title: Carbon monoxide confers protection in sepsis by enhancing beclin 1-dependent autophagy and phagocytosis.
abstract: OBJECTIVE
  Sepsis, a systemic inflammatory response to infection, represents the leading cause of death in critically ill patients. However, the pathogenesis of sepsis remains incompletely understood. Carbon monoxide (CO), when administered at low physiologic doses, can modulate cell proliferation, apoptosis, and inflammation in pre-clinical tissue injury models, though its mechanism of action in sepsis remains unclear.
  
  
  RESULTS
  CO (250 ppm) inhalation increased the survival of C57BL/6J mice injured by cecal ligation and puncture (CLP) through the induction of autophagy, the down-regulation of pro-inflammatory cytokines, and by decreasing the levels of bacteria in blood and vital organs, such as the lung and liver. Mice deficient in the autophagic protein, Beclin 1 (Becn1(+/-)) were more susceptible to CLP-induced sepsis, and unresponsive to CO therapy, relative to their corresponding wild-type (Becn1(+/+)) littermate mice. In contrast, mice deficient in autophagic protein microtubule-associated protein-1 light chain 3B (LC3B) (Map1lc3b(-/-)) and their corresponding wild-type (Map1lc3b(+/+)) mice showed no differences in survival or response to CO, during CLP-induced sepsis. CO enhanced bacterial phagocytosis in Becn1(+/+) but not Becn1(+/-) mice in vivo and in corresponding cultured macrophages. CO also enhanced Beclin 1-dependent induction of macrophage protein signaling lymphocyte-activation molecule, a regulator of phagocytosis.
  
  
  METHODS
  Our findings demonstrate a novel protective effect of CO in sepsis, dependent on autophagy protein Beclin 1, in a murine model of CLP-induced polymicrobial sepsis.
  
  
  CONCLUSIONS
  CO increases the survival of mice injured by CLP through systemic enhancement of autophagy and phagocytosis. Taken together, we suggest that CO gas may represent a novel therapy for patients with sepsis.
authors: 1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital , Harvard Medical School, Boston, Massachusetts.
authors: Seonmin
authors: S
authors: Lee
authors: Seon-Jin
authors: SJ
authors: Lee
authors: Anna A
authors: AA
authors: Coronata
authors: Laura E
authors: LE
authors: Fredenburgh
authors: Su Wol
authors: SW
authors: Chung
authors: Mark A
authors: MA
authors: Perrella
authors: Kiichi
authors: K
authors: Nakahira
authors: Stefan W
authors: SW
authors: Ryter
authors: Augustine M K
authors: AM
authors: Choi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects; D000071186:Beclin-1; D002248:Carbon Monoxide / Q000008:administration & dosage* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000382:microbiology; D008168:Lung / Q000187:drug effects / Q000382:microbiology; D051379:Mice; D010587:Phagocytosis / Q000187:drug effects*; D011677:Punctures / Q000009:adverse effects; D018805:Sepsis / Q000378:metabolism* / Q000473:pathology; D014947:Wounds and Injuries / Q000188:drug therapy / Q000382:microbiology
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D002248:Carbon Monoxide
references: J Biol Chem. 2004 Feb 13;279(7):5237-43
references: 14625309
references: Nature. 2007 Dec 20;450(7173):1253-7
references: 18097414
references: J Immunol. 2009 Mar 15;182(6):3335-41
references: 19265109
references: Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):15077-82
references: 14657337
references: J Biol Chem. 2003 Jan 10;278(2):1248-58
references: 12399465
references: Am J Respir Cell Mol Biol. 2011 Oct;45(4):867-73
references: 21441382
references: Br J Pharmacol. 1998 Dec;125(7):1437-44
references: 9884071
references: Cell Mol Biol (Noisy-le-grand). 2005 Oct 03;51(5):433-40
references: 16309564
references: Nature. 2008 Nov 13;456(7219):264-8
references: 18849965
references: Annu Rev Genet. 2009;43:67-93
references: 19653858
references: N Engl J Med. 2001 Nov 8;345(19):1368-77
references: 11794169
references: Am J Physiol. 1999 Apr;276(4):L688-94
references: 10198367
references: J Clin Invest. 2008 Jan;118(1):239-47
references: 18060048
references: Proc Natl Acad Sci U S A. 2005 Aug 9;102(32):11319-24
references: 16051704
references: Cell. 2008 Jan 11;132(1):27-42
references: 18191218
references: Antioxid Redox Signal. 2007 Nov;9(11):2013-26
references: 17822362
references: Nat Med. 2000 Apr;6(4):422-8
references: 10742149
references: Nat Immunol. 2011 Mar;12(3):222-30
references: 21151103
references: Autophagy. 2011 Aug;7(8):829-39
references: 21685724
references: Neuron. 2002 Aug 29;35(5):921-33
references: 12372286
references: N Engl J Med. 2001 Mar 8;344(10):699-709
references: 11236773
references: N Engl J Med. 2003 Jan 9;348(2):138-50
references: 12519925
references: Proc Natl Acad Sci U S A. 2011 Oct 18;108(42):17396-401
references: 21969579
references: Proc Natl Acad Sci U S A. 1968 Oct;61(2):748-55
references: 4386763
references: Chest. 1997 Jul;112(1):235-43
references: 9228382
references: J Immunol. 2013 Jun 15;190(12):6378-88
references: 23650615
references: Nat Immunol. 2010 Oct;11(10):920-7
references: 20818396
references: Antioxid Redox Signal. 2013 Feb 20;18(6):677-91
references: 22871044
references: Cell. 2011 Nov 11;147(4):728-41
references: 22078875
references: Nat Rev Immunol. 2012 Jun 15;12(7):492-502
references: 22699831
references: Cell. 2012 Aug 17;150(4):803-15
references: 22901810
references: Hepatology. 2011 Jun;53(6):2053-62
references: 21437926
references: J Biol Chem. 2007 Jan 19;282(3):1718-26
references: 17135272
references: Genomics. 1999 Jul 1;59(1):59-65
references: 10395800
references: Surg Infect (Larchmt). 2003 Winter;4(4):355-62
references: 15012862
references: Nature. 1999 Dec 9;402(6762):672-6
references: 10604474
references: Hepatology. 2001 Apr;33(4):925-37
references: 11283857
references: J Immunol. 2011 Nov 15;187(10):5255-67
references: 21967897
references: Trends Mol Med. 2013 Jan;19(1):3-11
references: 23140858
references: Physiol Rev. 2006 Apr;86(2):583-650
references: 16601269
references: J Biol Chem. 2010 Nov 26;285(48):37909-19
references: 20876581
references: Circulation. 2010 Feb 2;121(4):537-48
references: 20083679
references: Proc Natl Acad Sci U S A. 1989 Jan;86(1):99-103
references: 2911585
references: Contrib Nephrol. 2001;(132):354-66
references: 11395903
references: EMBO J. 2011 Nov 08;30(23):4701-11
references: 22068051
references: PLoS One. 2009 Dec 02;4(12):e8139
references: 19956541
references: Nat Immunol. 2009 May;10(5):461-70
references: 19381141
references: Annu Rev Pharmacol Toxicol. 2006;46:411-49
references: 16402911
references: Am J Respir Crit Care Med. 2004 Sep 15;170(6):613-20
references: 15142867
references: PLoS One. 2008 Oct 02;3(10):e3316
references: 18830406