title: Carbon monoxide-releasing molecule-2 (CORM-2) attenuates acute hepatic ischemia reperfusion injury in rats.
abstract: BACKGROUND
  Hepatic ischemia-reperfusion injury (I/Ri) is a serious complication occurring during liver surgery that may lead to liver failure. Hepatic I/Ri induces formation of reactive oxygen species, hepatocyte apoptosis, and release of pro-inflammatory cytokines, which together causes liver damage and organ dysfunction. A potential strategy to alleviate hepatic I/Ri is to exploit the potent anti-inflammatory and cytoprotective effects of carbon monoxide (CO) by application of so-called CO-releasing molecules (CORMs). Here, we assessed whether CO released from CORM-2 protects against hepatic I/Ri in a rat model.
  
  
  METHODS
  Forty male Wistar rats were randomly assigned into four groups (n = 10). Sham group underwent a sham operation and received saline. I/R group underwent hepatic I/R procedure by partial clamping of portal structures to the left and median lobes with a microvascular clip for 60 minutes, yielding approximately 70% hepatic ischemia and subsequently received saline. CORM-2 group underwent the same procedure and received 8 mg/kg of CORM-2 at time of reperfusion. iCORM-2 group underwent the same procedure and received iCORM-2 (8 mg/kg), which does not release CO. Therapeutic effects of CORM-2 on hepatic I/Ri was assessed by measuring serum damage markers AST and ALT, liver histology score, TUNEL-scoring of apoptotic cells, NFkB-activity in nuclear liver extracts, serum levels of pro-inflammatory cytokines TNF-alpha and IL-6, and hepatic neutrophil infiltration.
  
  
  RESULTS
  A single systemic infusion with CORM-2 protected the liver from I/Ri as evidenced by a reduction in serum AST/ALT levels and an improved liver histology score. Treatment with CORM-2 also up-regulated expression of the anti-apoptotic protein Bcl-2, down-regulated caspase-3 activation, and significantly reduced the levels of apoptosis after I/Ri. Furthermore, treatment with CORM-2 significantly inhibited the activity of the pro-inflammatory transcription factor NF-kappaB as measured in nuclear extracts of liver homogenates. Moreover, CORM-2 treatment resulted in reduced serum levels of pro-inflammatory cytokines TNF-alpha and IL-6 and down-regulation of the adhesion molecule ICAM-1 in the endothelial cells of liver. In line with these findings, CORM-2 treatment reduced the accumulation of neutrophils in the liver upon I/Ri. Similar treatment with an inactive variant of CORM-2 (iCORM-2) did not have any beneficial effect on the extent of liver I/Ri.
  
