Virus-Induced Mechs of Altered Airway Responsiveness

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DESCRIPTION (provided by applicant): An important interplay exists between specific viral respiratory infections, atopy, and altered airway responsiveness in the development of asthma. The mechanistic basis of this interplay, however, remains to be identified. Based on our recent evidence that under certain pro-asthmatic conditions of airway smooth muscle (ASM) sensitization the ASM itself is induced to express proinflammatory cytokines that autologously elicit pro-asthmatic-like changes in its constrictor and relaxant responsiveness, the interrelated hypotheses are raised that: I: Specific viral respiratory pathogens modulate the acquisition and/or expression of altered ASM responsiveness in the atopic sensitized state; II: The virus-induced changes in ASM responsiveness are attributed to activation of specific intrinsic Fc receptor/cytokine-coupled autocrine interactions in the virus inoculated ASM; and III: The induced changes in responsiveness in virus-inoculated ASM are associated with perturbations in certain receptor/G protein-coupled transmembrane signaling mechanisms that regulate ASM contraction and relaxation. In addressing these hypotheses, experiments are proposed to examine mechanisms of altered agonist responsiveness in rabbit ASM tissues and cultured human ASM cells inoculated with either rhinovirus, respiratory syncytial virus, or parainfluenza virus in the absence and presence of passive atopic sensitization (AS) of the ASM with human atopic asthmatic serum or administered IgE immune complexes. A: To investigate mechanisms underlying virus-induced changes in ASM constrictor and relaxant responsiveness, we will examine: 1) the evoked release and autocrine actions of specific cytokines in virus-inoculated naive and AS-sensitized ASM; 2) the expression and activation of specific Fc receptors and cellular adhesion molecules (CAMs) and other co-stimulatory molecules in virus-inoculated ASM; and 3) whether virus-induced expression of cytokines and CAMs/co-stimulatory molecules in ASM elicits activation of naive T cells exposed to the virus-inoculated ASM. B: To investigate mechanisms of altered receptor/G protein-coupled transmembrane signaling in virus-inoculated ASM, we will examine whether induced changes in ASM responsiveness are attributed to: 1) altered constrictor agonist-mediated receptor/G protein-coupled accumulation, metabolism, and receptor binding of the key calcium-mobilizing second messenger, inositol 1,4,5-trisphosphate (Ins(I,,4,5)P3) in ASM; and 2) altered beta-adrenoceptor mediated modulation of constrictor agonist-induced accumulation, metabolism, and receptor binding of Ins(I,,4,5)P3. It is anticipated that the findings from these proposed studies would yield important new insights into the mechanistic interplay between viral respiratory pathogens, atopy, and altered airway responsiveness.