Despite intense ongoing asthma research, there is currently an epidemic of this disease in the western world and the incidence is on the rise. Clinical and experimental investigations have demonstrated a strong correlation between the presence of CD4+ Th2 cells, eosinophils and disease severity suggesting an integral role for these cells in the pathophysiology of asthma. Th2 cells are thought to induce asthma through the secretion of an array of cytokines (IL-4, -5, -6, -9, -10, -13, -25). The ability of IL-13 blockade to abrogate several critical aspects of experimental asthma has led to the view that this is a critical cytokine in disease pathogenesis. Extensive studies have also demonstrated a central role for chemokines in orchestrating multiple aspects of the asthmatic response. In particular, CCR3 and its ligands (eotaxins) have emerged as central regulators of eosinophils during asthmatic responses. In our recent studies we have demonstrated that there is an intimate connection between eosinophils, chemokines, and IL-13 during the induction of experimental asthma. In particular, the eotaxins in conjunction with IL-5, induce lung eosinophilia, which in turn amplify IL-13 production. Furthermore, non-activating ligands for CCR3, which are produced in experimental asthma (e.g. monokine induced by gamma-interferon [Mig]), inhibit IL-13 associated lung responses. The central hypothesis of this grant application is that IL-13 and chemokines critically cooperate in the pathogenesis of eosinophil-associated lung inflammation. In particular, Th2 cell derived IL-13 promotes eotaxin production, which subsequently provides a critical signal for eosinophils to amplify IL-13 production (from eosinophils themselves and from Th2 cells) and IL-13-associated lung pathology. Furthermore, allergen-induced Mig paradoxically curtails aspects of allergen- and IL-13-associated allergic airway inflammation. We propose a series of aims designed to test our central hypothesis and uncover the molecular mechanisms and consequences of chemokine, eosinophil, and IL-13 interactions in the pathogenesis of experimental asthma.
In Aim I we propose studies designed to examine the role of CCR3 and eotaxins in IL-13-induced experimental asthma. We hypothesize that eotaxin-1, eotaxin-2, and CCR3 are critically involved in several aspects of IL-13-induced experimental asthma. We will also test the specific role of IL-13 in promoting allergen-induced chemokine expression in the lung.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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Children's Hospital Med Ctr (Cincinnati)
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