Macrophage Apoptosis in Resolution of Acute Lung Injury

描述（由申请人提供）：已知巨噬细胞在肺部炎症消退期间经历细胞凋亡，然而调节巨噬细胞死亡的机制尚不清楚。巨噬细胞必须被去除以解决炎症和完成组织修复的适当时间框架也仍然未知。解决这些知识差距是非常重要的，因为巨噬细胞在炎性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，激活死亡受体，Fas，驱动招募的巨噬细胞在自限性模型的急性肺损伤和巨噬细胞凋亡减少急性肺损伤（ALI）的非解决模型。基于我们的初步数据，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在急性肺损伤的非消退形式中防止适当定时的巨噬细胞凋亡。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获得的巨噬细胞中进行测试。还将使用ALI小鼠模型来确定必须从肺中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，为治疗非消退性ALI和其他形式的炎症性肺病的新疗法铺平道路。

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.