VIRUS INDUCED MECHANISMS OF ALTERED AIRWAY RESPONSIVENES

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An important interplay exists between viral respiratory infections, atopy, and altered airway responsiveness in the development of asthma. The mechanistic basis of this interplay, however, remains to be identified. In view of the latter, and given our recent evidence demonstrating that an autocrine system involving Fc receptor/cytokine interactions in airway smooth muscle (ASM) autologously induces its altered responsiveness in the atopic asthmatic state, secondary to perturbed receptor/G protein-coupled transmembrane signaling, the following interrelated hypotheses are raised: I: That specific viral respiratory pathogens modulate the acquisition of altered ASM responsiveness in the atopic asthmatic sensitized state; II: That this action of viral pathogens on ASM responsiveness is related to altered receptor/G protein-coupled transmembrane signaling in sensitized ASM; and III: That the viral-mediated changes in transmembrane signaling in ASM are attributed to induced altered autocrine interactions between specific Fc receptors, proinflammatory cytokines, and adhesion molecules in atopic sensitized ASM. In addressing these hypotheses, studies will examine mechanisms of altered ASM responsiveness in isolated rabbit and human ASM tissue and cultured ASM cells passively sensitized with human atopic/asthmatic serum in the absence and presence of inoculation with rhinovirus, parainfluenza type 3, or respiratory syncytial virus. I.A: To investigate mechanisms underlying viral pathogen-induced perturbations in ASM constrictor responsiveness, we will examine changes in: 1) the expression and modulatory actions of specific G proteins; and 2) agonist/receptor-coupled accumulation of the key Ca2+-mobilizing second messenger, inositol 1,4,5 trisphosphate (Ins(1,4,5)P3) its metabolism, and its intracellular receptor binding. I.B: To investigate mechanisms underlying viral pathogen-induced perturbations in beta-adrenoceptor-mediated ASM relaxation, we will examine changes in: 1) specific G protein expression and regulation of beta-adrenergic receptor binding and transduction; and 2) beta-adrenoceptor/G protein-coupled modulation of constrictor agonist-induced accumulation of Ins(1,4,5)P3, its metabolism, and its receptor binding. Finally, II: To assess the autocrine role of Fc receptor/cytokine interactions in mediating virus-induced changes in ASM responsiveness in the atopic sensitized state, we will examine: 1) whether the above viral pathogens induce altered autologous expression and autocrine actions of specific cytokines in sensitized ASM; and 2) whether the altered release of these cytokines is coupled to changes in expression of specific Fc receptors and adhesion molecules in sensitized ASM. Collectively, the proposed studies should yield important new insights into the potential autocrine role of the ASM in the mechanistic interplay between viral respiratory pathogens, atopy, and altered ASM responsiveness in the atopic/asthmatic sensitized state.