Protective effect of tropisetron on rodent hepatic injury after trauma-hemorrhagic shock through P38 MAPK-dependent hemeoxygenase-1 expression

PLoS One. 2012;7(12):e53203. doi: 10.1371/journal.pone.0053203. Epub 2012 Dec 28.

Abstract

Tropisetron can decrease inflammatory cell responses and alleviate organ damage caused by trauma-hemorrhage, but the mechanism of these effects remains unknown. The p38 mitogen-activated protein kinase/hemeoxygenase-1 (p38 MAPK/HO-1) pathway exerts anti-inflammatory effects on different tissues. The aim of this study was to investigate whether p38 MAPK/HO-1 plays any role in the tropisetron-mediated attenuation of hepatic injury after trauma-hemorrhage. Male Sprague-Dawley rats underwent trauma-hemorrhage (mean blood pressure maintained at approximately 35-40 mmHg for 90 min), followed by fluid resuscitation. During resuscitation, several treatment regimens were administered: four doses of tropisetron alone (0.1, 0.3, 1, 3 mg/kg body weight), or a single dose of tropisetron (1 mg/kg body weight) with and without a p38 MAPK inhibitor (SB-203580, 2 mg/kg body weight) or HO antagonist (chromium-mesoporphyrin, 2.5 mg/kg body weight). Various parameters were measured, and the animals were sacrificed at 24 h post-resuscitation. The results showed that trauma-hemorrhage increased the following parameters: plasma concentrations of aspartate (AST) and alanine aminotransferases (ALT), hepatic myeloperoxidase (MPO) activity, and levels of cytokine-induced neutrophil chemoattractant-1 and -3 (CINC-1 and CINC-3), intercellular adhesion molecule-1 (ICAM-1), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and macrophage inflammatory protein-1α (MIP-1α). These parameters were significantly improved in the tropisetron-treated rats subjected to trauma-hemorrhage. Tropisetron treatment also increased hepatic p38 MAPK and HO-1 expression compared with vehicle-treated trauma-hemorrhaged rats. Co-administration of SB-203580 or chromium-mesoporphyrin with tropisetron abolished the tropisetron-induced beneficial effects on the above parameters and hepatic injury. These results suggest that the protective effect of tropisetron administration on alleviation of hepatic injury after trauma-hemorrhage is likely mediated through p38 MAPK-dependent HO-1 expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Anti-Inflammatory Agents / therapeutic use
  • Cytoprotection / drug effects
  • Heme Oxygenase-1 / metabolism*
  • Indoles / pharmacology*
  • Indoles / therapeutic use
  • Liver / drug effects
  • Liver / injuries*
  • Liver / metabolism
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Shock, Hemorrhagic / drug therapy*
  • Shock, Hemorrhagic / etiology
  • Shock, Hemorrhagic / metabolism
  • Tropisetron
  • Wounds and Injuries / complications*
  • Wounds and Injuries / drug therapy
  • Wounds and Injuries / metabolism
  • p38 Mitogen-Activated Protein Kinases / drug effects
  • p38 Mitogen-Activated Protein Kinases / metabolism
  • p38 Mitogen-Activated Protein Kinases / physiology*

Substances

  • Anti-Inflammatory Agents
  • Indoles
  • Tropisetron
  • Heme Oxygenase-1
  • p38 Mitogen-Activated Protein Kinases

Grants and funding

This work was supported in part by grants from the National Science Council (NSC98-2314-B-182A-034-MY3) and Chang Gung Memorial Hospital (CMRPG381073) to HPY and from the National Science Council (NSC 101-2314-B-182 -082) and Chang Gung Memorial Hospital (CMRPG 392122) to FCL. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.