title: NF-κB inhibition after cecal ligation and puncture reduces sepsis-associated lung injury without altering bacterial host defense.
abstract: BACKGROUND
  Since 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.
  
  
  METHODS
  Mice 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.
  
  
  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-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.
  
  
  CONCLUSIONS
  Transiently 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.
authors.affiliation: 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.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Han
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Vasilly
authors.initials: V
authors.lastname: Polosukhin
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Fiona E
authors.initials: FE
authors.lastname: Yull
authors.affiliation: Departments of Medicine and Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA ; Department of Medicine, School of Medicine and Biomedical Sciences, University of New York at Buffalo, Buffalo, NY 14214, USA.
authors.forename: Brahm H
authors.initials: BH
authors.lastname: Segal
authors.affiliation: Division of Respiratory Medicine, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province 510080, China.
authors.forename: Can-Mao
authors.initials: CM
authors.lastname: Xie
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA ; Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA ; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA ; Department of Veterans Affairs Medical Center, Nashville, TN 37232, USA.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Blackwell
mesh_terms: D055371:Acute Lung Injury / Q000517:prevention & control*; D000818:Animals; D001424:Bacterial Infections / Q000276:immunology*; D002478:Cells, Cultured; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors; D007093:Imidazoles / Q000627:therapeutic use*; D008026:Ligation; D008264:Macrophages / Q000276:immunology; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009504:Neutrophils / Q000276:immunology; D010587:Phagocytosis / Q000187:drug effects; D011810:Quinoxalines / Q000627:therapeutic use*; D018805:Sepsis / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality
chemical_list: C471109:4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline; D007093:Imidazoles; D016328:NF-kappa B; D011810:Quinoxalines; D051550:I-kappa B Kinase