title: Inhibition of IκB kinase reduces the multiple organ dysfunction caused by sepsis in the mouse.
abstract: Nuclear factor κB (NF-κB) plays a pivotal role in sepsis. Activation of NF-κB is initiated by the signal-induced ubiquitylation and subsequent degradation of inhibitors of kappa B (IκBs) primarily via activation of the IκB kinase (IKK). This study was designed to investigate the effects of IKK inhibition on sepsis-associated multiple organ dysfunction and/or injury (MOD) and to elucidate underlying signaling mechanisms in two different in vivo models: male C57BL/6 mice were subjected to either bacterial cell wall components [lipopolysaccharide and peptidoglycan (LPS/PepG)] or underwent cecal ligation and puncture (CLP) to induce sepsis-associated MOD. At 1 hour after LPS/PepG or CLP, mice were treated with the IKK inhibitor IKK 16 (1 mg/kg body weight). At 24 hours, parameters of organ dysfunction and/or injury were assessed in both models. Mice developed a significant impairment in systolic contractility (echocardiography), and significant increases in serum creatinine, serum alanine aminotransferase and lung myeloperoxidase activity, thus indicating cardiac dysfunction, renal dysfunction, hepatocellular injury and lung inflammation, respectively. Treatment with IKK 16 attenuated the impairment in systolic contractility, renal dysfunction, hepatocellular injury and lung inflammation in LPS/PepG-induced MOD and in polymicrobial sepsis. Compared with mice that were injected with LPS/PepG or underwent CLP, immunoblot analyses of heart and liver tissues from mice that were injected with LPS/PepG or underwent CLP and were also treated with IKK 16 revealed: (1) significant attenuation of the increased phosphorylation of IκBα; (2) significant attenuation of the increased nuclear translocation of the NF-κB subunit p65; (3) significant attenuation of the increase in inducible nitric oxide synthase (iNOS) expression; and (4) a significant increase in the phosphorylation of Akt and endothelial nitric oxide synthase (eNOS). Here, we report for the first time that delayed IKK inhibition reduces MOD in experimental sepsis. We suggest that this protective effect is (at least in part) attributable to inhibition of inflammation through NF-κB, the subsequent decrease in iNOS expression and the activation of the Akt-eNOS survival pathway.
authors: Queen Mary University of London, Barts and The London School of Medicine and Dentistry, The William Harvey Research Institute, London, EC1M 6BQ, UK. s.m.coldewey@qmul.ac.uk
authors: Sina M
authors: SM
authors: Coldewey
authors: Mara
authors: M
authors: Rogazzo
authors: Massimo
authors: M
authors: Collino
authors: Nimesh S A
authors: NS
authors: Patel
authors: Christoph
authors: C
authors: Thiemermann
mesh_terms: D000818:Animals; D002432:Cecum / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D006334:Heart Function Tests / Q000187:drug effects; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008026:Ligation; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009102:Multiple Organ Failure / Q000150:complications* / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D000072000:NF-KappaB Inhibitor alpha; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010457:Peptidoglycan / Q000008:administration & dosage / Q000494:pharmacology; D011014:Pneumonia / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011677:Punctures; D018805:Sepsis / Q000150:complications* / Q000201:enzymology* / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; C000606205:Nfkbia protein, mouse; D010457:Peptidoglycan; D047428:Protein Kinase Inhibitors; D051996:Transcription Factor RelA; D000072000:NF-KappaB Inhibitor alpha; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D051550:I-kappa B Kinase
references: Crit Care Med. 2002 Jan;30(1 Suppl):S18-26
references: 11782557
references: Am J Respir Crit Care Med. 2003 Jun 1;167(11):1567-74
references: 12626346
