Virus-Induced Mechanics of Altered Airway Responsiveness

病毒引起的气道反应性改变的机制

• 批准号: 6720583
• 负责人: Michael Mateiu Grunstein
• 金额: $ 38.25万
• 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 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6720583
• 关键词: Paramyxovirus; adolescence (12-20); adrenal ferredoxin; antibody receptor; asthma; atopy; blood chemistry; bronchomotion; calcium binding protein; cell surface receptors; clinical research; human subject; inositol phosphates; laboratory rabbit; middle childhood (6-11); protein structure function; receptor coupling; receptor expression; respiratory airflow disorder; respiratory function; respiratory hypersensitivity; respiratory infections; respiratory syncytial virus; rhinovirus; virus diseases; virus receptors; young adult human (21-34)

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.

描述（由申请人提供）：在特定的病毒呼吸道感染，特应性和气道反应性改变哮喘的发生之间存在一个重要的相互作用。 但是，该相互作用的机械基础仍有待鉴定。 基于我们最近的证据，在气道平滑肌（ASM）的某些侵入性条件下，ASM本身被诱使表达促炎的细胞因子表达促进性细胞因子，即自体引起的依赖性的依据和轻松的反应性变化，并放松的反应性，并提高了相互呼吸的响应性，或改善了相互的响应性。敏化状态； II：病毒诱导的ASM反应性变化归因于特定的内在FC受体/细胞因子偶联自分泌相互作用在接种ASM的病毒中；和III：病毒接种ASM的反应性变化与某些受体/G蛋白偶联的跨膜信号传导机制的扰动有关，这些机制调节ASM收缩和放松。 在解决这些假设时，提出了实验，以检查兔ASM组织中激动剂反应改变的机制和培养的人ASM细胞，与鼻病毒，呼吸道促旋性病毒接种，或在不被驱动的应变敏感性的（ASM）的情况下，呼吸道促伴流病毒或parainfluenza病毒在不被驱动的敏感性或无源敏感性的情况下进行。 答：为了研究病毒诱导的ASM收缩和松弛反应性变化的机制，我们将检查：1）特定细胞因子在病毒接种的天真和敏感的ASM中的诱发释放和自分泌作用； 2）在病毒接种的ASM中，特定FC受体和细胞粘附分子（CAM）和其他共刺激分子的表达和激活； 3）病毒诱导的ASM中细胞因子和CAM/共刺激分子的表达是否会激活暴露于病毒接种的ASM的天真T细胞。 B：研究在接种的ASM病毒接种的受体/G蛋白偶联的跨膜信号的改变的机制，我们将检查ASM响应性诱导的变化是否归因于：1）约束激动剂激动剂介导的受体/G蛋白与蛋白质偶联的积累，代谢量和4个密钥含量的含有量钙化量含量钙化量，含量为4 （ins（i，4,5）p3）在ASM中；和2）改变了β-肾上腺素受体介导的限制器激动剂诱导的积累，代谢和受体结合的调节（i，4,5）p3。可以预料，这些提出的研究的发现将产生有关病毒呼吸道病原体，特温和气道反应性改变的机械相互作用的重要新见解。