Cytoprotective effects of a cyclic RGD peptide in steatotic liver cold ischemia and reperfusion injury.
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.
Fondevila
C
C
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.
Shen
X-D
XD
Duarte
S
S
Busuttil
R W
RW
Coito
A J
AJ
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
D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; D020780:Matrix Metalloproteinase 9
J Biol Chem. 2006 Oct 6;281(40):29614-24
16882662
Am J Pathol. 1997 May;150(5):1757-72
9137099
Am J Pathol. 2003 Apr;162(4):1229-39
12651615
Kidney Int. 1994 Oct;46(4):1050-8
7861698
Am J Pathol. 2007 Feb;170(2):567-77
17255325
J Biol Chem. 1987 Dec 25;262(36):17294-8
3693352
Transplantation. 1993 Jun;55(6):1265-72
7685932
Spine (Phila Pa 1976). 2005 Jun 1;30(11):1242-6
15928546
Transplantation. 1995 Mar 15;59(5):674-9
7886790
Transplantation. 1993 Aug;56(2):282-7
8356581
Proc Natl Acad Sci U S A. 2001 Jan 16;98(2):620-4
11209058
Annu Rev Pharmacol Toxicol. 1995;35:655-77
7598511
Blood. 2006 Nov 1;108(9):3143-51
16840734
J Immunol. 2008 Feb 1;180(3):1843-53
18209082
Hepatology. 1994 Oct;20(4 Pt 1):829-38
7927223
J Clin Invest. 1997 Nov 15;100(10):2417-23
9366554
Transplantation. 1999 Sep 27;68(6):803-13
10515381
Proc Natl Acad Sci U S A. 1997 Mar 18;94(6):2557-62
9122234
Biotechnology (N Y). 1995 Mar;13(3):265-70
9634769
J Thromb Haemost. 2007 Jul;5 Suppl 1:32-40
17635706
Am J Physiol. 1999 Jan;276(1):G1-6
9886971
BMJ. 1996 Apr 20;312(7037):989-90
8616380
J Invest Surg. 2003 May-Jun;16(3):149-59
12775431
J Clin Invest. 1997 Jun 1;99(11):2782-90
9169509
J Cell Biol. 1994 Dec;127(6 Pt 2):2037-48
7806580
J Immunol. 1998 Jan 1;160(1):467-74
9552005
J Immunol. 1992 Aug 15;149(4):1340-7
1354234
J Cell Biol. 1996 Aug;134(4):1063-73
8769427
Am J Pathol. 2000 Jul;157(1):297-302
10880399
Liver Int. 2006 Oct;26(8):912-9
16953830
Am J Pathol. 2009 Jun;174(6):2265-77
19443702
J Clin Invest. 1994 Jan;93(1):405-16
8282813
Hepatology. 2005 Mar;41(3):478-86
15723438
J Biol Chem. 1998 May 8;273(19):11576-82
9565574
Am J Physiol Renal Physiol. 2006 Jan;290(1):F159-66
16106036
Yale J Biol Med. 1997 Jul-Aug;70(4):391-402
9626759
Cell. 1991 May 31;65(5):859-73
1710173
J Invest Surg. 2007 May-Jun;20(3):195-203
17613695
J Clin Invest. 2001 Feb;107(4):439-47
11181643
Blood. 1994 Jan 15;83(2):345-50
7506946
Dev Immunol. 2000;7(2-4):239-48
11097215
J Exp Med. 2005 Nov 7;202(9):1163-9
16260491
J Immunol. 2001 Apr 1;166(7):4644-9
11254723
J Exp Med. 1989 Oct 1;170(4):1133-48
2477485
Semin Liver Dis. 2001;21(1):105-13
11296690
Immunol Today. 1997 Dec;18(12):586-91
9425737
J Biol Chem. 1997 May 16;272(20):13432-6
9148968
Transplantation. 1998 Jan 27;65(2):167-72
9458009
Transplantation. 2002 Feb 15;73(3):325-30
11884924
J Hepatol. 1996 Jun;24(6):731-8
8835749
Kidney Int. 2003 Mar;63(3):889-98
12631069
Cell. 1992 Apr 3;69(1):11-25
1555235
Hepatology. 1999 Apr;29(4):1139-46
10094958
Hepatology. 2008 Jan;47(1):186-98
17880014
J Leukoc Biol. 1995 Apr;57(4):592-9
7536788
J Immunol. 2005 Jan 15;174(2):1073-80
15634932
Surgery. 1983 Jan;93(1 Pt 1):64-9
6336859
Am J Physiol Gastrointest Liver Physiol. 2005 Feb;288(2):G396-402
15472011
J Exp Med. 1998 Mar 16;187(6):917-28
9500794