Hepatic Ischemia and Reperfusion Injury (IRI) occurs in a number of clinical hepatic surgeries, particularly in liver transplantation and hepatic resection 1, 2
, and hepatic steatosis is a primary factor increasing the extent of cellular injury incurred during IRI. The increasing use of steatotic livers for transplantation induces higher graft nonfunction rates, increased retransplantation rates and increased recipient mortality 3
Both pro-inflammatory cytokines and reactive oxygen species (ROS) play important part in liver IRI 4, 5
. ROS generated by Kupffer cells and hepatocytes can lead to direct damage on endothelial cells (ECs) and hepatocytes. The use of antioxidants to reduce oxidant injury during ischemia and reperfusion possess is postulated to improve hepatic recovery from dysfunction. The pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNFα) and interleukin-1 beta (IL-1β), released by activated Kupffer cells shortly after reperfusion, have dual role: over range expression of TNFα and IL-1β can induce more production of cytokines and granulocyte colony-stimulating factor, which enhance Kupffer cells activation and promote neutrophil infiltration in microcirculation of liver 6, 7
, then aggravate hepatic sterile inflammation after ischemia and reperfusion. One the other hand, TNFα and IL-1 are indispensable for liver regeneration 8
At the same time, cells can spontaneously respond to injury by activating defensive mechanisms of themselves. Among them, hypoxia inducible factor-1 alpha (HIF-1α) is a key nuclear factor act as the oxygen sensor. It plays an important role in the pathogenesis and development of various hypoxic/ischemic diseases 9, 10
. HIF-1α can also regulate the expression of genes such as heme oxygenase-1 (HO-1) and vascular endothelial growth factor (VEGF) 11-14
, which can effect on endothelial cells (ECs) proliferation, migration, and cell organization during recovery phases after hepatic microvascular dysfunction by promoting the secretion of growth and survival factors. The degradation of HIF-1α is mediated by proline hydroxylases (PHDs), which can catalyse the hydroxylation of specific proline residues in the HIF-1α subunits. The activation of PHDs is oxygen-dependent.
The molecular mechanisms underlying IRI are multifactorial, and many investigations have their focus on the intervention of hepatic IRI 15-17
. Ischemic preconditioning (IpreC), defined as brief periods of ischemia and reperfusion before sustained ischemia, and remote ischemia preconditioning (RIPC), which showed several brief ischemia of one organ confers protection on distant organs without direct stress or trauma to blood vessels of the organ, have been reported for reducing myocardial and renal injury 18- 20
. Recent studies have proved that several brief cycles of IR at the onset of sustained reperfusion after ischemia, termed ischemic postconditioning (IpostC), provided effective cardioprotection on IRI. But most of these studies were focused on hearts and little was known about whether IpostC could offer protections on hepatic IRI and the mechanism 21, 22
Proanthocyanidins, mainly presenting in the seeds of grapes, has been reported to possess a broad spectrum of biological, pharmacological and therapeutic activities against free radicals and oxidative stress 23, 24
. Vitro studies reported that proanthocyanidins were potent scavengers of peroxyl and hydroxyl radicals that were generated in the reperfusion myocardium after ischemia 25
. In addition to the ability to scavenge ROS, GSP has the ability to stimulate NO production in a dose dependent manner, which is a relatively stable free radical and acts as a signaling molecule in diverse physiological and pathological pathways. In our recent study 26
, we found that GSP could further improve the oxidation resistance in combined pre- and postconditioning groups, and its implementation was more convenient particularly in combined remote preconditioning and postconditioning group. Therefore, this study was designed to further investigate the effects of GSP on steatotic livers against IRI. The protective effects of GSP as pharmacological preconditioning, compared and combined with postconditioning strategies, were evaluated on the warm hepatic IRI model of standard chow diet and high-fat diet mice. The results show that all these strategies were effective on protecting liver against IRI, and providing the preservation of hepatic function. Combined GSP and postconditioning could offer additional protection over the individual treatment. In the high diet-induced hepatic steatosis with IRI group, which hepatocellular injury more severe than that in standard chow diet mice with IRI group, GSP was more effective than postconditioning on alleviating oxidative damage and cytokines release, as well as promoting hypoxia tolerance. In addition, the combined strategy was obviously superior to the solo treatment on protecting obese mice against hepatic IRI.
All these results provided experimental evidences to evaluate the protective effects of GSP/ postconditioning strategies against hepatic IRI in details and might guide future research on anti-IRI. GSP used as pharmacological ischemic preconditioning and combine with other treatment protocols might have huge potential to be used in clinical surgery.