E-cadherin shedding in chronic lung injury

描述（由申请人提供）：尽管在定义急性肺损伤/急性呼吸窘迫综合征（ALI/ARDS）的病理生理学和支持治疗方面取得了进展，但死亡率仍然高达30-40%，并且没有特定的药物干预可以推荐阻止ALI的进展。因此，最近的注意力集中在确定促进ALI解决的途径上。我们的新数据表明，E-cadherin脱落与表达CD103 （aE¿7整合素）的特殊树突状细胞（DC）群体的肺募集有关，CD103 （aE¿7整合素）是白细胞细胞表面受体，E-cadherin是唯一已知的配体。在铜绿假单胞菌感染或博来霉素毒性引起的ALI小鼠中，缺乏CD103的小鼠表现出中性粒细胞炎症的延迟消退，死亡率高于野生型小鼠。在体外，可溶性E-cadherin将lps诱导的骨髓树突状细胞的细胞因子谱改变为抗炎表型，并且在铜绿假单胞菌肺炎的体内溶解过程中，缺乏CD103的小鼠在支气管肺泡灌洗（BAL）中的抑制性调节性T细胞比野生型小鼠少得多。这些数据支持我们的总体假设，即E-cadherin-CD103相互作用促进急性肺损伤的解决。采用体内和体外互补的方法，我们将确定e -钙粘蛋白编程CD103+ DC解决肺部炎症的机制。特异性目标1将评估E-cadherin-CD103相互作用如何控制树突状细胞功能。特异性目的2将确定损伤肺中CD103+ DC激活的抗炎途径，特异性目的3将阐明CD103+ DC解决急性肺炎症的下游效应机制。意义：我们的长期目标是了解肺上皮损伤反应如何促进修复，提出的研究结果应构成旨在增强内源性肺修复的新策略的基础，在这种临床条件下，目前的治疗相当有限。

DESCRIPTION (provided by applicant): Despite progress in defining the pathophysiology of acute lung injury/acute respiratory distress syndrome (ALI/ARDS) and advances in supportive care, mortality remains high at 30-40%, and no specific pharmacological intervention can be recommended for blocking progression of ALI. Thus, recent attention has focused on identifying pathways that promote resolution of ALI. Our new data show that E-cadherin shedding is associated with pulmonary recruitment of a specialized population of dendritic cells (DC) expressing CD103 (aE¿7-integrin), a leukocyte cell-surface receptor for which E- cadherin is the only known ligand. In mice with ALI induced by Pseudomonas aeruginosa infection or bleomycin toxicity, mice lacking CD103 showed delayed resolution of neutrophilic inflammation and had higher mortality than wild type mice. In vitro, soluble E-cadherin altered the LPS-induced cytokine profile of bone marrow derived dendritic cells to an anti-inflammatory phenotype, and mice lacking CD103 had far fewer suppressor regulatory T cells in the bronchoalveolar lavage (BAL) than wild type mice during resolution of P. aeruginosa pneumonia in vivo. These data support our overall hypothesis that E-cadherin-CD103 interactions promote resolution of acute lung injury. Using complementary in vivo and in vitro approaches, we will define the mechanisms by which E-cadherin programs CD103+ DC to resolve pulmonary inflammation. Specific Aim 1 will assess how E-cadherin-CD103 interactions control dendritic cell function. Specific aim 2 will determine the anti-inflammatory pathways activated in pulmonary CD103+ DC in the injured lung, and Specific Aim 3 will elucidate the downstream effector mechanisms by which CD103+ DC resolve acute lung inflammation. Significance: Our long-term goal is to understand how lung epithelial injury responses promote repair, and the results of the proposed studies should form the basis for new strategies aimed at enhancing endogenous lung repair in this clinical conditions for which current therapy is quite limited. PUBLIC HEALTH RELEVANCE: Acute lung injury is a common and severe cause of lung disease with no specific pharmacologic treatment. In many patients, acute injury progresses to a chronic lung injury characterized by persistent lung dysfunction and debilitation. Although much has been learned about the biological processes that incite lung injury, little is known about the innate mechanisms that resolve acute lung injury. Consequently, the results of the planned studies should enhance fundamental understanding of how epithelial and immune cells interface to limit progression of lung injury and may identify new therapeutic strategies for this difficult clinical problem.