FK 409 ameliorates small-for-size liver graft injury by attenuation of portal hypertension and down-regulation of Egr-1 pathway.
OBJECTIVE
To investigate whether low-dose nitric oxide donor FK 409 could attenuate small-for-size graft injury in liver transplantation using small-for-size grafts.


BACKGROUND
The major concern of live donor liver transplantation is small-for-size graft injury at the early phase after transplantation. Novel therapeutic strategies should be investigated.


METHODS
We employed a rat orthotopic liver transplantation model using small-for-size (40%) graft. FK 409 was given at 30 minutes before graft harvesting (2 mg/kg) to the donor and immediately after reperfusion (1 mg/kg) to the recipient (FK group). Graft survival, intragraft genes expression, portal hemodynamics, and hepatic ultrastructural changes were compared between the 2 groups.


RESULTS
Seven-day graft survival rates in the FK group were significantly improved compared with those of rats not receiving FK 409 (control group; 80% versus 28.6%, P = 0.018). In the FK group, portal pressure was significantly decreased within the first 60 minutes after reperfusion whereas in the control group, transient portal hypertension was observed. Intragraft expression (both mRNA and protein) of early growth response-1, endothelin-1, endothelin-1 receptor A, tumor necrosis factor-alpha, macrophage-inflammatory protein-2, and inducible nitric oxide synthase was significantly down-regulated accompanied with up-regulation of heme oxygenase-1, A20, interferon-gamma-inducible protein-10, and interleukin-10 during the first 24 hours after reperfusion. Hepatic ultrastructure, especially the integrity of sinusoids was well protected in the FK group.


CONCLUSIONS
Low-dose FK 409 rescues small-for-size grafts in liver transplantation by attenuation of portal hypertension and amelioration of acute phase inflammatory response by down-regulation of Egr-1, together with prior induction of heat shock proteins.
Man
Kwan
K
Department of Surgery, Centre for the Study of Liver Disease, University of Hong Kong Medical Centre, Queen Mary Hospital, Hong Kong, China.
Lee
Terence K
TK
Liang
Ting Bo
TB
Lo
Chung Mau
CM
Fung
Peter Chin-Wan
PC
Tsui
Steven H
SH
Li
Xian Liang
XL
Ng
Kevin T
KT
Fan
Sheung Tat
ST
D000818:Animals; D017209:Apoptosis; D054426:Chemokine CXCL2; D018925:Chemokines / Q000378:metabolism; D019743:Chemokines, CXC / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects*; D051766:Early Growth Response Protein 1; D019332:Endothelin-1 / Q000378:metabolism; D015870:Gene Expression; D006085:Graft Survival / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing); D006975:Hypertension, Portal / Q000209:etiology / Q000517:prevention & control*; D017874:Immediate-Early Proteins / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008099:Liver / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D016031:Liver Transplantation / Q000009:adverse effects; D008297:Male; D020030:Nitric Oxide Donors / Q000008:administration & dosage*; D009574:Nitro Compounds / Q000008:administration & dosage*; D010105:Oxygenases; D011300:Preoperative Care; D011506:Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D015424:Reperfusion; D015398:Signal Transduction / Q000187:drug effects*; D014019:Tissue Donors; D020858:Tissue and Organ Harvesting; D014157:Transcription Factors / Q000378:metabolism*; D016335:Zinc Fingers
D054426:Chemokine CXCL2; D018925:Chemokines; D019743:Chemokines, CXC; C513296:Cxcl2 protein, rat; D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D019332:Endothelin-1; D006360:Heat-Shock Proteins; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D020030:Nitric Oxide Donors; D009574:Nitro Compounds; D011506:Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; C061872:FK 409; D010105:Oxygenases; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat