VIRUS INDUCED MECHANISMS OF ALTERED AIRWAY RESPONSIVENES

在哮喘的发展过程中，病毒性呼吸道感染、特应性和气道反应性改变之间存在重要的相互作用。 然而，这种相互作用的机制基础仍有待确定。 鉴于后者，并且鉴于我们最近的证据表明，涉及气道平滑肌（ASM）中Fc受体/细胞因子相互作用的自分泌系统自体诱导其在特应性哮喘状态中改变的反应性，继发于干扰的受体/G蛋白偶联的跨膜信号传导，提出以下相关假设：特异性病毒性呼吸道病原体调节特应性哮喘致敏状态下ASM反应性改变的获得; II：病毒病原体对ASM反应性的这种作用与致敏ASM中改变的受体/G蛋白偶联跨膜信号传导有关;和III：病毒介导的ASM中跨膜信号传导的变化归因于特应性致敏ASM中特异性Fc受体、促炎细胞因子和粘附分子之间诱导的自分泌相互作用的改变。 在解决这些假设，研究将检查机制改变ASM的反应，在分离的兔和人ASM组织和培养的ASM细胞被动致敏的人过敏性/哮喘血清中的存在和不存在接种鼻病毒，副流感病毒3型，或呼吸道合胞病毒。 I.A：为了研究病毒病原体诱导的ASM收缩反应性扰动的潜在机制，我们将研究以下方面的变化：1）特定G蛋白的表达和调节作用;和2）激动剂/受体偶联的关键Ca 2+动员第二信使1，4，5三磷酸肌醇（Ins（1，4，5）P3）的代谢及其细胞内受体结合。 I.B：为了研究病毒病原体诱导的β-肾上腺素能受体介导的ASM松弛扰动的潜在机制，我们将研究以下方面的变化：1）特异性G蛋白表达和β-肾上腺素能受体结合和转导的调节; 2）β-肾上腺素能受体/G蛋白偶联调节收缩肌激动剂诱导的Ins（1，4，5）P3积累、代谢及其受体结合。 最后，二：为了评估Fc受体/细胞因子相互作用在介导病毒诱导的特应性致敏状态下ASM反应性变化中的自分泌作用，我们将检查：1）上述病毒病原体是否诱导致敏ASM中特异性细胞因子的改变的自体表达和自分泌作用;以及2）这些细胞因子的改变的释放是否与致敏ASM中特异性Fc受体和粘附分子表达的变化相关联。 总的来说，拟议的研究应产生重要的新的见解，潜在的自分泌作用的ASM之间的机械相互作用的病毒性呼吸道病原体，特应性，并改变ASM的反应性在特应性/哮喘致敏状态。

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.