Liver preconditioning induced by iron in a rat model of ischemia/reperfusion

Abstract

Aims: Liver preconditioning against ischemia–reperfusion (IR) injury is a major area of experimental research, in which regulation of gene expression with cytoprotective responses due to transient oxidative stress development has been reported. Considering that significant cytoprotection occurs after exposure to low levels of iron (Fe), we tested the hypothesis that sub-chronic administration of Fe to rats underlying transient oxidative stress preconditions the liver against IR injury. Main methods: Animals received six doses (50 mg Fe–dextran/kg ip) every second day during 10 days, before partial IR (vascular clamping) or sham laparotomy (control). Transient oxidative stress was defined by liver glutathione and protein carbonyl contents (24, 48, and 72 h after Fe treatment). Plasma and liver Fe status and ferritin content (western blot) were assessed in animals not subjected to IR. Liver injury and inflammatory response were evaluated by serum transaminases, liver morphology and serum TNF-α. Fe preconditioning against IR injury was correlated with liver glutathione content and the redox-sensitive NF-κB signaling pathway (EMSA) and western blot analysis of haptoglobin. Key findings: Significant hepatoprotection against IR injury, underlying transient oxidative stress and enhancement in the total and labile Fe pools, was achieved by Fe administration. Abrogation of IR injury is related to reduced TNF-α response (91%), abolishment of the IR-induced liver glutathione depletion and recovery of the NF-κB signaling pathway (75%), lost during IR. Significance: Sub-chronic Fe administration protects the liver against IR injury through antioxidant and antiinflammatory responses, with recovery of NF-κB activation and related acute-phase response signaling.