Despite a substantial increase in our understanding of the mechanism involved in the pathology of asthma, the mortality and morbidity rates continue to rise, especially in inner-city children. The etiology of many inner city asthmatics appears to be related to cockroach-delivered allergens. In the present proposal, we have detailed studies to assess specific mechanisms of a murine model of cockroach allergen-induced airway hyperreactivity which resemble atopic human asthmatics responses. The allergic responses in this model include significant increases in allergen-specific serum IgE, immediate release of histamine in the BAL, allergen-specific airway eosinophilia, and significantly altered airway physiology which correlates to the airway inflammation. The specific focus of the studies in this proposal will examine the mechanisms by which specific chemokines induce airway hyperreactivity at different stages of the cockroach allergen-induced responses. Differential responses at certain stages of allergic airway disease appears to center around the intensity of inflammation at the time of allergen rechallenge and the specific chemokine-mediated activation of local leukocyte populations. We hypothesize that specific CC chemokines which utilize specific receptors will be responsible for inducing airway hyperreactivity at different stages of cockroach allergen-induced airway responses. To test this postulate, the studies outlined in this proposal will examine two CC family chemokines, MCP-1 and eotaxin, which specifically bind to CCR2 and CCR3, respectively, and appear to mediate different responses leading to airway hyperreactivity. Our studies will include the following: 1) To characterize the inflammatory response and chemokine expression profiles at different stages of allergic response, 2) To examine the alteration of inflammation and airway physiology after depletion of the chemokines or in chemokine """"""""knockout"""""""" (KO) on leukocyte populations during the development of allergic airway disease, 4) To determine the function of specific chemokine receptors in CCR2 and CCR3 KO mice, and 5) To elucidate the activational role of MCP-1 and eotaxin on specific leukocyte populations involved in the allergic airway responses. The development of these ideas will allow elucidation of the mechanistic activity of specific mediators and cell populations involved at different stages of cockroach allergen exacerbations of airway inflammation, leading to airway hyperreactivity and help define differences in disease progression within the allergic airway.
Showing the most recent 10 out of 438 publications
