Regulation of airway epithelial repair

气道上皮修复的调节

• 批准号: 7620384
• 负责人: STEVEN R WHITE
• 金额: $ 36.51万
• 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/7620384
• 关键词: Actins; Address; Asthma; Bronchoalveolar Lavage Fluid; Bronchoconstriction; Chronic; 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; 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（由适用提供）：对气道上皮的持续损害是慢性，严重哮喘的基本特征，并且在哮喘气道中经常不会发生这种损坏的上皮的修复。我们建议一个新的范式，可以解释为什么哮喘气道中的上皮修复无法正常运行。在正常气道中，损伤引起了“促炎性”细胞因子（例如TNFA和IL-1缺）的产生。两种细胞因子都激活了特定的信号通路，该特定信号通路激活有丝分裂原激活的蛋白激酶（MAPKS），例如p38 mark和JNK，进而开始在气道上皮细胞迁移的早期步骤中覆盖受损的气道。然而，哮喘气道的环境通过重复伸展和压缩气道通过严重和持续的支气管收缩来减缓这一修复过程，这会损害MAPK介导的迁移。为了解决此范式，我们提出以下特定目的：目标＃1。确定p38标记和JNK是否调节受伤后气道上皮细胞的迁移。我们假设通过MAPK途径在伤害的几分钟内通过MAPK途径发出信号会通过转录因子（例如ATF-2和AP-1）激活基因表达，从而整合了许多是依据的局部和区域刺激，并通过p38 MAPK介导的热休克蛋白-27激活p38 MAPK通过p38 mapk介导的肌动蛋白重塑。目标＃2。确定循环拉伸和压缩是否通过下调上皮细胞的迁移来下调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抑制上游途径。我们假设循环拉伸和压缩对抗前期信号，并部分通过下调p38 mapk和/或JNK的激活来抑制修复，这部分是通过抑制上游激活途径的激活而发生的。目标＃3。确定是否通过p38 MAPK和JNK加速了支气管肺泡灌洗液，IL-1和TNFA加速气道上皮细胞迁移，以及在环状伸展和压缩条件下IL-1¿和TNFA是否无法加速修复。我们假设TNFA和IL-13通过激活MAPK损伤后加速了上皮修复的过程，但是当通过循环拉伸和压缩来对抗时，tnfa和il-13却无法这样做。可以在支气管肺泡灌洗液中收集的哮喘气道中发现的其他产品，也可以刺激修复，但将无法克服环状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传导途径的步骤，细胞因子在启动迁移中的作用以及早期损害的物理力，需要信号传导，从而缓慢迁移将有助于我们了解气道上皮可能如何在慢性哮喘中适当修复。