and antigen-driven models of airway remodeling.
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