VIRUS INDUCED MECHANISMS OF ALTERED AIRWAY RESPONSIVENES

病毒诱发气道反应改变的机制

• 批准号: 6390062
• 负责人: Michael Mateiu Grunstein
• 金额: $ 31.45万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6390062
• 关键词: G protein; animal tissue; antibody receptor; asthma; autocrine; beta adrenergic receptor; biological signal transduction; calcium flux; cytokine; gene expression; human tissue; laboratory rabbit; membrane proteins; muscle contraction; muscle function; pathologic process; receptor binding; respiratory airflow disorder; respiratory infections; respiratory syncytial virus; rhinovirus; second messengers; smooth muscle; tissue /cell culture

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.

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着重要的相互作用。 然而，这种相互作用的机制基础仍有待确定。 鉴于后者，并考虑到我们最近的证据表明，气道平滑肌（ASM）中涉及 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下的反应性改变，继发于受体/G 蛋白偶联跨膜扰动信号传导，提出了以下相互关联的假设： I：特定的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 中受体/G 蛋白偶联跨膜信号传导的改变有关； III：ASM 中病毒介导的跨膜信号传导变化归因于特应性致敏 ASM 中特定 Fc 受体、促炎细胞因子和粘附分子之间自分泌相互作用的诱导改变。 为了解决这些假设，研究将检查在不存在或存在接种鼻病毒、副流感 3 型或呼吸道合胞病毒的情况下，分离的兔和人 ASM 组织以及培养的 ASM 细胞对人特应性/哮喘血清被动致敏的 ASM 反应性改变的机制。 I.A：为了研究病毒病原体引起的 ASM 缩窄反应性扰动的机制，我们将检查以下方面的变化：1）特定 G 蛋白的表达和调节作用； 2) 关键的 Ca2+ 动员第二信使肌醇 1,4,5 三磷酸 (Ins(1,4,5)P3) 的激动剂/受体偶联积累及其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 松弛扰动的机制，我们将检查以下方面的变化：1）特定 G 蛋白表达以及 β 肾上腺素能受体结合和转导的调节； 2) β-肾上腺素受体/G 蛋白偶联调节收缩剂激动剂诱导的 Ins(1,4,5)P3 积累、其代谢及其受体结合。 最后，II：为了评估 Fc 受体/细胞因子相互作用在介导特应性致敏状态下病毒诱导的 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特定自体表达和自分泌作用的改变致敏 ASM 中的细胞因子； 2) 这些细胞因子释放的改变是否与致敏 ASM 中特定 Fc 受体和粘附分子表达的变化有关。 总的来说，拟议的研究应该对 ASM 在病毒性呼吸道病原体、特应性和特应性/哮喘敏感状态下 ASM 反应性改变之间的机制相互作用中的潜在自分泌作用产生重要的新见解。