E-cadherin shedding in chronic lung injury

慢性肺损伤中 E-钙粘蛋白脱落

• 批准号: 7782241
• 负责人: John K McGuire
• 金额: $ 41.5万
• 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/7782241
• 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; 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; 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性护理方面取得了进展，但死亡率仍然高达30%-40%，并且没有推荐特定的药物干预来阻止ALI的进展。因此，最近的注意力集中在寻找促进ALI解决的途径上。我们的新数据显示，E-钙粘素的脱落与表达CD103(AE7-整合素)的树突状细胞(DC)的特殊群体的肺招募有关，CD103是一种白细胞表面受体，E-钙粘素是其唯一已知的配体。在铜绿假单胞菌感染或博莱霉素中毒所致的ALI小鼠中，缺乏CD103的小鼠中性粒细胞炎症消退延迟，且死亡率高于野生型小鼠。在体外，可溶性E-钙粘附素将脂多糖诱导的骨髓来源的树突状细胞的细胞因子谱改变为抗炎表型，在体内解决铜绿假单胞菌肺炎的过程中，缺乏CD103的小鼠在支气管肺泡灌洗液(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-钙粘素-CD103相互作用促进急性肺损伤的缓解。利用体内和体外互补的方法，我们将确定E-钙粘素编程CD103+DC来化解肺部炎症的机制。具体目标1将评估E-钙粘素-CD103相互作用如何控制树突状细胞的功能。特异靶2将确定肺CD103+DC在损伤肺中激活的抗炎途径，特异靶3将阐明CD103+DC缓解急性肺部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，拟议的研究结果应该成为在目前治疗相当有限的临床条件下旨在增强内源性肺修复的新策略的基础。 公共卫生相关性：急性肺损伤是肺部疾病的一种常见而严重的原因，没有特殊的药物治疗。在许多患者中，急性损伤进展为以持续性肺功能障碍和虚弱为特征的慢性肺损伤。虽然人们对激发肺损伤的生物学过程已经了解很多，但对解决急性肺损伤的内在机制知之甚少。因此，计划中的研究结果将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了解，并可能确定这一棘手的临床问题的新治疗策略。