Abstract
Hydrogen sulfide (H2S) is the third most common endogenously produced gaseous signaling molecule, but its impact on hepatic ischemia/reperfusion (I/R) injury, especially on mitochondrial function, remains unclear. In this study, rats were randomized into Sham, I/R, ischemia preconditioning (IPC) or sodium hydrosulfide (NaHS, an H2S donor) preconditioning groups. To establish a model of segmental (70%) warm hepatic ischemia, the hepatic artery, left portal vein and median liver lobes were occluded for 60 min and then unclamped to allow reperfusion. Preconditioning with 12.5, 25 or 50 μmol/kg NaHS prior to the I/R insult significantly increased serum H2S levels, and, similar to IPC, NaHS preconditioning decreased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in the plasma and prevented hepatocytes from undergoing I/R-induced necrosis. Moreover, a sub-toxic dose of NaHS (25 μmol/kg) did not disrupt the systemic hemodynamics but dramatically inhibited mitochondrial permeability transition pore (MPTP) opening and thus prevented mitochondrial-related cell death and apoptosis. Mechanistic studies revealed that NaHS preconditioning markedly increased the expression of phosphorylated protein kinase B (p-Akt), phosphorylated glycogen synthase kinase-3 beta (p-GSK-3β) and B-cell lymphoma-2 (Bcl-2) and decreased the release of mitochondrial cytochrome c and cleaved caspase-3/9 levels. Therefore, NaHS administration prior to hepatic I/R ameliorates mitochondrial and hepatocellular damage through the inhibition of MPTP opening and the activation of Akt-GSK-3β signaling. Furthermore, this study provides experimental evidence for the clinical use of H2S to reduce liver damage after perioperative I/R injury.
Highlights
Hepatic ischemia/reperfusion (I/R) injury influences the prognosis of patients in a variety of clinical contexts, including transplantation, liver resection surgery, trauma and hemorrhagic shock [1,2]
The reduction of ALT and AST serum levels did not occur in an H2S concentration-dependent manner, as no difference could be found between the 25 μmol/kg and 50 μmol/kg NaHS-treated groups (ALT: 706U/L in 25 μmol/kg versus 832 U/L in 50 μmol/kg NaHS; AST: 509 U/L in 25 μmol/kg NaHS versus 512 U/L in 50 μmol/kg NaHS, P >0.05)
Rats that were preconditioned with 25 or 50 μmol/kg NaHS and rats that received ischemia preconditioning (IPC) displayed less liver damage (Figure 4A) and lower Suzuki’s scores (Figure 4B) than rats in the I/R group. These results suggested that NaHS preconditioning protects rats from I/R-induced hepatic injury by inhibiting cell death, similar to IPC
Summary
Hepatic ischemia/reperfusion (I/R) injury influences the prognosis of patients in a variety of clinical contexts, including transplantation, liver resection surgery, trauma and hemorrhagic shock [1,2]. Evidence suggests that liver I/R injury occurs along with an inflammatory process that causes cellular damage due to complex factors, such as the production of reactive oxygen species (ROS), chemokines, and cytokines [3]. It causes a disruption of the proton gradient and electrical potential across the inner mitochondrial membrane, which leads to an influx of solutes and water and eventual rupture of the outer membrane, culminating in necrotic cell death. The underlying mechanisms of protection appear to include suppressing oxidative stress via antioxidant activities, reducing inflammatory mediators, such as tumor necrosis factor-α (TNFα), interleukin-10 (IL-10) and intercellular cell adhesion molecule-1 (ICAM-1), and reducing hepatocyte apoptosis. We employed a rat model of 70% warm hepatic I/R to elucidate the role of H2S preconditioning on the susceptibility of the MPTP and the underlying mechanism of H2S-mediated protection of the liver
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