Introduction. Since the NF- B pathway regulates both inflammation and host defense, it is uncertain whether interventions targeting NF- B would be beneficial in sepsis. Based on the kinetics of the innate immune response, we postulated that selective NF- B inhibition during a defined time period after the onset of sepsis would reduce acute lung injury without compromising bacterial host defense. Methods. Mice underwent cecal ligation and puncture (CLP). An NF- B 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. Results. Mice 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- B 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. Conclusion. Transiently blocking NF- B 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. 1. Introduction Severe sepsis remains a challenging clinical problem that accounts for 1.3% of all hospitalizations and is the leading cause of mortality and morbidity in intensive care units [1, 2]. The most life-threatening complication of sepsis is the development of the multiorgan dysfunction syndrome (MODS), which most commonly affects the lungs and kidneys. Acute lung injury (ALI) occurs in approximately 30% of septic patients, and unfortunately there are no specific treatments available to reduce mortality other than low tidal volume ventilation [3]. Sepsis occurs when infections trigger the systemic inflammatory response syndrome in the host. As a central regulator of inflammation, nuclear factor- B (NF- B) has long been considered to be a critical pathway involved in the pathogenesis of sepsis [4, 5]. Available information suggests that inhibition of NF- B could be a promising therapeutic target in sepsis. A number of studies have investigated the effects of manipulating NF- B activity using genetic or pharmacologic approaches during sepsis and/or endotoxemia [6–12].
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