• Hui Li, Wei Han, Vasilly Polosukhin, Fiona E Yull, Brahm H Segal, Can-Mao Xie, and Timothy S Blackwell.
• Division of Respiratory Medicine, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province 510080, China ; Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA ; Division of Respiratory Medicine, Nanjing Drum Tower Hospital & the Affiliated Hospital of Nanjing University, Nanjing, Jiangsu 210008, China.
• Mediators Inflamm. 2013 Jan 1;2013:503213.

IntroductionSince the NF-κB pathway regulates both inflammation and host defense, it is uncertain whether interventions targeting NF-κB would be beneficial in sepsis. Based on the kinetics of the innate immune response, we postulated that selective NF-κB inhibition during a defined time period after the onset of sepsis would reduce acute lung injury without compromising bacterial host defense.MethodsMice underwent cecal ligation and puncture (CLP). An NF-κB inhibitor, BMS-345541 (50 µg/g mice), was administered by peroral gavage beginning 2 hours after CLP and repeated at 6 hour intervals for 2 additional doses.ResultsMice treated with BMS-345541 after CLP showed reduced neutrophilic alveolitis and lower levels of KC in bronchoalveolar lavage fluid compared to mice treated with CLP+vehicle. In addition, mice treated with CLP+BMS had minimal histological evidence of lung injury and normal wet-dry ratios, indicating protection from acute lung injury. Treatment with the NF-κB inhibitor did not affect the ability of cultured macrophages to phagocytose bacteria and did not alter bacterial colony counts in blood, lung tissue, or peritoneal fluid at 24 hours after CLP. While BMS-345541 treatment did not alter mortality after CLP, our results showed a trend towards improved survival.ConclusionTransiently blocking NF-κB activity after the onset of CLP-induced sepsis can effectively reduce acute lung injury in mice without compromising bacterial host defense or survival after CLP.

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