  
  CONCLUSIONS
  CORM-2 treatment at the time of reperfusion had several distinct beneficial effects on severity of hepatic I/Ri that may be of therapeutic value for the prevention of tissue damage as a result of I/Ri during hepatic surgery.
authors.affiliation: Third department of General Surgery, First Clinical Hospital Harbin, Harbin Medical University, Harbin 150001, Heilongjiang, China. y.wei@chir.umcg.nl
authors.forename: Yunwei
authors.initials: Y
authors.lastname: Wei
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.forename: Marco
authors.initials: M
authors.lastname: de Bruyn
authors.forename: Weihui
authors.initials: W
authors.lastname: Zhang
authors.forename: Edwin
authors.initials: E
authors.lastname: Bremer
authors.forename: Wijnand
authors.initials: W
authors.lastname: Helfrich
mesh_terms: D000208:Acute Disease; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D016207:Cytokines / Q000096:biosynthesis / Q000187:drug effects; D004247:DNA / Q000032:analysis; D004195:Disease Models, Animal; D020287:In Situ Nick-End Labeling; D007511:Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000098:blood supply* / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D009942:Organometallic Compounds / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012428:Ruthenium; D016896:Treatment Outcome
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D009942:Organometallic Compounds; C447082:tricarbonyldichlororuthenium (II) dimer; D012428:Ruthenium; D004247:DNA
references.citation: World J Gastroenterol. 2004 Jul 1;10(13):1934-8
references.pmid: 15222040
references.citation: Am J Physiol Gastrointest Liver Physiol. 2008 Jan;294(1):G184-91
references.pmid: 17991708
references.citation: Hepatology. 2006 Mar;43(3):474-84
references.pmid: 16496306
references.citation: Am J Physiol Gastrointest Liver Physiol. 2009 Mar;296(3):G664-70
references.pmid: 19109403
references.citation: J Am Soc Nephrol. 2009 Sep;20(9):1901-5
references.pmid: 19628669
references.citation: Biochem Pharmacol. 2006 Jan 12;71(3):307-18
references.pmid: 16329999
references.citation: FASEB J. 2005 Jan;19(1):106-8
references.pmid: 15514102
references.citation: Am J Pathol. 2003 Oct;163(4):1587-98
references.pmid: 14507665
references.citation: Am J Transplant. 2001 Jul;1(2):121-8
references.pmid: 12099359
references.citation: Blood. 1994 Oct 1;84(7):2068-101
references.pmid: 7522621
references.citation: Hepatology. 1996 Mar;23(3):506-14
references.pmid: 8617430
references.citation: Liver Transpl. 2006 Nov;12(11):1634-9
references.pmid: 17058249
references.citation: J Invest Dermatol. 1982 Mar;78(3):206-9
references.pmid: 6276474
references.citation: Am J Physiol Gastrointest Liver Physiol. 2008 Jan;294(1):G236-44
references.pmid: 18006605
references.citation: FASEB J. 2004 Apr;18(6):771-2
references.pmid: 14977880
references.citation: J Pathol. 2000 Feb;190(3):255-66
references.pmid: 10685060
references.citation: Hepatology. 2002 Apr;35(4):815-23
references.pmid: 11915027
references.citation: J Hepatol. 2002 Jan;36(1):53-9
references.pmid: 11804664
references.citation: Inflammation. 2010 Apr;33(2):92-100
references.pmid: 19842024
references.citation: Am J Physiol Gastrointest Liver Physiol. 2007 Sep;293(3):G623-30
references.pmid: 17627971
references.citation: Liver Transpl. 2009 Oct;15(10):1306-14
references.pmid: 19790158
references.citation: Br J Pharmacol. 2005 Jul;145(6):800-10
references.pmid: 15880142
references.citation: Nat Med. 2000 Apr;6(4):422-8
references.pmid: 10742149
references.citation: J Burn Care Res. 2007 Jan-Feb;28(1):173-81
references.pmid: 17211222
references.citation: Am J Surg. 2001 Feb;181(2):160-6
references.pmid: 11425059
references.citation: Am J Physiol Renal Physiol. 2004 Nov;287(5):F979-89
references.pmid: 15292046
references.citation: Gastroenterology. 2007 Aug;133(2):632-46
references.pmid: 17681182
references.citation: Transpl Int. 2007 Sep;20(9):784-9
references.pmid: 17535306
references.citation: J Surg Res. 2007 Mar;138(1):88-99
references.pmid: 17174338
references.citation: Surgery. 1995 Feb;117(2):195-200
references.pmid: 7846625
references.citation: Am J Transplant. 2004 Mar;4(3):352-62
references.pmid: 14961987
references.citation: J Leukoc Biol. 2007 Dec;82(6):1382-9
references.pmid: 17652447
references.citation: J Immunol. 2004 Mar 15;172(6):3553-63
references.pmid: 15004156
references.citation: Int J Biol Sci. 2008 Aug 22;4(5):270-8
references.pmid: 18726003
references.citation: Biochem Soc Trans. 2007 Nov;35(Pt 5):1142-6
references.pmid: 17956297
references.citation: Shock. 2005 Oct;24(4):370-5
references.pmid: 16205323
references.citation: Hepatology. 2008 Nov;48(5):1608-20
references.pmid: 18972563
references.citation: Nat Med. 2002 Mar;8(3):240-6
references.pmid: 11875494
references.citation: J Am Soc Nephrol. 2005 Apr;16(4):950-8
references.pmid: 15728782
references.citation: Thromb Haemost. 2002 Sep;88(3):473-80
references.pmid: 12353078
references.citation: J Hepatol. 2006 Jul;45(1):20-7
references.pmid: 16600417
references.citation: Hepatology. 1998 Apr;27(4):1172-7
references.pmid: 9537464
references.citation: Transplantation. 2002 Jul 15;74(1):96-102
references.pmid: 12134106
references.citation: Gastroenterology. 2003 Sep;125(3):917-36
references.pmid: 12949736
references.citation: Cancer Res. 2009 Oct 15;69(20):8017-24
references.pmid: 19808972
references.citation: Surgery. 2005 Aug;138(2):229-35
references.pmid: 16153431
references.citation: Liver Transpl. 2002 Nov;8(11):990-9
references.pmid: 12424711
references.citation: Int J Biol Sci. 2008 Jun 16;4(3):176-83
references.pmid: 18566696
references.citation: J Surg Res. 2007 Jan;137(1):69-74
references.pmid: 17064733
references.citation: Surgery. 1997 Jul;122(1):45-52
references.pmid: 9225914
references.citation: Biochem Biophys Res Commun. 2006 Jun 16;344(4):1172-8
references.pmid: 16647044
references.citation: Surgery. 2008 Sep;144(3):385-93
references.pmid: 18707037
references.citation: J Exp Med. 2003 Dec 1;198(11):1707-16
references.pmid: 14657222