title: Cytoprotective effects of a cyclic RGD peptide in steatotic liver cold ischemia and reperfusion injury.
abstract: The serious need for expanding the donor population has attracted attention to the use of steatotic donor livers in orthotopic liver transplantation (OLT). However, steatotic livers are highly susceptible to hepatic ischemia-reperfusion injury (IRI). Expression of fibronectin (FN) by endothelial cells is an important feature of hepatic response to injury. We report the effect of a cyclic RGD peptide with high affinity for the alpha5beta1, the FN integrin receptor, in a rat model of steatotic liver cold ischemia, followed by transplantation. RGD peptide therapy ameliorated steatotic IRI and improved the recipient survival rate. It significantly inhibited the recruitment of monocyte/macrophages and neutrophils, and depressed the expression of pro-inflammatory mediators, such as inducible nitric oxide synthase (iNOS) and interferon (IFN)-gamma. Moreover, it resulted in profound inhibition of metalloproteinase-9 (MMP-9) expression, a gelatinase implied in leukocyte migration in damaged livers. Finally, we show that RGD peptide therapy reduced the expression of the 17-kDa active caspase-3 and the number of apoptotic cells in steatotic OLTs. The observed protection against steatotic liver IRI by the cyclic RGD peptides with high affinity for the alpha5beta1 integrin suggests that this integrin is a potential therapeutic target to allow the successful utilization of marginal steatotic livers in transplantation.
authors.affiliation: The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Fondevila
authors.forename: X-D
authors.initials: XD
authors.lastname: Shen
authors.forename: S
authors.initials: S
authors.lastname: Duarte
authors.forename: R W
authors.initials: RW
authors.lastname: Busuttil
authors.forename: A J
authors.initials: AJ
authors.lastname: Coito
mesh_terms: D000818:Animals; D015153:Blotting, Western; D003080:Cold Temperature; D019610:Cytoprotection / Q000187:drug effects*; D004195:Disease Models, Animal; D015536:Down-Regulation; D005234:Fatty Liver / Q000473:pathology*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007371:Interferon-gamma / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009504:Neutrophils / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology*; D051381:Rats; D015427:Reperfusion Injury / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate
chemical_list: D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; D020780:Matrix Metalloproteinase 9
references.citation: J Biol Chem. 2006 Oct 6;281(40):29614-24
references.pmid: 16882662
references.citation: Am J Pathol. 1997 May;150(5):1757-72
references.pmid: 9137099
references.citation: Am J Pathol. 2003 Apr;162(4):1229-39
references.pmid: 12651615
references.citation: Kidney Int. 1994 Oct;46(4):1050-8
references.pmid: 7861698
references.citation: Am J Pathol. 2007 Feb;170(2):567-77
references.pmid: 17255325
references.citation: J Biol Chem. 1987 Dec 25;262(36):17294-8
references.pmid: 3693352
references.citation: Transplantation. 1993 Jun;55(6):1265-72
references.pmid: 7685932
references.citation: Spine (Phila Pa 1976). 2005 Jun 1;30(11):1242-6
references.pmid: 15928546
references.citation: Transplantation. 1995 Mar 15;59(5):674-9
references.pmid: 7886790
references.citation: Transplantation. 1993 Aug;56(2):282-7
references.pmid: 8356581
references.citation: Proc Natl Acad Sci U S A. 2001 Jan 16;98(2):620-4
references.pmid: 11209058
references.citation: Annu Rev Pharmacol Toxicol. 1995;35:655-77
references.pmid: 7598511
references.citation: Blood. 2006 Nov 1;108(9):3143-51
references.pmid: 16840734
references.citation: J Immunol. 2008 Feb 1;180(3):1843-53
references.pmid: 18209082
references.citation: Hepatology. 1994 Oct;20(4 Pt 1):829-38
