Ischemic Preconditioning on Liver Ischemia Reperfusion Injury: How Far is the Bedside from the Bench?

This article refers to:

Protective Effects of Ischemic Preconditioning Protocols on Ischemia-Reperfusion Injury in Rat Liver

Ischemia reperfusion injury (IRI) is a complex pathophysiologic process that occurs during liver transplantation and liver resection. It is a significant cause of morbidity and mortality in liver surgery [1–3]. Ischemic preconditioning (IPC) is deliberate brief period of ischemia followed by a short interval of reperfusion prior to a prolonged period of ischemia. The protective effects of IPC were initially demonstrated in a canine model of myocardial ischemia by Murry et al in 1986 [4], and was first validated in the liver by Lloris-Carsí et al in 1993 [5]. IPC can be either applied directly to the target organ [4] or remotely to a distant vascular bed [6]. Although IPC confer protective effects against liver IRI in small animal models [7–11], the optimal protocol remains poorly understood. The two major IPC methods established using a rat partial hepatic warm IRI model are 5 min of ischemia/10 min of reperfusion and 10 min of ischemia/10 min of reperfusion. it is not known which of these two methods results in better outcomes and whether hepatic IRI is similar to IRI in cardiac muscle, skeletal muscle, and other tissues and organs in that shorter times (5 min of ischemia/5 min of reperfusion) performed for multiple cycles would result in improved protective effects.

To help answer these questions, Recently, Lin et al. compared several preconditioning protocols of the IR cycle in rats to aid in identifying the optimal IPC protocol [12]. Three IPC conditions as follows: (1) ischemia for 5 min/reperfusion for 10 min; (2) ischemia for 5 min/reperfusion for 5 min, repeated three times; and (3) ischemia for 10 min/reperfusion for 10 min. Compared to the IRI control group, all of the IPC groups showed significant decreases in liver transaminase activity levels, alleviation of pathological injury-associated changes, and a decrease in liver cell apoptosis. The extensively protective effects were observed in rats with three repetitions of 5 min of ischemia/5 min of reperfusion, providing the optimal protection against liver IRI among the protocols studied.

The precise mechanism by which IPC confers protection remains poorly understood. This protection has been linked to various mechanisms, such as the preservation of the energetic pool, decrease of cellular apoptosis, increase of autophagy and modulation of microcirculation disturbance and inhibition of innate immune responses [13,14]. Reactive oxygen species (ROS) and oxidant stress are the most significant pathologic mediators of IRI [15–17]. In this study, IRI significantly decreased the superoxide dismutase (SOD) activity and glutathione (GSH) content in the liver while significantly increased the malondialdehyde (MDA) content, indicating that IRI decreased tissue antioxidation ability and induced lipid over-oxidation. At the same time, IRI increased the number of TUNEL-positive cells. However, compared to the IRI group, the SOD activity and GSH content of all IPC groups increased significantly, the MDA content, TUNEL-positive cell number significantly decreased, indicating that IPC may attenuate liver cell apoptosis induced by oxidative stress, thus protecting the liver from IRI.

IPC has mainly been described as a protective approach against liver IRI in animal models of liver surgery. Its beneficial effects in clinical trials of liver resection and liver transplantation are controversial [18–21]. A meta-analysis of 13 randomized control trials involving 913 patients that underwent liver resection failed to find any statistically significant difference in morbidity or mortality rates among study participants [22]. Subgroup analysis revealed that the postoperative morbidity in the cirrhosis subgroup and the cirrhosis subgroup was significantly less for the IPC group compared with the control group. Moreover, a recent meta-analysis of IPC performed on transplant donor livers prior to graft retrieval found evidence of a reduction in liver injury following transplantation and a large reduction in 1-year mortality which was not statistically significant [23]. A possible explanation for this discrepancy is that the magnitude of the benefit conferred by IPC is proportional to the severity of the IR injury [24]. In the majority of clinical studies, IPC was more effective in reducing IRI in subjects with steatotic or cirrhotic livers [22]. Furthermore, these conflicting results may also be caused by the IPC protocols that vary between studies and are unlikely to be optimal.

In conclusion, IRI is a major cause of post-operative liver dysfunction, morbidity and mortality following liver resection and transplantation. IPC has emerged as a protective approach to attenuate IRI in small animals. Its translation into clinical practice has been difficult. Future high-quality clinical trials are needed to illustrate the role of IPC in patients with different IPC protocols, different liver background and diseases, different surgical protocols and extent of liver resections.

Disclosure statement

No potential conflict of interest was reported by the authors.