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）：在哮喘的发展过程中，特定病毒性呼吸道感染、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。 基于我们最近的证据，即在气道平滑肌（ASM）致敏的某些促哮喘条件下，ASM本身被诱导表达促炎细胞因子，这些细胞因子自体引起其收缩和舒张反应性的促哮喘样变化，提出了相关的假设I：特定的病毒性呼吸道病原体调节特应性敏感状态下 ASM 反应性改变的获得和/或表达； II：病毒引起的 ASM 反应性变化归因于病毒接种的 ASM 中特定内在 Fc 受体/细胞因子偶联自分泌相互作用的激活； III：病毒接种的 ASM 中反应性的诱导变化与调节 ASM 收缩和舒张的某些受体/G 蛋白偶联跨膜信号传导机制的扰动有关。 为了解决这些假设，提出了实验来检查在不存在或存在被动特应性致敏（AS）的情况下，接种鼻病毒、呼吸道合胞病毒或副流感病毒的兔 ASM 组织和培养的人 ASM 细胞中激动剂反应性改变的机制。 ASM 与人特应性哮喘血清或施用 IgE 免疫复合物。 答：为了研究病毒诱导的 ASM 收缩肌和松弛反应性变化的机制，我们将检查：1）病毒接种的初始 ASM 和 AS 致敏的 ASM 中特定细胞因子的诱发释放和自分泌作用； 2）病毒接种的ASM中特异性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) ASM 中病毒诱导的细胞因子和 CAM/共刺激分子的表达是否会引起暴露于病毒接种的 ASM 的初始 T 细胞的激活。 B：为了研究病毒接种的 ASM 中受体/G 蛋白偶联跨膜信号传导改变的机制，我们将检查 ASM 反应性的诱导变化是否归因于：1) 改变的缩窄激动剂介导的受体/G 蛋白偶联积累、代谢，以及 ASM 中关键的钙动员第二信使肌醇 1,4,5-三磷酸 (Ins(I,,4,5)P3) 的受体结合； 2)改变β-肾上腺素受体介导的缩窄激动剂诱导的Ins(I,,4,5)P3积累、代谢和受体结合的调节。预计这些拟议研究的结果将对病毒性呼吸道病原体、特应性和气道反应性改变之间的机制相互作用产生重要的新见解。