references: Clin Infect Dis. 2005 Mar 1;40(5):719-27
references: 15714419
references: Shock. 2001 Feb;15(2):135-42
references: 11220642
references: Eur J Pharmacol. 1990 Jul 17;182(3):591-5
references: 2226626
references: Shock. 2010 Mar;33(3):242-6
references: 19536045
references: Microcirculation. 2011 Feb;18(2):152-62
references: 21199094
references: J Surg Res. 1980 Aug;29(2):189-201
references: 6997619
references: Chest. 1992 Jun;101(6):1644-55
references: 1303622
references: Eur J Pharmacol. 2004 Sep 13;498(1-3):295-301
references: 15364008
references: Pathobiology. 2013;80(2):70-86
references: 22986917
references: Crit Care Med. 2007 Jun;35(6):1599-608
references: 17452940
references: Curr Drug Targets. 2009 Jan;10(1):60-70
references: 19149537
references: Crit Care Med. 2007 May;35(5):1244-50
references: 17414736
references: N Engl J Med. 2001 Nov 8;345(19):1368-77
references: 11794169
references: Bioorg Med Chem Lett. 2006 Jan 1;16(1):108-12
references: 16236504
references: Dis Model Mech. 2013 Jul;6(4):1021-30
references: 23519033
references: Cell. 1995 May 19;81(4):641-50
references: 7538909
references: Crit Care Med. 2001 Jul;29(7):1303-10
references: 11445675
references: Infect Immun. 2000 Apr;68(4):1942-5
references: 10722586
references: Thromb Haemost. 2009 Nov;102(5):837-45
references: 19888517
references: Science. 1999 Apr 9;284(5412):321-5
references: 10195897
references: Free Radic Biol Med. 2006 Aug 15;41(4):579-89
references: 16863991
references: Kidney Int. 2013 Sep;84(3):482-90
references: 23594675
references: Crit Care Med. 2007 Oct;35(10):2408-16
references: 17948334
references: Proc Natl Acad Sci U S A. 1995 Nov 7;92(23):10688-92
references: 7479866
references: Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12472-6
references: 7528923
references: Am J Physiol Renal Physiol. 2012 Apr 15;302(8):F1045-54
references: 22237800
references: Science. 2002 May 31;296(5573):1655-7
references: 12040186
references: Crit Care Med. 2005 Sep;33(9):1903-12
references: 16148458
references: Crit Care Med. 2004 Jan;32(1):1-12
references: 14707554
references: Mol Cell. 2002 Feb;9(2):401-10
references: 11864612
references: Crit Care Med. 2006 Feb;34(2):307-13
references: 16424707
references: Crit Care Med. 2004 Jan;32(1):21-30
references: 14707556
references: Circ Res. 2002 May 3;90(8):866-73
references: 11988487
references: Am J Physiol Cell Physiol. 2009 Jan;296(1):C182-92
references: 18945937
references: Br J Pharmacol. 1996 Dec;119(7):1411-21
references: 8968550
references: Crit Care Med. 2004 Jan;32(1):13-20
references: 14707555
references: J Neurosci Res. 1991 Jul;29(3):336-45
references: 1656059
references: J Cell Sci. 2005 Oct 15;118(Pt 20):4589-92
references: 16219681
references: Br J Pharmacol. 1997 Jun;121(4):695-704
references: 9208136
references: Crit Care Med. 2006 May;34(5):1489-96
references: 16557150
references: Shock. 2005 May;23(5):393-9
references: 15834303
references: Cell. 1998 Dec 11;95(6):749-58
references: 9865693
references: Nature. 1995 Jun 1;375(6530):408-11
references: 7539113
references: Am J Physiol Regul Integr Comp Physiol. 2003 Jan;284(1):R1-12
references: 12482742
references: Heart Fail Rev. 2010 Nov;15(6):605-11
references: 20571889
references: Br J Pharmacol. 1993 Mar;108(3):786-92
references: 7682137
references: J Exp Med. 1999 Jun 7;189(11):1839-45
references: 10359587
references: Crit Care Med. 2007 Aug;35(8):1928-36
references: 17581480
references: Cardiovasc Res. 2005 Mar 1;65(4):772-81
references: 15721857
references: Cell. 1986 Aug 29;46(5):705-16
references: 3091258
references: Am J Respir Crit Care Med. 2010 Dec 15;182(12):1506-15
references: 20693380
references: Cell Res. 2013 Feb;23(2):201-12
references: 23318584
references: Am J Physiol. 1992 Dec;263(6 Pt 2):H1963-6
references: 1481919
references: Am J Pathol. 2010 Oct;177(4):1834-47
references: 20709805
references: Am J Physiol. 1998 Dec;275(6):H2211-8
references: 9843821