Blockade of the ?-arginine/NO synthase pathway worsens hepatic apoptosis and liver transplant preservation injury

Abstract

Organ graft preservation injury is a major problem complicating liver transplantation. The L-arginine/nitric oxide pathway has protective effects in several models of liver injury. The purpose of this study was to evaluate the role of the L-arginine/NO synthase (NOS) pathway on liver preservation injury and to characterize endogenous inducible NOS (iNOS) expression. Orthotopic liver transplantation was performed with 18-hour University of Wisconsin preservation solution in syngeneic rats. Recipient rats were either untreated or treated with L-arginine, D-arginine, nonspecific NOS inhibitor N G -nitro-L-arginine methyl ester (L-NAME), or iNOS selective inhibitor L-N 6 -(1-imino-ethyl)lysine (L-NIL) after revascularization. As early as 1 hour following reperfusion, circulating arginine levels decreased 10-fold and ornithine levels increased 4-fold. A corresponding increase in arginase I protein was detected in serum. To address the profound arginine deficiency, we supplemented recipients with arginine after transplantation. L-arginine (but not D-arginine) supplementation significantly reduced preservation injury 12 hours after reperfusion, suggesting that the protective effect of L-arginine was mediated through the generation of NO. iNOS protein expression peaked in the liver 6 to 12 hours following reperfusion. Blockade of the L-arginine/NO pathway with L-NAME significantly increased necrotic and apoptotic cell death in the transplanted graft. Addition of the iNOS selective inhibitor L-NIL mildly increased liver transaminase levels and also increased apoptosis in the liver graft. In conclusion, transplant recipients are profoundly arginine deficient postreperfusion due to arginase release. L-Arginine supplementation and NO synthesis decrease necrotic and apoptotic cell death and ameliorate liver transplant preservation injury. (HEPATOLOGY 2002;36:573-581.)

Urea production during normothermic machine perfusion: Price of success?

“…1 Although it is yet unproven, data exist that show that L-arginine, for example, reduces preservation injury through the stimulation of nitric oxide production. 5 Further work is needed to determine whether the benefit of amino acid infusion outweighs any deleterious effects. If it does, high levels of urea production may be unavoidable and will need to be addressed in another way.…”

Arginase blockade protects against hepatic damage in warm ischemia-reperfusion

“…Inflammatory cytokines, such as TNFα and IL-6, have been shown to play key roles in the pathophysiology of hepatic I/R injury (12,13). We measured hepatic levels of these cytokines after I/R using real time quantitative PCR.…”

L-arginine in the ischemic phase protects against liver ischemia-reperfusion injury

“…Hepatoprotection via the LG-NOS pathway has been previously established in animal models of IRI 18,19 . Given that the LG-NOS pathway has been reported to play critical roles during inflammation, our data support the hypothesis that the administration of LG during the ischemic phase is beneficial by attenuating liver injury in a model of warm hepatic IRI.…”

“…Collectively, these observations suggest a balance between the local NO concentration and the time of NO exposure in determining the outcome of liver IRI 8 . Irrespective of the precise mechanisms involved, increased inflammation and cytotoxicity are key components in hepatocellular dysfunction during the pathogenesis of liver IRI [16][17][18][19][20] .…”

“…The LG-NOS pathway has been critically implicated in liver IRI, and most studies have suggested that intravenous LG infusion increases NO levels and protects the liver against damage due to IRI [8][9][10][11][12][13][14][15][16][17][18][19][20] .…”