Minocycline Decreases Liver Injury after Hemorrhagic Shock and Resuscitation in Mice

Christoph Czerny,John J Lemasters,Andaleb Kholmukhamedov,Mark Lehnert,Ingo Marzi,Tom P Theruvath,Venkat K Ramshesh,Zhi Zhong,Eduardo N Maldonado

doi:10.1155/2012/259512

Abstract

Patients that survive hemorrhage and resuscitation (H/R) may develop a systemic inflammatory response syndrome (SIRS) that leads to dysfunction of vital organs (multiple organ dysfunction syndrome, MODS). SIRS and MODS may involve mitochondrial dysfunction. Under pentobarbital anesthesia, C57BL6 mice were hemorrhaged to 30 mm Hg for 3 h and then resuscitated with shed blood plus half the volume of lactated Ringer's solution containing minocycline, tetracycline (both 10 mg/kg body weight) or vehicle. Serum alanine aminotransferase (ALT), necrosis, apoptosis and oxidative stress were assessed 6 h after resuscitation. Mitochondrial polarization was assessed by intravital microscopy. After H/R with vehicle or tetracycline, ALT increased to 4538 U/L and 3999 U/L, respectively, which minocycline decreased to 1763 U/L (P < 0.01). Necrosis and TUNEL also decreased from 24.5% and 17.7 cells/field, respectively, after vehicle to 8.3% and 8.7 cells/field after minocycline. Tetracycline failed to decrease necrosis (23.3%) but decreased apoptosis to 9 cells/field (P < 0.05). Minocycline and tetracycline also decreased caspase-3 activity in liver homogenates. Minocycline but not tetracycline decreased lipid peroxidation after resuscitation by 70% (P < 0.05). Intravital microscopy showed that minocycline preserved mitochondrial polarization after H/R (P < 0.05). In conclusion, minocycline decreases liver injury and oxidative stress after H/R by preventing mitochondrial dysfunction.

Highlights

Trauma and surgical procedures, including gastrointestinal and hepatobiliary surgery, can lead to severe hemorrhage and hypovolemic shock
Patients that survive hemorrhage and resuscitation (H/R) may develop a systemic inflammatory response syndrome (SIRS) that leads to dysfunction of vital organs
C57BL6 mice were hemorrhaged for 3 h and resuscitated with shed blood followed by half the volume of lactated Ringer solution, containing minocycline (10 mg/kg), tetracycline (10 mg/kg), or vehicle

Summary

Introduction

Trauma and surgical procedures, including gastrointestinal and hepatobiliary surgery, can lead to severe hemorrhage and hypovolemic shock. Fluid resuscitation after less than one hour of severe hemorrhagic shock restores hemodynamics and typically leads to full recovery. Effective strategies to extend this golden hour for resuscitation are needed to improve the treatment of hemorrhagic shock and decrease the incidence of MODS and its lethal consequence. Experimental strategies to inhibit the MPT after liver transplantation in rats improved survival and decreased mitochondrial dysfunction [7]. Mechanisms by which minocycline exerts neuroprotection include inhibition of apoptotic pathways, decreased mitochondrial release of proapoptotic factors like cytochrome c, and upregulation of antiapoptotic Bcl-2 and inhibitor of apoptosis proteins (IAPs) [13, 14]. In orthotopic rat liver transplantation, minocycline cytoprotection against storage/reperfusion injury is mediated by suppression of the MPT through inhibition of the mitochondrial calcium uniporter [7]. We investigated whether resuscitation with minocycline decreases liver injury after H/R

Materials and Methods

Results

Mitochondrial Dysfunction In Vivo after Hemorrhage and Resuscitation

Discussion