Virus-Induced Mechanics of Altered Airway Responsiveness

描述（由申请人提供）：在哮喘的发展过程中，特异性病毒性呼吸道感染、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。根据我们最近的证据，在某些促哮喘的气道平滑肌（ASM）致敏条件下，ASM本身被诱导表达促炎细胞因子，这些细胞因子会自动引起其收缩和松弛反应性的促哮喘样变化，相关的假设被提出：1：特异性病毒性呼吸道病原体调节在特应性致敏状态下改变的ASM反应性的获得和/或表达；II：病毒诱导的ASM反应性变化归因于病毒接种的ASM中特异性内在Fc受体/细胞因子偶联自分泌相互作用的激活；ⅲ：病毒接种的肌髓质反应性的改变与调节肌髓质收缩和舒张的某些受体/G蛋白偶联的跨膜信号机制的扰动有关。为了解决这些假设，研究人员提出了实验来检测兔ASM组织和培养的人ASM细胞中激动剂反应性改变的机制，这些细胞分别接种了鼻病毒、呼吸道合胞病毒或副流感病毒，在没有和存在被动特应性致敏（AS）的情况下，用人特应性哮喘血清或给予IgE免疫复合物。A：为了研究病毒诱导的ASM收缩性和弛缓性变化的机制，我们将研究：1)在病毒接种的初始和as致敏的ASM中，特异性细胞因子的诱发释放和自分泌作用；2)特异性Fc受体和细胞粘附分子（CAMs）及其他共刺激分子在病毒接种ASM中的表达和激活；3)病毒诱导的ASM中细胞因子和CAMs/共刺激分子的表达是否引起暴露于病毒接种的ASM的初始T细胞的活化。B：为了研究病毒接种ASM中受体/G蛋白偶联跨膜信号传导改变的机制，我们将研究ASM反应性的改变是否归因于：1)收缩剂介导的受体/G蛋白偶联积累、代谢和关键钙动员第二信使肌醇1,4,5-三磷酸（Ins(1,4,5)P3）在ASM中的受体结合改变；2) β -肾上腺素能受体介导的收缩激动剂诱导的Ins积累、代谢和受体结合的改变（1,4,5）P3。预计这些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。

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.