Published online Dec 15, 2004. doi: 10.3748/wjg.v10.i24.3654
Revised: May 6, 2004
Accepted: May 13, 2004
Published online: December 15, 2004
AIM: To investigate the effect of pyrrolidine dithiocarbamate (PDTC), a novel nuclear factor-κB (NF-κB) inhibitor, on expression of multiple inflammatory mediators and neutrophilic inflammation of cold preserved grafts after rat liver transplantation and its significance.
METHODS: Orthotopic liver transplantation (OLT) was performed after 24 h of cold storage using University of Wisconsin solution with varied concentrations of PDTC. We determined the time course of NF-κB activation and expression of multiple inflammatory signals, such as tumor necrosis factor-α (TNF-α), cytokine-inducible neutrophil chemoattractant (CINC), and intercellular adhesion molecule-1 (ICAM-1) by ELISA methods. Serum alanine aminotransferase (ALT), intrahepatic myeloperoxidase (MPO)/WBC (a measure of neutrophil accumulation) and Mac-1 expression (a measure of circulating neutrophil activity) were also evaluated.
RESULTS: PDTC decreased NF-κB activation induced by prolonged cold preservation in a dose dependent manner (from 20 mmol/L to 60 mmol/L), diminished TNF-α, CINC, ICAM-1 proteins in the grafts, and reduced the expression of increases in plasma TNF-α levels induced by prolonged cold preservation. Neutrophilic inflammation of the graft was significantly suppressed after preservation with PDTC (P < 0.05). The total neutrophil accumulation in PDTC (40 mmol/L) group (7.04 ± 0.97) was markedly reduced compared to control group (14.07 ± 1.31) (P < 0.05). Mac-1 expression was significantly reduced in PDTC (40 mmol/L) group (181 ± 11.3%) compared with the control group (281 ± 13.2%) (P < 0.05) at 6 h after reperfusion. Furthermore, PDTC inhibited the increased serum ALT levels after liver transplantation.
CONCLUSION: PDTC can inhibit B NF-κB activation and expression of the inflammatory mediators, which are associated with improved graft viability via inhibiting intrahepatic neutrophilic inflammation. Our study suggests that a therapeutic strategy directed at inhibition of NF-κB activation in the transplanted liver might be effective in reducing intrahepatic neutrophilic inflammation, and would be beneficial to cold preserved grafts.