Mechanisms Regulating Human Neutrophil Apoptosis

细胞凋亡（Ao）被认为是人类炎症反应有序消退的重要病理生理机制。 在过去的几年里，人们越来越认识到，多形核白细胞（PMN）在维持调节和失调的炎症反应之间的稳态中起着核心作用。 正常的PMN功能（即杀菌能力）有助于维持健康，而上调的PMN功能（即过度的蛋白水解酶释放和氧化剂产生）有助于各种疾病状态，包括ARDS和SIRS。 越来越多的证据表明，PMN Ao的失调与PMN半衰期的增加在促进这些不同的过程中起着关键作用。 随着越来越多的认识，肺损伤是区室化的病因，细胞因子的作用，调节中性粒细胞Ao在血管内空间已被研究。 然而，重要的是，对于PMN诱导的组织损伤发生必须发生的两个关键过程，即渗出进入结缔组织，随后通过与基质蛋白结合的整合素刺激和低氧血症+复氧形式的氧化应激，尚未探讨它们对PMN Ao的影响。 因此，了解调节控制PMN Ao的过程的基本机制对于提高我们维持炎症反应有序解决的能力至关重要。 我们的中心假设是，那些对同时开始炎症反应至关重要的过程是控制Ao反应的触发因素。 具体而言，我们建议整合素参与通过基质蛋白粘附和氧化应激的过程代表了两个关键的病理生理过程，调节PMN Ao。此外，我们建议，包括在这个过程中的机制的理解也将提供机会来调节PMN的半衰期（即随着时间的推移，Ao率），从而操纵人类炎症反应。

Apoptosis (Ao) is thought to represent a central pathophysiologic mechanism that contributes to the orderly resolution of the human inflammatory. Over the past several years, there has been an increasing recognition that the polymorphonuclear leukocyte (PMN) plays a central role in maintaining the homeostasis between a regulated and dysregulated inflammatory response. Normal PMN function (i.e. bactericidal capability) contributes to maintaining health while upregulated PMN function (i.e. excessive proteolytic enzyme release and oxidant production) contributes to various disease states including ARDS and SIRS. Increasing evidence suggests that dysregulated PMN Ao with increase PMN half-life plays a critical role in contributing to these diverse processes. With the increasing recognition that lung injury is compartmentalized in its etiology, the role of cytokines regulating PMN Ao in the intravascular space has been previously studied. Importantly, however, two critical processes that must occut for PMN-induced tissue injury to occur, i.e. diapedesis into the interstitium with subsequent integrin stimulation via binding to matrix proteins and oxidative stress in the form of hypoxemia + reoxygenation have not been probed with regard to their effect on PMN Ao. Therefore, understanding the fundamental mechanisms that regulate those processes that control PMN Ao is crucial to advance our ability to maintain an orderly resolution of the inflammatory response. Our central hypothesis is that those processes that are essential to beginning an inflammatory response at the same time are triggers that control the Ao response. Specifically, we propose that the processes of integrin engagement via matrix protein adherence and oxidative stress represent two key pathophysiologic processes that regulate PMN Ao. Further, we propose that an understanding of the mechanisms included in this process will also provide the opportunity to modulate the PMN half-life (i.e. rate of Ao over time) and thereby manipulate the human inflammatory response.