Hepatocyte protection by a protease inhibitor against ischemia/reperfusion injury of human liver.
BACKGROUND
Total clamping of the hepatic pedicle can induce profound hepatic ischemia/reperfusion (I/R) injury, which remains a potentially lethal problem after hepatectomy.


METHODS
The purpose of this study was to evaluate the efficacy of a protease inhibitor in ameliorating I/R injury of the human liver. In a prospective, randomized, clinical study, 66 patients who underwent liver resection under conditions of continuous inflow occlusion were randomly assigned to three groups: 25 patients were given a synthetic protease inhibitor (gabexate mesilate [GM], 2.0 mg/kg/hr) intravenously starting 24 hours before surgery until postoperative day 3 (preop GM group); 16 were similarly given GM at the beginning of surgery (intraop GM group); and 25 served as controls (without GM group). Laboratory data and intraoperative and postoperative variables were analyzed and plasma levels of cytokines--tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and interleukin-6 (IL-6)--were measured to determine the relationship between surgical stress and hepatic I/R injury.


RESULTS
The three groups of patients were similar in terms of age, gender, preoperative assessments, hepatic inflow occlusion time (approximately 50 minutes), extent of resection (proportion of major and minor hepatectomy), and background liver conditions. Preoperative administration of gabexate mesilate (preop GM group) substantially ameliorated hepatic I/R injury as compared with the other patients (intraop and without GM groups); postoperative serum transaminase levels were notably decreased in association with marked suppression of IL-6 levels in blood circulation during liver surgery. This was accompanied by a lower rate of postoperative complications and no mortality. Gabexate mesilate pretreatment abrogated the positive correlation between postreperfusion hepatocyte injury and hepatic ischemia time.


CONCLUSIONS
Preoperative administration of GM is useful for preventing I/R injury of the human liver, accompanied by suppression of the plasma proinflammatory cytokine IL-6.
Kim
Yang-Il
YI
Department of Surgery, Biomolecular Engineering Center, Liver Research Institute, Kyungpook National University, School of Medicine, Taegu, Korea.
Hwang
Yoon-Jin
YJ
Song
Kyung-Eun
KE
Yun
Young-Kook
YK
Lee
Jong-Won
JW
Chun
Byung-Yeol
BY
D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D005260:Female; D016670:Gabexate / Q000627:therapeutic use*; D006498:Hepatectomy / Q000009:adverse effects; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D008099:Liver / Q000098:blood supply*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D015427:Reperfusion Injury / Q000209:etiology / Q000517:prevention & control*; D015842:Serine Proteinase Inhibitors / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D015850:Interleukin-6; D015842:Serine Proteinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D016670:Gabexate