Sepsis protects the myocardium and other organs from subsequent ischaemic/reperfusion injury via a MAPK-dependent mechanism

BACKGROUND: Sepsis has been shown to precondition the intact heart against ischaemia/reperfusion (IR) injury, and prior endotoxin exposure of cells in in vitro models has shown evidence of protection against subsequent simulated ischaemia. Our aim in this study is to validate these findings and further investigate the signaling pathways involved. METHODS: Adult male Sprague Dawley rats were randomised to control (n = 7) or caecal ligation and perforation (CLP)-induced sepsis (n = 7). Hearts were harvested at 48 h, suspended in Langendorff mode and subjected to 30-min global ischaemia followed by 90-min reperfusion. In subsequent experiments, designed to determine the mechanisms by which sepsis protected against ischaemic injury, endotoxin-stimulated isolated cardiomyocytes, pulmonary A549 cells and renal HK2 cells were subjected to normoxic and hypoxic conditions. The roles of key pathways, including mitogen-activated protein (MAP) kinases extracellular-regulated protein kinase (ERK) 1/2, p38 MAPK (p38), c-Jun NH2-terminal protein kinase (JNK)), and nuclear factor-kappaB (NF-κB) were examined. RESULTS: Systemic sepsis protected isolated hearts from subsequent ischaemic/reperfusion-induced injury, enhancing functional recovery on reperfusion [developed left ventricular pressure ((d)LVP) mean(SE) 66.63(±10.7) mmHg vs. 54.13(±9.9) mmHg; LVP(max) at 60 min 67.29(±11.9) vs. 72.48(±9.3), sepsis vs. control] despite significantly reduced baseline LV function in CLP animals (p < 0.001). Septic preconditioning significantly reduced infarct size after IR injury (p < 0.05). Endotoxin exposure protected isolated cardiomyocytes against hypoxia-induced cell death (p < 0.001). This effect appeared mediated in part via the p38, JNK and NF-κB pathways, but was independent of the ERK pathway, and did not appear to be mediated via HMGB1. The preconditioning effect of endotoxin was also demonstrated in isolated kidney and lung cells, suggesting that this preconditioning effect of sepsis is not confined to the myocardium. CONCLUSIONS: Sepsis preconditions the isolated rat heart against myocardial IR injury. These effects appeared to be mediated in part via the p38, JNK and NF-κB and pathways, but were independent of the ERK and HMGB pathways.