Abstract
BackgroundThe nuclear protein high-mobility group box 1 (HMGB1) is a key trigger for the inflammatory reaction during liver ischemia reperfusion injury (IRI). Hydrogen treatment was recently associated with down-regulation of the expression of HMGB1 and pro-inflammatory cytokines during sepsis and myocardial IRI, but it is not known whether hydrogen has an effect on HMGB1 in liver IRI.MethodsA rat model of 60 minutes 70% partial liver ischemia reperfusion injury was used. Hydrogen enriched saline (2.5, 5 or 10 ml/kg) was injected intraperitoneally 10 minutes before hepatic reperfusion. Liver injury was assessed by serum alanine aminotransferase (ALT) enzyme levels and histological changes. We also measured malondialdehyde (MDA), hydroxynonenal (HNE) and 8-hydroxy-guanosine (8-OH-G) levels as markers of the peroxidation injury induced by reactive oxygen species (ROS). In addition, pro-inflammatory cytokines including TNF-α and IL-6, and high mobility group box B1 protein (HMGB1) were measured as markers of post ischemia-reperfusion inflammation.ResultsHydrogen enriched saline treatment significantly attenuated the severity of liver injury induced by ischemia-reperfusion. The treatment group showed reduced serum ALT activity and markers of lipid peroxidation and post ischemia reperfusion histological changes were reduced. Hydrogen enriched saline treatment inhibited HMGB1 expression and release, reflecting a reduced local and systemic inflammatory response to hepatic ischemia reperfusion.ConclusionThese results suggest that, in our model, hydrogen enriched saline treatment is protective against liver ischemia-reperfusion injury. This effect may be mediated by both the anti-oxidative and anti-inflammatory effects of the solution.
Highlights
The nuclear protein high-mobility group box 1 (HMGB1) is a key trigger for the inflammatory reaction during liver ischemia reperfusion injury (IRI)
The pathophysiology of hepatic ischemia reperfusion injury (IRI) is multifactorial and involves direct cellular damage, microcirculatory failure and an inflammatory response to tissue damage that culminates in organ dysfunction and failure [1,2]
HMGB1 release following liver ischemia is triggered by the production of reactive oxygen species that activate a Toll-like receptor 4-dependent pathway mediated by calcium signaling [8]
Summary
The nuclear protein high-mobility group box 1 (HMGB1) is a key trigger for the inflammatory reaction during liver ischemia reperfusion injury (IRI). Hydrogen treatment was recently associated with down-regulation of the expression of HMGB1 and pro-inflammatory cytokines during sepsis and myocardial IRI, but it is not known whether hydrogen has an effect on HMGB1 in liver IRI. Implicated as a later mediator of sepsis [6], recent work [7,8] has shown that HMGB1 is an early mediator of injury and inflammation in liver IRI, and demonstrates a rapid increase in plasma levels following tissue reperfusion. Inhibition of HMGB1 release or application of anti-HMGB1 or HMGB1-receptor antagonist have been shown to reduce cytokine expression and preserve hepatic function in animal models, indicating that manipulation of HMGB1 may be a therapeutic target in hepatic IRI [7]. Antioxidant strategies for inhibiting HMGB1 release may be of therapeutic value in the prevention and treatment of hepatic IRI
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