Inhibition of matrix metalloproteinase-9 attenuates acute small-for-size liver graft injury in rats.
Ischemia/reperfusion (I/R) and portal hypertension have been implicated in small-for-size liver graft dysfunction. Matrix metalloproteinases-2 and -9 (MMP-2/9) are critically proposed to involve in hepatic I/R injury and activated by hemodynamic force. We hypothesized that MMP-2/9 overexpression played a crucial role in acute graft injury following small-for-size liver transplantation (LT). Rats were randomly assigned into four groups: 75% partial hepatectomy (PH); 100% LT; 25% LT and 25% LT treated with CTT peptide (MMP-2/9 inhibitor). ELISA, real-time PCR, gelatin zymography and immunohistochemistry were used to determine the expression pattern of MMP-2/9 in liver tissue. MMP-9 expression was significantly increased 6 h after reperfusion and reached a peak 12 h in the 25% LT group, whereas MMP-2 was expressed in all groups invariably. Compared with the 25% LT group, rats from CTT-treated group exhibited markedly decreased alanine aminotransferase and total bilirubin values, downregulated proinflammatory cytokines, attenuated malondialdehyde (MDA) and myeloperoxidase (MPO) activities, and improved liver histology. Likewise, MMP-9 inhibition significantly reduced number of TUNEL-positive cells and caspase-3 activity, along with decreased protein levels of Fas and Fas-L. Specifically, rat survival was also improved in the CTT-treated group. These results support critical function of MMP-9 involved in acute small-for-size livergraft injury.
Ma
Z Y
ZY
Liver Transplant Section, Center for Organ Transplantation, Huashan Hospital, Fudan University, Shanghai, China.
Qian
J M
JM
Liver Transplant Section, Center for Organ Transplantation, Huashan Hospital, Fudan University, Shanghai, China.
Rui
X H
XH
Liver Transplant Section, Center for Organ Transplantation, Huashan Hospital, Fudan University, Shanghai, China.
Wang
F R
FR
Liver Transplant Section, Center for Organ Transplantation, Huashan Hospital, Fudan University, Shanghai, China.
Wang
Q W
QW
Liver Transplant Section, Center for Organ Transplantation, Huashan Hospital, Fudan University, Shanghai, China.
Cui
Y Y
YY
Liver Transplant Section, Center for Organ Transplantation, Huashan Hospital, Fudan University, Shanghai, China.
Peng
Z H
ZH
Department of General Surgery, First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
D000818:Animals; D004797:Enzyme-Linked Immunosorbent Assay; D007150:Immunohistochemistry; D016031:Liver Transplantation / Q000009:adverse effects*; D061965:Matrix Metalloproteinase Inhibitors; D009929:Organ Size; D016133:Polymerase Chain Reaction; D011480:Protease Inhibitors / Q000494:pharmacology*; D051381:Rats; D015427:Reperfusion Injury / Q000517:prevention & control*
D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors