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: 8460822
• 负责人: William Janssen
• 金额: $ 51.94万
• 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 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8460822
• 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; Lung diseases; 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; inhibitor/antagonist; insight; lung injury; macrophage; monocyte; mouse model; neutrophil; novel; 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分辨率期间会凋亡，但是调节巨噬细胞死亡的机制尚不清楚。必须去除巨噬细胞以解决炎症和完整的组织修复的适当时间范围也未知。解决这些知识的差距至关重要，因为巨噬细胞在炎症性病变中的持久性与组织损伤，组织修复异常甚至纤维化有关。我们的数据表明，在急性肺损伤的自限模型中，死亡受体FAS的激活驱动了菌只巨噬细胞的细胞凋亡，并且在急性肺损伤（ALI）的非分辨模型中，巨噬细胞凋亡降低了。基于我们的初步数据，我们假设抗凋亡分子，细胞抗抑制蛋白（C-FLIP）是巨噬细胞凋亡的关键调节剂，并且C-FLIP可以预防在非分解形式的急性肺损伤形式中适当定时的巨噬细胞凋亡。该假设将在ALI的小鼠模型和从患有急性呼吸窘迫综合征的人类受试者获得的巨噬细胞中进行检验。 ALI的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和延迟巨噬细胞凋亡的病理后果的最佳时间。实现该提案的目的将为调节炎症终止并影响组织修复的生物学机制提供重要的见解，为治疗非分解ALI和其他形式的炎症性肺部病的新疗法铺平了道路。