Bronchial asthma is characterized by airway inflammation, exaggerated airway narrowing to bronchoconstrictor agonists and attenuated responsiveness to beta-adrenoceptor-mediated airway relaxation. Various cytokines have been implicated in the pathogenesis of the inflammatory response in asthmatic airways, and specific cytokines, most notably IL-1beta, have also been shown to directly regulate airway smooth muscle (ASM) responsiveness. In view of the latter, together with our recent observations demonstrating an important autocrine role for IL-1beta in coupling Fc receptor activation and changes in ASM responsiveness in the atopic asthmatic sensitized state, this proposal is designed to examine the role of the IL-1 axis of molecules (i.e., IL-1alpha, IL-1beta, IL-1RI, -RII, IL-1ra, and ICE), in mediating the altered functional and proinflammatory phenotype that characterizes the atopic asthmatic sensitized ASM. Accordingly, studies are proposed to examine the interrelated hypotheses that: I: The human ASM constitutes an autocrine environment which, when activated in the atopic (IgE-mediated) sensitized state, induces the autologous elaboration of various molecules constituting the IL-1 axis and; II: These molecules play an interactive role in the autocrine induction of altered ASM responsiveness, as well as in the altered expression and release of specific TH1- and TH2-type cytokines and their receptors in the atopic sensitized state. Accordingly, the Specific Aims of this project are to: I) examine the autologously- induced altered expression of the IL-1 axis and determine the role of activation of specific Fc receptors in inducing the altered expression of the IL-1 axis of molecules in the atopic sensitized state; 2) examine the role and mechanism of altered induced expression of the IL-1 axis in mediating changes in ASM responsiveness in the atopic sensitized state, and assess the presence of induced altered receptor/G protein-coupled expression and action, as well as agonist-mediated accumulation of the principal second messengers, inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) and cAMP; and 3) examine the autocrine regulatory interactions between altered expression of the IL-1 axis and the TH2-type cytokines IL-4, IL-5 and GM-CSF, and the TH1-type cytokines, IL-2, IL-12 and IFN-gamma, and their receptors and to determine whether the above TH1- and TH2-type cytokines also exert a reciprocal modulatory action on the autocrine expression of the IL-1 axis of molecules. We anticipate that the results from our proposed studies will elucidate the role and mechanism of action of the IL-1 axis in the development of the """"""""pro-asthmatic"""""""" ASM phenotype.
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| Hakonarson, H; Wjst, M (2001) Current concepts on the genetics of asthma. Curr Opin Pediatr 13:267-77 |
