Pyrrolidine dithiocarbamate provides protection against hypothermic preservation and transplantation injury in the rat liver: the role of heme oxygenase-1.
BACKGROUND
Pyrrolidine dithiocarbamate (PDTC) represents a class of antioxidants and is a potent inducer of the heme oxygenase-1 (HO-1) gene and an inhibitor of nuclear factor-kappa B (NF-kappa B). We examined the impact of PDTC preconditioning against cold ischemia and reperfusion injury in the rat liver.


METHODS
Lewis rats were treated subcutaneously with saline or PDTC solution 24 hours before harvesting. Some animals pretreated with PDTC were also given zinc protoporphyrin IX intravenously immediately after reperfusion. HO-1 expression and enzyme activity in liver tissues were analyzed at different time points after each treatment. After transplantation of 24-hour preserved livers, serum levels of transaminases and gene expression of tumor necrosis factor-alpha, interleukin-1 beta, and NF-kappa B were measured. Animal survival and cellular viability were monitored.


RESULTS
HO-1 gene expression and protein synthesis were enhanced in PDTC-treated livers, leading to increased enzyme activity (P <.05). The PDTC treatment group showed lower transaminase levels (P <.05), lower cytokine and NF-kappa B messenger RNA expression (P <.05), and fewer nonviable cells (P <.05) than did the control group, whereas these PDTC effects were abolished with zinc protoporphyrin injection after reperfusion (P <.05). The best animal survival rate was observed in the PDTC group (P <.05).


CONCLUSIONS
PDTC preconditioning reduces inflammatory responses during reperfusion. PDTC appears to exert this protective effect by induction of an antioxidative stress protein and inhibition of proinflammatory cytokines.
Tsuchihashi
Sei-ichiro
S
Department of Surgery, Research Institute for Artificial Organs, Transplantation and Gene Therapy, Sapporo Hokuyu Hospital, Sapporo, Japan.
Tamaki
Tohru
T
Tanaka
Mitsuko
M
Kawamura
Akio
A
Kaizu
Takashi
T
Ikeda
Atsushi
A
Kakita
Akira
A
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002470:Cell Survival; D015925:Cryopreservation; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism; D051547:Heme Oxygenase-1; D007375:Interleukin-1 / Q000235:genetics; D008099:Liver / Q000201:enzymology; D016031:Liver Transplantation / Q000009:adverse effects* / Q000401:mortality; D008297:Male; D016328:NF-kappa B / Q000235:genetics; D009926:Organ Preservation / Q000009:adverse effects*; D011392:Proline / Q000031:analogs & derivatives* / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000209:etiology* / Q000517:prevention & control*; D013859:Thiocarbamates / Q000494:pharmacology*; D000637:Transaminases / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D000975:Antioxidants; D007375:Interleukin-1; D016328:NF-kappa B; D012333:RNA, Messenger; D013859:Thiocarbamates; D014409:Tumor Necrosis Factor-alpha; C066229:prolinedithiocarbamate; D011392:Proline; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D000637:Transaminases