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过程中发生凋亡，但调节巨噬细胞死亡的机制尚不清楚。清除巨噬细胞以消除炎症和完成组织修复的适当时间框架也尚不清楚。由于巨噬细胞在炎性病变中的持续存在与组织损伤、组织异常修复甚至纤维化有关，因此解决这些知识空白具有重要意义。我们的数据显示，在自限性急性肺损伤模型中，死亡受体Fas的激活驱动募集的巨噬细胞凋亡，而在非溶解性急性肺损伤模型（ALI）中，巨噬细胞凋亡减少。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在非溶解型急性肺损伤中阻止适当时间的巨噬细胞凋亡。这一假设将在ALI小鼠模型和从急性呼吸窘迫综合征患者身上获得的巨噬细胞中进行验证。ALI小鼠模型还将用于确定巨噬细胞必须从肺部清除以终止炎症的最佳时间以及巨噬细胞延迟凋亡的病理后果。实现这一提议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，为治疗非解决性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.