Title: Response to antioxidant therapy in liver ischemia-reperfusion injury
Abstract: Medina et al.1 propose the use of antioxidant therapies shown benefits in chronic liver disease, to settings of liver ischemia-reperfusion (I/R) injury, as some mechanisms for liver injury are similar. However, the pathways of liver injury are complex and there are also major differences. Acute adenosine triphosphate depletion occurs with ischemia but not in chronic liver disease. Also, the signaling pathways and the mechanisms of cell death are different in settings of acute liver injury and chronic liver disease.2, 3 I/R, ischemia-reperfusion. Medina et al.1 cite nitric oxide as a good example of a common pathogenesis. However, there is still controversy in the literature regarding the role of nitric oxide in liver I/R.4-6 Different studies have shown inducible nitric oxide synthase inhibition to be either beneficial or detrimental.7 Furthermore, use of a selective inducible nitric oxide synthase inhibitor showed beneficial effects in experimental models with endotoxemia,8, 9 but not with liver I/R.9 We have found (our unpublished data) that large amounts of nitric oxide are generated during the late phase of liver I/R injury and that the beneficial effects of N-acetylcysteine are associated with reduced levels of nitric oxide. AM3 (Immunoferon) could have a role in modulating liver I/R due to its effect on inducible nitric oxide synthase inhibition.10 However, it also has other mechanisms of action that could affect liver I/R (inhibits tumor necrosis factor-α and interleukin-1β and elevates serum cortisol), which would have to be considered in any preclinical evaluation. We would agree that exogenous thiols have a promising role in modulating liver I/R injury, although there is limited and conflicting human data at the present time.11 Exogenous glutathione administration has limited cellular uptake due to its large molecular size. Glutathione precursors such as N-acetylcysteine, bucillamine, and possibly S-adenosylmethionine could be more effective in situations associated with severe intracellular oxidative stress. Our experimental studies in animals with normal or steatotic livers, undergoing lobar warm liver I/R injury,12, 13 and in a small randomized clinical trial in patients undergoing liver resections,14 showed beneficial effects of N-acetylcysteine administration. However, a pilot prospective randomized clinical trial on the administration of N-acetyl cysteine to donors, in human liver transplantation, also by our own group, showed no objective evidence of clinical benefit, perhaps highlighting the difficulty of tailoring a therapy without a readily-measurable end-point.15 Finally, we would suggest caution in assuming that combining antioxidant therapies with other strategies against liver I/R would necessarily be beneficial. Two experimental studies have found that N-acetyl cysteine administration reversed the protective effects of ischemic preconditioning.16, 17 Reactive oxygen species may be essential for the preconditioning response against I/R injury; the mechanisms of direct and indirect preconditioning must be fully determined before human clinical trials on combination therapies against liver I/R can be recommended. Georgios K. Glantzounis Phone: 44 207 8302757, FAX: 44 207 83026808 [email protected]*, Brian R. Davidson*, * HPB and Liver Transplant Unit, University Department of Surgery, Royal Free and University College Medical School, University College London, London, UK