Macrophage Apoptosis in Resolution of Acute Lung Injury

巨噬细胞凋亡在缓解急性肺损伤中的作用

• 批准号: 9043930
• 负责人: William Janssen
• 金额: $ 44.51万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9043930
• 关键词: Accounting; Acids; Acute; Acute Lung Injury; Address; Adult Respiratory Distress Syndrome; Affect; Agonist; Alveolar Macrophages; Apoptosis; Apoptotic; Area; Bleomycin; CASP8 and FADD-like apoptosis regulating protein; CD95 Antigens; Cell Death; Cells; Cessation of life; Cicatrix; Clinical; Clinical Treatment; Clinical Trials; Contracts; Data; Development; Disease; Excision; Exhibits; Fas Signaling Pathway; Fibrosis; Granulation Tissue; Health Care Costs; Hour; Impaired wound healing; Individual; Inflammation; Inflammatory; Injury; Kidney; Knowledge; Lead; Length of Stay; Lesion; Liver; Lung; Malignant Neoplasms; Modeling; Outcome; Pathologic; Pathway interactions; Patients; Phase; Process; Recovery; Recruitment Activity; Resistance; Resolution; Role; Signal Transduction; Skin; Structure; Testing; Time; Tissues; United States; Work; Wound Healing; base; human subject; inflammatory lung disease; inhibitor/antagonist; insight; lung injury; macrophage; monocyte; mouse model; neutrophil; novel therapeutics; prevent; receptor; tissue repair

DESCRIPTION (provided by applicant): Macrophages are known to undergo apoptosis during the resolution of inflammation in the lungs, however the mechanisms that regulate macrophage cell death are not known. The appropriate time frame during which macrophages must be removed to resolve inflammation and complete tissue repair also remains unknown. Addressing these gaps in knowledge is of significant importance since persistence of macrophages in inflammatory lesions is associated with tissue injury, abnormal tissue repair and even fibrosis. Our data show that activation of the death receptor, Fas, drives the apoptosis of recruited macrophages in self-limited models of acute lung injury and that macrophage apoptosis is reduced in non-resolving models of acute lung injury (ALI). Based on our preliminary data, we hypothesize that the anti-apoptotic molecule, cellular FLICE inhibitory protein (c-FLIP) is a critical regulator of macrophage apoptosis, and that c-FLIP prevents appropriately timed macrophage apoptosis in non-resolving forms of acute lung injury. This hypothesis will be tested in mouse models of ALI and in macrophages obtained from human subjects with the acute respiratory distress syndrome. Mouse models of ALI will also be used to determine the optimal time during which macrophages must be cleared from the lungs to terminate inflammation and the pathologic consequences of delayed macrophage apoptosis. Achieving the aims of this proposal will provide important insights into the biologic mechanisms that regulate the termination of inflammation and affect tissue repair, paving the way for novel therapies to treat non-resolving ALI and other forms of inflammatory lung disease.

描述（由申请人提供）：已知巨噬细胞在肺部炎症消退过程中会发生凋亡，但调节巨噬细胞死亡的机制尚不清楚。必须清除巨噬细胞以解决炎症和完成组织修复的适当时间范围也仍然未知。解决这些知识空白非常重要，因为巨噬细胞在炎症病变中的持续存在与组织损伤、异常组织修复甚至纤维化有关。我们的数据表明，死亡受体 Fas 的激活可驱动急性肺损伤自限性模型中募集的巨噬细胞凋亡，并且在急性肺损伤（ALI）非缓解模型中巨噬细胞凋亡减少。根据我们的初步数据，我们假设抗凋亡分子细胞 FLICE 抑制蛋白 (c-FLIP) 是巨噬细胞凋亡的关键调节因子，并且 c-FLIP 在适当时间的急性肺非消退形式中预防巨噬细胞凋亡受伤。这一假设将在 ALI 小鼠模型和从患有急性呼吸窘迫综合征的人类受试者中获得的巨噬细胞中进行测试。 ALI 小鼠模型还将用于确定必须从肺部清除巨噬细胞以终止炎症的最佳时间以及延迟巨噬细胞凋亡的病理后果。实现该提案的目标将为调节炎症终止和影响组织修复的生物学机制提供重要见解，为治疗未解决的 ALI 和其他形式的炎症性肺部疾病的新疗法铺平道路。