ROLE OF IL-1 AXIS IN SENSITIZED AIRWAY SMOOTH MUSCLE

IL-1 轴在敏感气道平滑肌中的作用

• 批准号: 6527143
• 负责人: Hakon Hakonarson
• 金额: $ 24.22万
• 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: 1999-09-01 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6527143
• 关键词: antibody receptor; asthma; autocrine; beta adrenergic receptor; bronchomotion; clinical research; cyclic AMP; cytokine; cytokine receptors; fluorescent dye /probe; human subject; inflammation; inositol phosphates; interleukin 1; laboratory rabbit; pathologic process; phlebotomy; polymerase chain reaction; receptor coupling; respiratory hypersensitivity; smooth muscle

Bronchial asthma is characterized by airway inflammation, exaggerated airway narrowing to bronchoconstrictor agonists and attenuated responsiveness to beta-adrenoceptor-mediated airway relaxation. Various cytokines have been implicated in the pathogenesis of the inflammatory response in asthmatic airways, and specific cytokines, most notably IL-1beta, have also been shown to directly regulate airway smooth muscle (ASM) responsiveness. In view of the latter, together with our recent observations demonstrating an important autocrine role for IL-1beta in coupling Fc receptor activation and changes in ASM responsiveness in the atopic asthmatic sensitized state, this proposal is designed to examine the role of the IL-1 axis of molecules (i.e., IL-1alpha, IL-1beta, IL-1RI, -RII, IL-1ra, and ICE), in mediating the altered functional and proinflammatory phenotype that characterizes the atopic asthmatic sensitized ASM. Accordingly, studies are proposed to examine the interrelated hypotheses that: I: The human ASM constitutes an autocrine environment which, when activated in the atopic (IgE-mediated) sensitized state, induces the autologous elaboration of various molecules constituting the IL-1 axis and; II: These molecules play an interactive role in the autocrine induction of altered ASM responsiveness, as well as in the altered expression and release of specific TH1- and TH2-type cytokines and their receptors in the atopic sensitized state. Accordingly, the Specific Aims of this project are to: I) examine the autologously- induced altered expression of the IL-1 axis and determine the role of activation of specific Fc receptors in inducing the altered expression of the IL-1 axis of molecules in the atopic sensitized state; 2) examine the role and mechanism of altered induced expression of the IL-1 axis in mediating changes in ASM responsiveness in the atopic sensitized state, and assess the presence of induced altered receptor/G protein-coupled expression and action, as well as agonist-mediated accumulation of the principal second messengers, inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) and cAMP; and 3) examine the autocrine regulatory interactions between altered expression of the IL-1 axis and the TH2-type cytokines IL-4, IL-5 and GM-CSF, and the TH1-type cytokines, IL-2, IL-12 and IFN-gamma, and their receptors and to determine whether the above TH1- and TH2-type cytokines also exert a reciprocal modulatory action on the autocrine expression of the IL-1 axis of molecules. We anticipate that the results from our proposed studies will elucidate the role and mechanism of action of the IL-1 axis in the development of the "pro-asthmatic" ASM phenotype.

支气管哮喘的特征是气道炎症、对支气管收缩剂激动剂的气道过度狭窄以及对β-肾上腺素受体介导的气道松弛的反应减弱。多种细胞因子与哮喘气道炎症反应的发病机制有关，并且特定细胞因子，尤其是 IL-1β，也被证明可以直接调节气道平滑肌 (ASM) 反应性。鉴于后者，加上我们最近的观察表明 IL-1β 在耦合 Fc 受体激活和特应性哮喘致敏状态下 ASM 反应性变化中具有重要的自分泌作用，本提案旨在检查 IL-1β 的作用分子轴（即 IL-1α、IL-1β、IL-1RI、-RII、IL-1ra 和 ICE），介导功能改变和促炎表型的特征特应性哮喘致敏 ASM。因此，提出研究来检验以下相互关联的假设： I：人类 ASM 构成了一个自分泌环境，当在特应性（IgE 介导的）致敏状态下被激活时，会诱导构成 IL-1 轴的各种分子的自体合成; II：这些分子在 ASM 反应性改变的自分泌诱导以及特应性致敏状态下特定 TH1 和 TH2 型细胞因子及其受体的表达和释放改变中发挥相互作用。因此，该项目的具体目标是：I) 检查自体诱导的 IL-1 轴表达改变，并确定特定 Fc 受体的激活在诱导 IL-1 轴分子表达改变中的作用。特应性敏感状态； 2) 检查IL-1轴诱导表达改变在介导特应性敏感状态下ASM反应性变化中的作用和机制，并评估诱导改变的受体/G蛋白偶联表达和作用以及激动剂的存在-介导主要第二信使肌醇 1,4,5-三磷酸 (Ins(1,4,5)P3) 和 cAMP 的积累； 3) 检查 IL-1 轴表达改变与 TH2 型细胞因子 IL-4、IL-5 和 GM-CSF 以及 TH1 型细胞因子 IL-2、IL-12 和 GM-CSF 之间的自分泌调节相互作用。 IFN-γ及其受体，并确定上述TH1型和TH2型细胞因子是否也对分子IL-1轴的自分泌表达发挥相互调节作用。我们预计我们提出的研究结果将阐明 IL-1 轴在“促哮喘”ASM 表型发展中的作用和作用机制。

项目成果

Genetic analyses in asthma: current concepts and future directions.

• DOI: 10.2165/00129785-200202030-00001
• 发表时间: 2002-01-01
• 期刊: American journal of pharmacogenomics : genomics-related research in drug development and clinical practice
• 作者: Hakonarson, Hakon;Halapi, Eva
• 通讯作者: Halapi, Eva

Advances in the development of genetic markers for the diagnosis of disease and drug response.

• DOI: 10.1586/14737159.2.5.411
• 发表时间: 2002-09-01
• 期刊: Expert review of molecular diagnostics
• 影响因子: 5.1
• 作者: Halapi, Eva;Hakonarson, Hakon
• 通讯作者: Hakonarson, Hakon