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: 7149160
• 负责人: Michael Mateiu Grunstein
• 金额: $ 36.27万
• 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/7149160
• 关键词: Address; Adolescence; Adrenergic Receptor; Adult; Agonist; Antigen-Antibody Complex; Asthma; Binding; Bronchoconstrictor Agents; Calcium; Cell Adhesion; Cell Adhesion Molecules; Chronic; Clinical; Condition; Cytokine Receptors; Development; Fc Receptor; G-Protein-Coupled Receptors; Genetic; Human; IgE; Inositol; Inositol 1,4,5-Trisphosphate; Investigation; Lead; Life; Lymphocyte Activation; Mechanics; Mediating; Metabolism; Muscle Contraction; Muscle relaxants; Oryctolagus cuniculus; Parainfluenza; Phenotype; Recurrence; Relaxation; Research Personnel; Respiratory Tract Infections; Respiratory syncytial virus; Rhinovirus; Risk Factors; Role; Second Messenger Systems; Serum; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; Stimulus; T-Lymphocyte; Viral; Virus; Wheezing; airway inflammation; atopy; autocrine; base; beta-adrenergic receptor; cytokine; early childhood; insight; parainfluenza virus; pathogen; programs; receptor binding; receptor coupling; research study; respiratory; respiratory smooth muscle; second messenger; tissue culture

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，特定的病毒性呼吸道感染、特应性和呼吸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。根据我们最近的证据，在某些促哮喘条件下，气道平滑肌(ASM)致敏，ASM本身被诱导表达促炎细胞因子，从而自动引起其收缩和松弛反应性的促哮喘样变化，提出了相关的假设：I：在特应性致敏状态下，特定的病毒呼吸道病原体调节改变的ASM反应性的获得和/或表达；II：病毒诱导的ASM反应性的改变归因于激活病毒接种的ASM中特定的固有Fc受体/细胞因子偶联自分泌相互作用；III：病毒感染引起的ASM反应性改变与调节ASM收缩和松弛的某些受体/G蛋白偶联的跨膜信号机制的扰动有关。为了解决这些假说，我们提出了一些实验，目的是在人工接种鼻病毒、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，检测ASM与人特应性哮喘血清或免疫复合物的被动特应性致敏(AS)存在的情况下，ASM激动剂反应性改变的机制。A：为了探讨病毒引起ASM收缩和松弛反应改变的机制，我们将检测：1)病毒接种的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)病毒感染的ASM中特定的Fc受体和细胞黏附分子(CAM)和其他共刺激分子的表达和激活；3)病毒诱导ASM中细胞因子和CAMS/共刺激分子的表达是否诱导暴露于病毒感染的ASM中的幼稚T细胞激活。B：为了探讨病毒感染ASM中受体/G蛋白偶联跨膜信号改变的机制，我们将研究ASM反应性的诱导改变是否归因于：1)收缩激动剂介导的受体/G蛋白偶联在ASM中的聚集、代谢和受体结合的改变；以及2)β-肾上腺素受体介导的调节收缩激动剂诱导的INS(I，4，5)P3的聚集、代谢和受体结合。预计这些拟议研究的发现将对病毒呼吸道病原体、特应性和呼吸道反应性改变之间的机制相互作用产生重要的新见解。