title: An alteration of the gut-liver axis drives pulmonary inflammation after intoxication and burn injury in mice.
abstract: Approximately half of all adult burn patients are intoxicated at the time of their injury and have worse clinical outcomes than those without prior alcohol exposure. This study tested the hypothesis that intoxication alters the gut-liver axis, leading to increased pulmonary inflammation mediated by burn-induced IL-6 in the liver. C57BL/6 mice were given 1.2 g/kg ethanol 30 min prior to a 15% total body surface area burn. To restore gut barrier function, the specific myosin light chain kinase inhibitor membrane-permeant inhibitor of kinase (PIK), which we have demonstrated to reduce bacterial translocation from the gut, was administered 30 min after injury. Limiting bacterial translocation with PIK attenuated hepatic damage as measured by a 47% reduction in serum alanine aminotransferase (P < 0.05), as well as a 33% reduction in hepatic IL-6 mRNA expression (P < 0.05), compared with intoxicated and burn-injured mice without PIK. This mitigation of hepatic damage was associated with a 49% decline in pulmonary neutrophil infiltration (P < 0.05) and decreased alveolar wall thickening compared with matched controls. These results were reproduced by prophylactic reduction of the bacterial load in the intestines with oral antibiotics before intoxication and burn injury. Overall, these data suggest that the gut-liver axis is deranged when intoxication precedes burn injury and that limiting bacterial translocation in this setting attenuates hepatic damage and pulmonary inflammation.
authors.affiliation: Burn and Shock Trauma Research Institute, Loyola University Medical Center, Maywood, Illinois; Alcohol Research Program, Loyola University Medical Center, Maywood, Illinois; Loyola University Chicago Stritch School of Medicine, Maywood, Illinois; and.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Chen
authors.affiliation: Burn and Shock Trauma Research Institute, Loyola University Medical Center, Maywood, Illinois; Alcohol Research Program, Loyola University Medical Center, Maywood, Illinois;
authors.forename: Anita
authors.initials: A
authors.lastname: Zahs
authors.affiliation: Department of Surgery, Loyola University Medical Center, Maywood, Illinois; Burn and Shock Trauma Research Institute, Loyola University Medical Center, Maywood, Illinois;
authors.forename: Mary M
authors.initials: MM
authors.lastname: Brown
authors.affiliation: Department of Surgery, Loyola University Medical Center, Maywood, Illinois; Burn and Shock Trauma Research Institute, Loyola University Medical Center, Maywood, Illinois;
authors.forename: Luis
authors.initials: L
authors.lastname: Ramirez
authors.affiliation: Department of Pathology, University of Chicago, Chicago, Illinois.
authors.forename: Jerrold R
authors.initials: JR
authors.lastname: Turner
authors.affiliation: Department of Surgery, Loyola University Medical Center, Maywood, Illinois; Burn and Shock Trauma Research Institute, Loyola University Medical Center, Maywood, Illinois; Alcohol Research Program, Loyola University Medical Center, Maywood, Illinois; Loyola University Chicago Stritch School of Medicine, Maywood, Illinois; and.
authors.forename: Mashkoor A
authors.initials: MA
authors.lastname: Choudhry
authors.affiliation: Department of Surgery, Loyola University Medical Center, Maywood, Illinois; Burn and Shock Trauma Research Institute, Loyola University Medical Center, Maywood, Illinois; Alcohol Research Program, Loyola University Medical Center, Maywood, Illinois; Loyola University Chicago Stritch School of Medicine, Maywood, Illinois; and ekovacs@luc.edu.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Kovacs
mesh_terms: D000435:Alcoholic Intoxication / Q000150:complications* / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D018988:Bacterial Translocation / Q000187:drug effects; D002056:Burns / Q000150:complications* / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D000431:Ethanol; D005234:Fatty Liver / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007422:Intestines / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000382:microbiology*; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D009219:Myosin-Light-Chain Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D020556:Neutrophil Infiltration; D011014:Pneumonia / Q000209:etiology* / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction
chemical_list: D000900:Anti-Bacterial Agents; D018836:Inflammation Mediators; D015850:Interleukin-6; D047428:Protein Kinase Inhibitors; C577686:interleukin-6, mouse; D000431:Ethanol; D009219:Myosin-Light-Chain Kinase
keywords: IL-6; ethanol; myosin light chain kinase; steatosis; trauma
references.citation: J Burns Wounds. 2007 Jun 12;7:e1
references.pmid: 17625613
references.citation: Injury. 1994 Oct;25(8):539-43
references.pmid: 7960073
references.citation: Expert Rev Gastroenterol Hepatol. 2013 Mar;7(3):253-61
references.pmid: 23445234
references.citation: Chest. 1995 Apr;107(4):1062-73
