Hind Limb Remote Preconditioning of the Liver: A Role for Nitric Oxide and HO-1

Abstract

Lai et al. have shown a reduction in liver warm ischemia–reperfusion injury (IRI) with four cycles of 10 min hind limb remote ischemic preconditioning (RIPC) (1). This beneficial effect was demonstrated in a model of partial lobar ischemia, which differs considerably from the global ischemia found in the clinical scenario in liver resection or transplantation. We have previously shown in a more clinically relevant model of total hepatic ischemia (2) and reperfusion that three cycles of 10 min hind limb RIPC is sufficient to reduce the adverse effects of total hepatic IRI on the liver, lungs, and the cardiovascular system (3, 4). Lai et al. have shown the induction of heme oxygenase-1 but have not demonstrated a mechanism for RIPC in their study and speculated the involvement of nitric oxide. We have shown that nitric oxide is an important modulator of the protective effect of RIPC on hepatic IRI. There was a significant increase in hepatic vein and systemic arterial plasma nitrate/nitrite levels (5) in animals that underwent hind limb RIPC before total hepatic IRI, and this was associated with an increase in total hepatic blood flow (Fig. 1A, B) (4).FIGURE 1.: (A) Peripheral arterial and hepatic vein nitrate and nitrite (NOx) and (B) total hepatic blood flow at the end of two-hour reperfusion is reduced in the IRI group. RIPC indicates remote ischemic preconditioning; IRI, ischemia reperfusion injury.Another interesting finding in the study by Lai et al. was an absence of an increase in heme oxygenase-1 expression in peripheral lymphocytes in animals that underwent RIPC before partial liver IRI (1). This would suggest another more stable humoral mediator such as adenosine, which induces nitric oxide in the liver (4) resulting in activation of signal pathways and further induction of heme oxygenase-1 (1). The involvement of a second mediator or a neurogenic path as shown in remote cardiac (6) and gastric (7) preconditioning warrants further investigation in liver RIPC. Establishing the key mediators of RIPC is essential to optimizing the therapeutic benefit to patients undergoing liver transplantation because the mechanism will dictate whether organ donors or recipients are the target for RIPC. Sanjeev Kanoria Alexander M. Seifalian HPB and Liver Transplant Unit University Department of Surgery Royal Free Hospital London, U.K. Roger Williams Institute of Hepatology University College London Hospitals Royal Free and University College Medical School London, U.K. Brian R. Davidson HPB and Liver Transplant Unit University Department of Surgery Royal Free Hospital London, U.K.