Regulation of airway epithelial repair

气道上皮修复的调节

• 批准号: 7278605
• 负责人: STEVEN R WHITE
• 金额: $ 36.54万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-17 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7278605
• 关键词: Actins; Address; Asthma; Bronchoalveolar Lavage Fluid; Bronchoconstriction; Chronic; Condition; Disease; Eating; Epithelial; Epithelial Cells; Epithelium; Gene Expression; Heat Shock Protein 27; Hour; Immigration; Inflammatory; Injury; Interleukin-1 beta; Interleukin-13; JUN gene; Lead; MAP-kinase-activated kinase 2; MAPK14 gene; MAPKAP kinase-2; Mediating; Mitogen-Activated Protein Kinases; Mucous Membrane; N-terminal; Numbers; Pathogenesis; Pathway interactions; Process; Production; Protein Kinase; Regulation; Role; Signal Pathway; Signal Transduction; Stimulus; Stream; Stretching; Transcription Factor AP-1; Tumor Necrosis Factor-alpha; airway epithelium; airway remodeling; asthmatic airway; cell motility; common cellular transcription factor ATF; cytokine; human MAPK14 protein; injured airway; insight; migration; repaired; transcription factor

DESCRIPTION (provided by applicant): Persistent damage to airway epithelium is a cardinal feature in chronic, severe asthma, and repair of this damaged epithelium frequently does not occur in asthmatic airways. We suggest a new paradigm that may explain why epithelial repair in asthmatic airways does not function properly. In normal airways, injury induces the production of "pro-inflammatory" cytokines such as TNFa and IL-1¿. Both cytokines activate specific signaling pathways that activate the mitogen-activated protein kinases (MAPKs), such as p38 MARK and JNK, that in turn initiate early steps in the migration of airway epithelial cells to cover damaged airways. However, the milieu of the asthmatic airway acts to slow this repair process, by repeated stretching and compressing airways via severe and continued bronchoconstriction that will impair MAPK-mediated migration. To address this paradigm we propose the following specific aims: Aim #1. Determine whether or not p38 MARK and JNK regulate the migration of airway epithelial cells after injury. We hypothesize that signaling via MAPK pathways within minutes to hours of injury integrates a number of local and regional stimuli that are pro-reparative, by activating gene expression via transcription factors such as ATF-2 and AP-1, and by initiating actin remodeling via p38 MAPK mediated activation of heat shock protein-27. Aim #2. Determine whether or not cyclic stretch and compression impairs airway epithelial cell migration by down-regulating activation of p38 MAPK and JNK, specifically by suppressing upstream pathways that ordinarily lead to their activation. We hypothesize that cyclic stretch and compression counter the proreparative signals and inhibit repair in part by down-regulating activation of p38 MAPK and/or JNK, and that this occurs in part by suppressing activation of upstream activating pathways. Aim #3. Determine whether or not bronchoalveolar lavage fluid, IL-1¿ and TNFa accelerate airway epithelial cell migration via p38 MAPK and JNK, and whether IL-1¿ and TNFa fail to accelerate repair under conditions of cyclic stretch and compression. We hypothesize that TNFa and IL-13 accelerate the process of epithelial repair after injury via activation of MAPKs, but fail to do so when countered by cyclic stretch and compression. Other products found within asthmatic airways, as can be collected in bronchoalveolar lavage fluid, also stimulate repair but will not be able to overcome the inhibitory effects of cyclic deformation on airway epithelial cell migration. Understanding the steps in the signaling pathway in early cell migration, the role of cytokines in initiating migration, and the physical forces that impair early, required signaling and thereby slow migration will help us to understand how the airway epithelium may fail to repair adequately in chronic asthma.

描述（由申请人提供）：气道上皮细胞的持续性损伤是慢性重度哮喘的主要特征，在哮喘气道中通常不会发生这种受损上皮细胞的修复。我们提出了一个新的范例，可以解释为什么上皮修复哮喘气道不能正常工作。在正常气道中，损伤诱导“促炎”细胞因子如TNF α和IL-1？的产生。这两种细胞因子激活特异性信号通路，其激活促分裂原活化蛋白激酶（MAPK），如p38 MARK和JNK，其继而启动气道上皮细胞迁移以覆盖受损气道的早期步骤。然而，哮喘气道的环境通过严重和持续的支气管收缩反复拉伸和压缩气道，从而减缓了这种修复过程，这将损害MAPK介导的迁移。为了解决这个问题，我们提出了以下具体目标：目标#1。确定p38 MARK和JNK是否调节损伤后气道上皮细胞的迁移。我们假设，通过MAPK途径在损伤后数分钟至数小时内的信号传导整合了许多局部和区域刺激，这些刺激是促修复的，通过转录因子如ATF-2和AP-1激活基因表达，并通过p38 MAPK介导的热休克蛋白-27激活启动肌动蛋白重塑。目标2。确定周期性拉伸和压缩是否通过下调p38 MAPK和JNK的激活（特别是通过抑制通常导致其激活的上游途径）来损害气道上皮细胞迁移。我们假设周期性伸展和压缩会抵消修复信号并部分通过下调p38 MAPK和/或JNK的激活来抑制修复，并且这部分是通过抑制上游激活途径的激活来发生的。目标3。确定支气管肺泡灌洗液、IL-1 <$和TNFa是否通过p38 MAPK和JNK加速气道上皮细胞迁移，以及IL-1 <$和TNFa是否不能在周期性拉伸和压缩条件下加速修复。我们假设TNF α和IL-13通过激活MAPK加速损伤后上皮修复的过程，但当受到周期性拉伸和压缩时却不能做到这一点。在哮喘气道内发现的其他产物，如可以在支气管肺泡灌洗液中收集的，也刺激修复，但不能克服循环变形对气道上皮细胞迁移的抑制作用。了解早期细胞迁移的信号通路步骤，细胞因子在启动迁移中的作用，以及损害早期所需信号传导从而减缓迁移的物理力量，将有助于我们了解慢性哮喘气道上皮细胞如何无法充分修复。