Inflammation is a localized protective response that serves to destroy, both the noxious agent and injured tissue. It results from substances released by selectively recruited and activating tissue-resident and circulating cells. An adequate inflammatory response is important in controlling infections, wound repair, and vasomotor responses. However dysregulated or inflammation leads to pathologic conditions such as acute lung injury, ischemia reperfusion and occlusive thrombosis. The consistent pattern of development and resolution of inflammatory reactions suggests the existence of a series of overlapping but distinct mechanisms for cell recruitment, importantly including critical mediators of the cellular inflammatory response, cell adhesion molecules (CAM). These proteins participate in every step of the inflammatory response and are subjected to an intricate and incompletely understood regulation. Cytokines, endotoxins, and more recently, reactive oxygen species (ROS) including hydrogen peroxide (H2O2), superoxide (O2), nitric oxide (NO) and lipid hydroperoxide (LOOH) have been shown to play key signaling roles in cell function. One of them, NO, has recently been recognized to have the ability to mediate signal transduction events via stimulation of guanylate cyclase-mediated cGMP synthesis. Furthermore, NO is able to modulate oxygen radical reactions and pathological processes associated with oxidant injury, including the modulation of inflammatory responses. In this context, the overall goal of this proposed research plan is to explore mechanisms whereby NO modulates pulmonary inflammation. To understand the conditions and reactions underlying the precise mechanisms by which NO exerts either tissue protection or tissue toxicity in acute lung injury and its associated inflammatory reactions, a number of experimental aims will be pursued to test the hypothesis that NO mediates acute inflammatory events by redox experimental aims will be pursued to test the hypothesis that No mediates acute inflammatory events by redox modulation of CAM expression. Specifically, we will 10 examine the influence of NO on in vitro migration and adhesion of inflammatory cells; 2) define the impact of NO on the expression of transcriptional factors regulation the expression of the cell adhesion molecules ICAM-1, VCAM-1 and P-selectin and 3) explore the mechanisms underlying the modulatory action of NO towards cytokine-(e.g. TNF-alpha IL-1) and reactive species-induced cell adhesion molecule expression. Successful accomplishment of the proposed aims will reveal the regulatory roles played by NO in the acute inflammation and diverse pathological processes. Finally, the proposed studies serve as a platform for understanding and developing novel therapeutic strategies towards inflammatory tissue injury.
