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Divergent roles of endothelial NF-B in multiple organ injury and bacterial clearance in mouse models of sepsis

Department of Medicine, Division of Pulmonary and Critical Care Medicine, Long Island Jewish Medical Center, Long Island Campus for the Albert Einstein College of Medicine, New Hyde Park, NY 11040

CORRESPONDENCE Shu Fang Liu: Sliu{at}lij.edu

To define the roles of endothelial-intrinsic nuclear factor B (NF-B) activity in host defense and multiple organ injury in response to sepsis, we generated double transgenic (TG) mice (EC-rtTA/I-Bmt) that conditionally overexpress a degradation-resistant form of the NF-B inhibitor I-B (I-Bmt) selectively on vascular endothelium. The EC-rtTA/I-Bmt mice had no basal, but a relatively high level of doxycycline-inducible, I-Bmt expression. I-Bmt expression was detected in endothelial cells, but not in fibroblasts, macrophages, and whole blood cells, confirming that transgene expression was restricted to the endothelium. When subjected to endotoxemia, EC-rtTA/I-Bmt mice showed endothelial-selective blockade of NF-B activation, repressed expression of multiple endothelial adhesion molecules, reduced neutrophil infiltration into multiple organs, decreased endothelial permeability, ameliorated multiple organ injury, reduced systemic hypotension, and abrogated intravascular coagulation. When subjected to cecal ligation and puncture–induced sepsis, the TG mice had less severe multiple organ injury and improved survival compared with wild-type (WT) mice. WT and EC-rtTA/I-Bmt mice had comparable capacity to clear three different pathogenic bacteria. Our data demonstrate that endothelial NF-B activity is an essential mediator of septic multiple organ inflammation and injury but plays little role in the host defense response to eradicate invading pathogenic bacteria.

X. Ye and J. Ding contributed equally to this work.

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