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.
