Recombinant thrombomodulin prevented hepatic ischemia-reperfusion injury by inhibiting high-mobility group box 1 in rats

Eur J Pharmacol. 2019 Nov 15;863:172681. doi: 10.1016/j.ejphar.2019.172681. Epub 2019 Sep 19.

Abstract

Recombinant thrombomodulin (rTM) is a novel anticoagulant and anti-inflammatory agent that inhibits secretion of high-mobility group box 1 (HMGB1) from liver. We evaluated the protective effects of rTM on hepatic ischemia-reperfusion injury in rats. Ischemia was induced by clamping the portal vein and hepatic artery of left lateral and median lobes of the liver. At 30 min before ischemia and at 6 h after reperfusion, 0.3 ml of saline (IR group) or 0.3 ml of saline containing 6 mg/kg body weight of rTM (IR-rTM group) was injected into the liver through inferior vena cava or caudate vein. Blood flow was restored at 60 min of ischemia. Blood was collected 30 min prior to induction of ischemia and before restoration of blood flow, and at 6, 12, and 24 h after reperfusion. All the animals were euthanized at 24 h after reperfusion and the livers were harvested and subjected to biochemical and pathological evaluations. Serum levels of ALT, AST, and HMGB1 were significantly lower after reperfusion in the IR-rTM group compared to IR group. Marked hepatic necrosis was present in the IR group, while necrosis was almost absent in IR-rTM group. Treatment with rTM significantly reduced the expression of TNF-α and formation of 4-hydroxynonenal in the IR-rTM group compared to IR group. The results of the present study indicate that rTM could be used as a potent therapeutic agent to prevent IR-induced hepatic injury and the related adverse events.

Keywords: 4-Hydroxynonenal; HMGB1; Ischemia; Ischemia-reperfusion injury; Recombinant-thrombomodulin.

MeSH terms

  • Alanine Transaminase / blood
  • Aldehydes / metabolism
  • Animals
  • Aspartate Aminotransferases / blood
  • HMGB1 Protein / antagonists & inhibitors*
  • HMGB1 Protein / blood
  • Liver / blood supply*
  • Liver / drug effects*
  • Liver / metabolism
  • Male
  • Malondialdehyde / metabolism
  • Rats
  • Rats, Wistar
  • Recombinant Proteins / pharmacology*
  • Reperfusion Injury / blood
  • Reperfusion Injury / metabolism*
  • Reperfusion Injury / prevention & control*
  • Thrombomodulin / metabolism*
  • Tumor Necrosis Factor-alpha / biosynthesis

Substances

  • Aldehydes
  • HMGB1 Protein
  • Recombinant Proteins
  • Thrombomodulin
  • Tumor Necrosis Factor-alpha
  • Malondialdehyde
  • Aspartate Aminotransferases
  • Alanine Transaminase
  • 4-hydroxy-2-nonenal