Overexpression Of Matrix Metalloproteinase-9 Correlates With Acute Graft Injury After Small-for-size Liver Transplantation

Partâ… Overexpression of Matrix Metalloproteinase-9 Correlates with Acute Graft Injury in Rats Following Small-for-size Liver TransplantationObjective:Portal hypertension and ischemia/reperfusion (I/R) have been implicated in small-for-size liver graft dysfunction. Matrix metalloproteinases-2 and -9 (MMP-2/9) are critically involved in hepatic I/R injury. The goal of this study was to investigate the role of MMP-2/9 in acute small-for-size graft injury.Methods:108 rats were divided into three groups:100% (full-size),50% (half-size) and 25%(quarter-size) liver transplantation group. Blood and liver samples were collected to assess liver function, hepatic Malondialdehyde (MDA) content, tissue Myeloperoxidase (MPO) activity and histological changes. ELISA, real-time PCR, gelatin zymography, and immunohistochemistry were used to determine the expression pattern of MMP-2/9 in liver grafts.Results:The expression levels of MMP-9 were significantly higher in quarter-size and half-size grafts than those in full-size liver grafts 6,12, and 24 h after reperfusion (P<0.05). And the elevated levels of MMP-9 were related to graft size inversely (P<0.05). However, MMP-2 was expressed and remained in all groups invariably. MMP-9 overexpression was accompanied by extensive liver I/R injury, as evidenced by significant increases in hepatic microscopic damage scores, MDA content, MPO activity and liver function levels (P<0.05). Furthermore, MMP-9 was found mainly to locate around periportal area. The presence of the active form of MMP-9 was significantly higher in small-for-size grafts (P<0.05),which was correlated with sinusoidal dilatation, congestion and hemorrhage.Conclusion:These results support critical function of MMP-9 in acute small-for-size liver graft injury. Moreover, portal hypertension may be a crucial trigger for expression and activation of MMP-9.Partâ…¡Inhibition of Matrix Metalloproteinase-9 Attenuates Acute Small-for-Size Liver Graft Injury in RatsObjective: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).Methods: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.Results:MMP-9 expression was significantly increased 6 h after reperfusion and reached a peak 12 h in the 25% LT group (P<0.05), 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 (P<0.05), down-regulated proinflammatory cytokines (P<0.05), attenuated malondialdehyde (MDA) and myeloperoxidase (MPO) activities (P<0.05), and improved liver histology (P<0.05). Likewise, MMP-9 inhibition significantly reduced number of TUNEL-positive cells and caspase-3 activity (P<0.05), along with decreased protein levels of Fas and Fas-L(P<0.05). Specifically, rat survival was also improved in the CTT-treated group (P<0.05)Conclusion:These results support critical function of MMP-9 involved in acute small-for-size liver graft injury.Partâ…¢Effrcts of Inhibition of Matrix Metalloproteinase-9 on Liver Regeneration after Small-for-size Liver Transplantation in RatsObjective:To study the effects of inhibition of matrix metalloproteinase-9 on liver regeneration after small-for-size liver transplantation in rats.Method:Rats were divided into four groups:75% partial hepatectomy (PH); 100% LT; 25% LT and 25% LT treated with CTT peptide (MMP-2/9 inhibitor),Until the animals were killed at 24 and 48 hour after surgery, PVP, Mitotic index (MI), Bromode oxyuridine Labeling index (BrdU LI) of hepatocytes, CD34 Labeling MVD and HGF,IL-6,TNF-a of serum were measured. Results:MI,Labeling index of BrdU,MVD and gene level of HGF, IL-6 TNF-a were remarkably increased in the rats receiving 75%PH (P<0.05). There was no statistical difference in indexes mentioned above between 25%LT and CTT-treated groups at any time point (P>0.05)Conclusion:Inhibition of matrix metalloproteinase-9 has no negative effects on liver regeneration after small-for-size liver transplantation in rats...