Role of reactive metabolites of oxygen and nitrogen in the pathophysiology of post-ischemic liver injury.

摘要

Hepatic ischemia and reperfusion injury is a consequence of liver transplantation and resectional surgery. The mechanisms responsible for this injury are not well understood but appear to involve the synthesis and release of certain pro-inflammatory cytokines in the presence of an imbalance in the production of superoxide and nitric oxide (NO). The objective of this dissertation, therefore, was to characterize hepatic I/R in a mouse model and to define the role of and sources of nitric oxide and superoxide and their relationship to pro-inflammatory cytokine expression in the pathophysiology of post-ischemic liver injury.; The first series of studies addressed the expressional profile and role of tumor necrosis factor alpha (TNF-alpha), interleukin 1 beta (IL-1beta), and interleukin 12 (IL-12) in the post-ischemic mouse liver following both short and long periods of ischemia. The results of this study indicated that these cytokines are strongly expressed following both periods of I/R, that they are capable of injuring the post-ischemic liver in the absence of infiltrating neutrophils, and that their individual roles may be dependent on the length of ischemia.; The second series of studies identified the potent protective role of NO derived from endothelium within the post-ischemic liver. From these studies, it was apparent that NO is capable of modulating the expression of certain pro-inflammatory cytokines. In the following study, we identified interesting, yet paradoxical increases in liver injury in inducible NOS deficient mice in the absence of an up-regulation of this isoform in the post-ischemic wild type liver.; Finally, we identified the ability of superoxide itself to directly or indirectly injure the post-ischemic tissue injury. Further examination revealed the ability of superoxide scavenging to reduce the expression of TNF-alpha while also detailing important differences in the liver's response to short versus long periods of ischemia. We also provide evidence to implicate complement activation as an additional component of post-ischemic liver injury, independent of pro-inflammatory cytokine expression. Taken together, data presented in these studies demonstrates the ability of an imbalance in NO and superoxide to modulate the expression of certain pro-inflammatory mediators and mediate post-ischemic liver injury.