Abstract 2841: Endothelial Selective NF-κB Inhibition Improves Survival and Preserves Host Defense Capacity in Bacterial Model of Sepsis

Abstract

NF-κB plays a predominant role in septic pathology and is a desired target for developing therapies for septic shock. However, NF-κB blockade impairs bacterial clearance capability (BCC), which is detrimental. We have demonstrated that endothelial-restricted NF-κB blockade effectively prevents endotoxemic multiple organ injury (Circulation, 114: II-257). In this study, we examined whether endothelial-selective NF-κB blockade preserves BCC and improves survival in bacterial model of sepsis. Wild type (WT) and transgenic mice (TG) that conditionally overexpress a degradation-resistant I-κBα (I-κBαmt) selectively on endothelial cells were intravenously injected with saline (1 ml/kg) or pathogenic bacteria. Bacterial colonies formed in blood and tissue homogenate cultures of lungs, liver, spleen and kidney were counted. TG mice were induced to express I-κBαmt by feeding with doxycycline in drinking water. No bacteria grew in blood and any tissue homogenate culture from WT and TG mice injected with saline. Bacterial colony counts in blood and the 4 tissue homogenate cultures were similar between TW and TG mice 12 hrs after 10 7 CFU S. pneumoniae or 10 8 CFU S. enterica injection or 24 hrs after 10 8 CFU L. monocytogenes injection (Table ). TG mice showed an improved survival in the cecal ligation and puncture model of sepsis. The survival rate was 33% and 67% for WT and TG mice. Our results demonstrate that endothelial-selective blockade of NF-κB activation improves survival and preserves bacterial clearance capacity in bacterial model of sepsis. Bacterial Colony Counts (CFU per ml blood or gram tissue)