Regulation of Pro-Asthmatic and Glucocorticoid Signaling by Airway Smooth Muscle

气道平滑肌对促哮喘和糖皮质激素信号的调节

• 批准号: 7755519
• 负责人: Michael Mateiu Grunstein
• 金额: $ 41.13万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7755519
• 关键词: 1-Phosphatidylinositol 3-Kinase; Address; Adhesions; Adverse effects; Allergens; Asthma; Breathing; CD4 Positive T Lymphocytes; Cell Communication; Cell surface; Cells; Coupled; Cytokine Signaling; Development; Enzymes; Event; Exhibits; Exposure to; Glucocorticoid Receptor; Glucocorticoids; Human; Hydroxysteroid Dehydrogenases; IgE; Light; Lipopolysaccharides; MAPK11 gene; MHC Class II Genes; Mediating; Mitogen Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Muscle Contraction; Muscle function; Pathway interactions; Phenotype; Play; Proteins; Receptor Signaling; Regulation; Relaxation; Respiratory Tract Infections; Rhinovirus; Risk Factors; Role; Signal Pathway; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; Stimulus; Superantigens; T-Cell Activation; T-Lymphocyte; Up-Regulation; Viral; abstracting; airborne allergen; asthmatic airway; asthmatic patient; atopy; cytokine; improved; meetings; microbial; pathogen; phosphodiesterase IV; pyroglyphid; receptor; respiratory smooth muscle; stress-activated protein kinase 1

DESCRIPTION (provided by applicant): Atopy and airway exposure to aeroallergens and microbial pathogens are primary risk factors for development of asthma. Compelling evidence that airway smooth muscle (ASM) plays a critical role in regulating the airway asthmatic phenotype includes that demonstrating that ASM expresses receptors for atopic and non-atopic stimuli that represent the above risk factors, and responds to these sensitizing stimuli by releasing cytokines, notably including Th2-type cytokines, that evoke pro-asthmatic changes in ASM constrictor and relaxation responsiveness. Recent studies demonstrate that activation of CD4+ T cells by superantigen (SAg)-presenting ASM cells also elicits Th2 cytokine release coupled to changes in ASM responsiveness. Contrasting these pro- asthmatic actions, our new findings demonstrate that ASM also exhibits a Th2 cytokine-induced mechanism that enables it to activate endogenous glucocorticoids (GCs) and, thereby, homeostatically oppose the adverse effects of Th2 cytokine signaling on ASM function. This new evidence, together with that demonstrating that both the cytokine-induced pro-asthmatic and homeostatic GC signaling in sensitized ASM are attributed to activation of MAPK signaling, raise the hypotheses that: I: The pro-asthmatic changes in ASM function elicited by atopic and non-atopic sensitizing stimuli, and by ASM/T cell interaction, are mediated by MAPK-dependent regulation of both cytokine expression and action; II: GC-mediated protection of ASM from the pro-asthmatic effects of cytokines is due to MAPK-dependent upregulation of GC signaling in the sensitized state; and III: ASM isolated from asthmatic patients exhibits enhanced MAPK-regulated pro-asthmatic signaling and impaired MAPK-regulated CG signaling. These hypotheses will be addressed in studies on ASM cells isolated from non- asthmatic and asthmatic airways. Accordingly, I: To investigate MAPK-dependent induction of pro-asthmatic changes in responsiveness in sensitized ASM, we will examine: 1) MAPK-dependent regulation of cytokine release and action in ASM sensitized by atopic (IgE) and by non-atopic stimuli including rhinovirus, dust mite allergen, or lipopolysaccharide; 2) Gi protein-mediated MAPK activation, resulting in altered PDE4 expression and its regulation of ASM contraction and relaxation; 3) MAPK-dependent regulation of CD4+ T cell activation by SAg-presenting ASM cells. II. To investigate MAPK-dependent regulation of GC signaling, we will examine MAPK-dependent regulation of the GC-activating enzyme, 11ss-hydroxysteroid dehydrogenase-1 (11ss-HSD1), and glucocorticoid receptor (GR) signaling in sensitized ASM; III. To determine whether asthmatic ASM exhibits perturbations in MAPK-dependent regulation of pro-asthmatic and GC signaling, we will compare asthmatic vs. non-asthmatic sensitized ASM cells with respect to differences in regulation of PDE4 expression and action, GC activation and signaling, and T cell activation by SAg-presenting ASM cells. The results from these studies are anticipated to identify key intrinsic perturbations in the signaling mechanisms in ASM that underlie expression of the airway asthmatic phenotype. (End of Abstract)

描述（由申请人提供）： 特应性和气道接触空气过敏原和微生物病原体是哮喘发生的主要危险因素。令人信服的证据表明，气道平滑肌 (ASM) 在调节气道哮喘表型中发挥着关键作用，包括证明 ASM 表达代表上述危险因素的特应性和非特应性刺激的受体，并通过释放细胞因子对这些敏化刺激做出反应，特别是包括 Th2 型细胞因子，可引起 ASM 收缩肌和松弛反应性的促哮喘变化。最近的研究表明，呈递超抗原 (SAg) 的 ASM 细胞激活 CD4+ T 细胞也会引起 Th2 细胞因子的释放，并导致 ASM 反应性的变化。与这些促哮喘作用相比，我们的新发现表明，ASM 还表现出 Th2 细胞因子诱导机制，使其能够激活内源性糖皮质激素 (GC)，从而稳态地对抗 Th2 细胞因子信号转导对 ASM 功能的不利影响。这一新证据，连同证明致敏 ASM 中细胞因子诱导的促哮喘和稳态 GC 信号传导均归因于 MAPK 信号传导的激活，提出了以下假设： I：特应性引起的 ASM 功能中的促哮喘变化和非特应性敏化刺激，以及 ASM/T 细胞相互作用，由细胞因子表达和作用的 MAPK 依赖性调节介导； II：GC 介导的 ASM 保护免受细胞因子促哮喘效应的影响，是由于敏化状态下 GC 信号的 MAPK 依赖性上调； III：从哮喘患者中分离出的 ASM 表现出增强的 MAPK 调节的促哮喘信号传导和受损的 MAPK 调节的 CG 信号传导。这些假设将在对从非哮喘和哮喘气道中分离的 ASM 细胞的研究中得到解决。因此，我：为了研究致敏 ASM 中促哮喘反应性变化的 MAPK 依赖性诱导，我们将检查： 1) 在特应性 (IgE) 和非特应性刺激致敏的 ASM 中，MAPK 依赖性细胞因子释放和作用调节包括鼻病毒、尘螨过敏原或脂多糖； 2) Gi蛋白介导的MAPK激活，导致PDE4表达改变及其对ASM收缩和舒张的调节； 3) SAg 呈递的 ASM 细胞对 CD4+ T 细胞激活的 MAPK 依赖性调节。二.为了研究 GC 信号传导的 MAPK 依赖性调节，我们将检查致敏 ASM 中 GC 激活酶、11ss-羟基类固醇脱氢酶-1 (11ss-HSD1) 和糖皮质激素受体 (GR) 信号传导的 MAPK 依赖性调节；三．为了确定哮喘 ASM 是否表现出对促哮喘和 GC 信号传导的 MAPK 依赖性调节的扰动，我们将比较哮喘与非哮喘致敏的 ASM 细胞在 PDE4 表达和作用、GC 激活和信号传导的调节方面的差异，以及呈递 SAg 的 ASM 细胞激活 T 细胞。这些研究的结果预计将确定 ASM 信号机制中关键的内在扰动，这些扰动是气道哮喘表型表达的基础。 （摘要完）