E-cadherin shedding in chronic lung injury

慢性肺损伤中 E-钙粘蛋白脱落

• 批准号: 8204957
• 负责人: John K McGuire
• 金额: $ 41.09万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8204957
• 关键词: Acute; Acute Lung Injury; Adult Respiratory Distress Syndrome; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Attention; Binding; Biological Process; Bleomycin; Bone Marrow; Bronchoalveolar Lavage; Cell Surface Receptors; Cell physiology; Cells; Chronic; Clinical; Data; Dendritic Cells; E-Cadherin; Epithelial; Epithelium; Functional disorder; Goals; Immune; Immune response; In Vitro; Infection; Inflammation; Inflammatory; Injury; Integrins; Intensive Care Units; Interleukin-10; Interleukin-6; Intervention; Knockout Mice; Learning; Leukocytes; Ligands; Location; Lung; Lung Inflammation; Lung diseases; Matrilysin; Messenger RNA; Mus; Pathway interactions; Patients; Pharmacological Treatment; Phase; Phenotype; Pneumonia; Population; Positioning Attribute; Process; Pseudomonas aeruginosa; Public Health; Regulatory T-Lymphocyte; Resolution; Role; Signal Transduction; Structure of parenchyma of lung; Supportive care; Survivors; T-Lymphocyte; Tissues; Toxic effect; Wild Type Mouse; base; cytokine; functional genomics; in vivo; injured; lung injury; lung repair; mortality; novel therapeutics; prevent; programs; public health relevance; receptor; repaired; response; response to injury; sensor

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.

描述（由申请方提供）：尽管在定义急性肺损伤/急性呼吸窘迫综合征（ALI/ARDS）的病理生理学方面取得了进展，支持性治疗也取得了进展，但死亡率仍高达30- 40%，并且不推荐特定的药物干预来阻断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-钙粘蛋白脱落与表达CD 103（aE 7-整联蛋白）的树突状细胞（DC）的特化群体的肺募集相关，CD 103是一种白细胞表面受体，E-钙粘蛋白是其唯一已知的配体。在铜绿假单胞菌感染或博莱霉素毒性诱导的ALI小鼠中，缺乏CD 103的小鼠表现出嗜酸性炎症的延迟消退，并且比野生型小鼠具有更高的死亡率。在体外，可溶性E-钙粘蛋白改变了LPS诱导的骨髓来源的树突状细胞的细胞因子谱，使其具有抗炎表型，并且在体内铜绿假单胞菌肺炎消退期间，缺乏CD 103的小鼠在支气管肺泡灌洗液（BAL）中具有比野生型小鼠少得多的抑制性调节性T细胞。这些数据支持我们的总体假设，即E-钙粘蛋白-CD 103相互作用促进急性肺损伤的解决。使用互补的体内和体外的方法，我们将定义的机制，E-cadherin程序CD 103 + DC解决肺部炎症。具体目标1将评估E-cadherin-CD 103相互作用如何控制树突状细胞功能。特异性目标2将确定损伤肺中肺CD 103 + DC中激活的抗炎途径，特异性目标3将阐明CD 103 + DC解决急性肺部炎症的下游效应机制。重要性：我们的长期目标是了解肺上皮损伤反应如何促进修复，并且所提出的研究的结果应该形成旨在增强这种临床条件下的内源性肺修复的新策略的基础，目前的治疗方法非常有限。 公共卫生相关性：急性肺损伤是肺部疾病的常见和严重原因，无特定的药物治疗。在许多患者中，急性损伤进展为慢性肺损伤，其特征在于持续的肺功能障碍和虚弱。尽管人们对引起肺损伤的生物学过程了解很多，但对解决急性肺损伤的先天机制却知之甚少。因此，计划中的研究结果应该加强对上皮细胞和免疫细胞如何相互作用以限制肺损伤进展的基本理解，并可能为这一困难的临床问题确定新的治疗策略。