references.pmid: 7705118
references.citation: Am J Respir Cell Mol Biol. 1999 Jun;20(6):1229-37
references.pmid: 10340942
references.citation: Alcohol. 2013 May;47(3):223-9
references.pmid: 23462222
references.citation: Burns. 1999 Aug;25(5):403-10
references.pmid: 10439148
references.citation: Mediators Inflamm. 2013;2013:971481
references.pmid: 24379525
references.citation: Burns. 2008 Jun;34(4):441-51
references.pmid: 18243566
references.citation: J Trauma. 1975 May;15(5):369-79
references.pmid: 1092877
references.citation: Saudi J Kidney Dis Transpl. 2009 Jul;20(4):632-8
references.pmid: 19587506
references.citation: World J Gastroenterol. 2010 Mar 21;16(11):1321-9
references.pmid: 20238398
references.citation: Alcohol Alcohol. 2005 Jul-Aug;40(4):269-73
references.pmid: 15870091
references.citation: JAMA. 2003 Jan 1;289(1):70-5
references.pmid: 12503979
references.citation: Clin Mol Hepatol. 2012 Dec;18(4):337-46
references.pmid: 23323248
references.citation: Alcohol Clin Exp Res. 2005 Dec;29(12 Suppl):246S-50S
references.pmid: 16385231
references.citation: Biochem Biophys Res Commun. 2000 Nov 2;277(3):686-90
references.pmid: 11062014
references.citation: Alcohol Clin Exp Res. 2010 Oct;34(10):1733-41
references.pmid: 20608903
references.citation: J Biol Chem. 2001 Nov 9;276(45):41930-7
references.pmid: 11551956
references.citation: J Burn Care Res. 2010 Jul-Aug;31(4):652-60
references.pmid: 20616655
references.citation: J Lab Clin Med. 1992 Nov;120(5):693-8
references.pmid: 1385556
references.citation: Alcohol. 2002 Nov;28(3):137-49
references.pmid: 12551755
references.citation: J Burn Care Res. 2009 May-Jun;30(3):482-8
references.pmid: 19349879
references.citation: Keio J Med. 1998 Mar;47(1):1-9
references.pmid: 9560526
references.citation: J Leukoc Biol. 1997 Dec;62(6):733-40
references.pmid: 9400814
references.citation: Acta Chir Plast. 1996;38(4):122-7
references.pmid: 9037788
references.citation: J Trauma. 2001 Oct;51(4):736-9
references.pmid: 11586168
references.citation: Clin Gastroenterol Hepatol. 2012 Jul;10(7):819; author reply 819-20
references.pmid: 22343691
references.citation: J Burn Care Rehabil. 1992 Mar-Apr;13(2 Pt 1):218-20
references.pmid: 1587921
references.citation: Am J Physiol. 1995 Dec;269(6 Pt 1):G827-32
references.pmid: 8572213
references.citation: J Biol Chem. 2003 Mar 7;278(10):8435-41
references.pmid: 12482856
references.citation: J Burn Care Rehabil. 2005 Jan-Feb;26(1):85-91
references.pmid: 15640741
references.citation: Shock. 2013 Apr;39(4):373-9
references.pmid: 23376955
references.citation: J Burn Care Res. 2008 Sep-Oct;29(5):784-9
references.pmid: 18695611
references.citation: JAMA. 2004 Mar 10;291(10):1238-45
references.pmid: 15010446
references.citation: Burns. 1999 Mar;25(2):131-6
references.pmid: 10208387
references.citation: J Burn Care Res. 2007 May-Jun;28(3):490-9
references.pmid: 17438481
references.citation: J Burn Care Res. 2011 Jul-Aug;32(4):489-97
references.pmid: 21593683
references.citation: Am J Physiol Gastrointest Liver Physiol. 2001 Nov;281(5):G1135-9
references.pmid: 11668021
references.citation: Am J Pathol. 2006 Sep;169(3):784-94
references.pmid: 16936255
references.citation: Am J Physiol Gastrointest Liver Physiol. 2012 Sep 15;303(6):G705-12
references.pmid: 22790598
references.citation: Nutr Metab Cardiovasc Dis. 2012 Jun;22(6):471-6
references.pmid: 22546554
references.citation: Methods. 2001 Dec;25(4):402-8
references.pmid: 11846609
references.citation: Gastroenterology. 1998 Aug;115(2):443-51
references.pmid: 9679050
references.citation: J Burn Care Res. 2008 Mar-Apr;29(2):323-30
references.pmid: 18354289
references.citation: Am J Physiol Gastrointest Liver Physiol. 2002 Jan;282(1):G6-15
references.pmid: 11751152
references.citation: Ann Emerg Med. 1999 Jun;33(6):659-68
references.pmid: 10339681
references.citation: J Trauma. 1999 Mar;46(3):428-32
references.pmid: 10088845
references.citation: J Trauma. 1993 Sep;35(3):335-9
references.pmid: 8371288
references.citation: Mol Med. 2009 Sep-Oct;15(9-10):337-51
references.pmid: 19603107
references.citation: Pharm Res. 2008 Jun;25(6):1377-86
references.pmid: 18163202
references.citation: Alcohol Clin Exp Res. 2006 Jan;30(1):76-85
references.pmid: 16433734
references.citation: J Burn Care Rehabil. 1988 Mar-Apr;9(2):169-71
references.pmid: 3360821
references.citation: Ann Surg. 2008 Sep;248(3):387-401
references.pmid: 18791359
references.citation: Shock. 1998 Aug;10(2):135-40
references.pmid: 9721981
references.citation: J Leukoc Biol. 2008 Sep;84(3):607-13
references.pmid: 18362209
references.citation: J Emerg Trauma Shock. 2008 Jul;1(2):81-7
references.pmid: 19561986
references.citation: Alcohol. 2000 Aug;22(1):35-44
references.pmid: 11109026
references.citation: Alcohol Clin Exp Res. 2000 Sep;24(9):1443-8
references.pmid: 11003212
references.citation: Nihon Arukoru Yakubutsu Igakkai Zasshi. 2006 Oct;41(5):400-6
references.pmid: 17176845
references.citation: J Burn Care Rehabil. 1996 Nov-Dec;17(6 Pt 1):532-9
references.pmid: 8951541