references.pmid: 7927223
references.citation: J Clin Invest. 1997 Nov 15;100(10):2417-23
references.pmid: 9366554
references.citation: Transplantation. 1999 Sep 27;68(6):803-13
references.pmid: 10515381
references.citation: Proc Natl Acad Sci U S A. 1997 Mar 18;94(6):2557-62
references.pmid: 9122234
references.citation: Biotechnology (N Y). 1995 Mar;13(3):265-70
references.pmid: 9634769
references.citation: J Thromb Haemost. 2007 Jul;5 Suppl 1:32-40
references.pmid: 17635706
references.citation: Am J Physiol. 1999 Jan;276(1):G1-6
references.pmid: 9886971
references.citation: BMJ. 1996 Apr 20;312(7037):989-90
references.pmid: 8616380
references.citation: J Invest Surg. 2003 May-Jun;16(3):149-59
references.pmid: 12775431
references.citation: J Clin Invest. 1997 Jun 1;99(11):2782-90
references.pmid: 9169509
references.citation: J Cell Biol. 1994 Dec;127(6 Pt 2):2037-48
references.pmid: 7806580
references.citation: J Immunol. 1998 Jan 1;160(1):467-74
references.pmid: 9552005
references.citation: J Immunol. 1992 Aug 15;149(4):1340-7
references.pmid: 1354234
references.citation: J Cell Biol. 1996 Aug;134(4):1063-73
references.pmid: 8769427
references.citation: Am J Pathol. 2000 Jul;157(1):297-302
references.pmid: 10880399
references.citation: Liver Int. 2006 Oct;26(8):912-9
references.pmid: 16953830
references.citation: Am J Pathol. 2009 Jun;174(6):2265-77
references.pmid: 19443702
references.citation: J Clin Invest. 1994 Jan;93(1):405-16
references.pmid: 8282813
references.citation: Hepatology. 2005 Mar;41(3):478-86
references.pmid: 15723438
references.citation: J Biol Chem. 1998 May 8;273(19):11576-82
references.pmid: 9565574
references.citation: Am J Physiol Renal Physiol. 2006 Jan;290(1):F159-66
references.pmid: 16106036
references.citation: Yale J Biol Med. 1997 Jul-Aug;70(4):391-402
references.pmid: 9626759
references.citation: Cell. 1991 May 31;65(5):859-73
references.pmid: 1710173
references.citation: J Invest Surg. 2007 May-Jun;20(3):195-203
references.pmid: 17613695
references.citation: J Clin Invest. 2001 Feb;107(4):439-47
references.pmid: 11181643
references.citation: Blood. 1994 Jan 15;83(2):345-50
references.pmid: 7506946
references.citation: Dev Immunol. 2000;7(2-4):239-48
references.pmid: 11097215
references.citation: J Exp Med. 2005 Nov 7;202(9):1163-9
references.pmid: 16260491
references.citation: J Immunol. 2001 Apr 1;166(7):4644-9
references.pmid: 11254723
references.citation: J Exp Med. 1989 Oct 1;170(4):1133-48
references.pmid: 2477485
references.citation: Semin Liver Dis. 2001;21(1):105-13
references.pmid: 11296690
references.citation: Immunol Today. 1997 Dec;18(12):586-91
references.pmid: 9425737
references.citation: J Biol Chem. 1997 May 16;272(20):13432-6
references.pmid: 9148968
references.citation: Transplantation. 1998 Jan 27;65(2):167-72
references.pmid: 9458009
references.citation: Transplantation. 2002 Feb 15;73(3):325-30
references.pmid: 11884924
references.citation: J Hepatol. 1996 Jun;24(6):731-8
references.pmid: 8835749
references.citation: Kidney Int. 2003 Mar;63(3):889-98
references.pmid: 12631069
references.citation: Cell. 1992 Apr 3;69(1):11-25
references.pmid: 1555235
references.citation: Hepatology. 1999 Apr;29(4):1139-46
references.pmid: 10094958
references.citation: Hepatology. 2008 Jan;47(1):186-98
references.pmid: 17880014
references.citation: J Leukoc Biol. 1995 Apr;57(4):592-9
references.pmid: 7536788
references.citation: J Immunol. 2005 Jan 15;174(2):1073-80
references.pmid: 15634932
references.citation: Surgery. 1983 Jan;93(1 Pt 1):64-9
references.pmid: 6336859
references.citation: Am J Physiol Gastrointest Liver Physiol. 2005 Feb;288(2):G396-402
references.pmid: 15472011
references.citation: J Exp Med. 1998 Mar 16;187(6):917-28
references.pmid: 9500794