Regional Ischemic Preconditioning Has Clinical Value in Cirrhotic HCC Through MAPK Pathways

Abstract

Background: This study assessed the clinical value of regional ischemic preconditioning (RIP) and the role of the mitogen-activated protein kinase (MAPK) pathways in the protective mechanism of RIP in cirrhotic hepatocellular carcinoma (HCC) patients undergoing hepatectomy.

Methods: Liver resection was performed with hemi-hepatic vascular inflow occlusion (HHV) under RIP (RIP group) or with HHV alone (HHV group). Clinical data, surgical outcomes, and the levels of phosphorylated MAPKs before occlusion and 30 min after reperfusion were estimated.

Results: HHV under RIP was associated with less intraoperative blood loss (300 vs. 400 ml; P = 0.042), postoperative plasma transfused (400 vs. 800 ml; P = 0.019), and a higher level of prothrombin activity at postoperative days 3, 5, and 7 compared to HHV alone. The level of phosphorylated ERK protein was significantly increased and the levels of phosphorylated p38 and JNK proteins were significantly decreased 30 min after reperfusion compared to HHV group in the RIP group.

Conclusions: HHV under RIP may have clinical value in cirrhotic HCC patients requiring resection and the protective mechanism of RIP may be associated with changes in the protein phosphorylation level of MAPK pathways.

Keywords: Cirrhosis; Hepatocellular carcinoma; Mitogen-activated protein kinase; Regional ischemic preconditioning.

Fig. 1

Treatment schemes. The first porta hepatis was elaborately dissected to reveal the left and right branch of the hepatic artery and portal vein; a rubber band was preset on each vessel. The right hepatic inflow was occluded by tightening the rubber band on the right branch of the hepatic artery (RHA) and portal vein (RPV); the occluded right hepatic inflow was restored by loosening the rubber band. Methodology of regional ischemic preconditioning is based on right hepatic inflow occlusion. RHA, right hepatic artery; RPV, right portal vein; PH, porta hepatis; CB, common bile duct; LHA/LPV, left hepatic artery/left portal vein

Fig. 2

Liver function tests after liver resection with (blue line, n = 23) versus without (red line, n = 49) RIP. There were no significant differences between the RIP and HHV groups except for prothrombin activity at postoperative days 3, 5, and 7 (P < 0.05). D0, preoperative day; D1, postoperative day 1; D3, postoperative day 3; D5, postoperative day 5; D7, postoperative day 7; ALT, alanine transaminase; AST, aspartate transaminase; TBIL, total bilirubin; ALB, albumin; PTA, prothrombin activity

Fig. 3

Liver morphology change before vascular occlusion and 30 min after reperfusion. The RIP group showed less hepatocyte injury and inflammatory cell infiltration than the HHV group. ×200. HHV, hemi-hepatic vascular inflow occlusion; RIP, regional ischemic preconditioning

Fig. 4

Protein phosphorylation levels before vascular occlusion and 30 min after reperfusion. a JNK phosphorylation level; b p38 phosphorylation level; c ERK phosphorylation level. bc, before; ad, after; HHV, hemi-hepatic vascular inflow occlusion; RIP, regional ischemic preconditioning; p, phosphorylated. The level of pERK was increased and the levels of pJNK and pp38 were decreased in the RIP group 30 min after reperfusion compared to the HHV group. # compared to HHV group before ischemia P > 0.05, *compared to HHV group after occlusion P < 0.05