Pyrrolidine dithiocarbamate provides protection against hypothermic preservation and transplantation injury in the rat liver: the role of heme oxygenase-1

Surgery. 2003 May;133(5):556-67. doi: 10.1067/msy.2003.124.

Abstract

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).

Conclusion: 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.

MeSH terms

  • Animals
  • Antioxidants / pharmacology*
  • Cell Survival
  • Cryopreservation*
  • Heme Oxygenase (Decyclizing) / genetics
  • Heme Oxygenase (Decyclizing) / metabolism
  • Heme Oxygenase-1
  • Interleukin-1 / genetics
  • Liver / enzymology
  • Liver Transplantation / adverse effects*
  • Liver Transplantation / mortality
  • Male
  • NF-kappa B / genetics
  • Organ Preservation / adverse effects*
  • Proline / analogs & derivatives*
  • Proline / pharmacology*
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Inbred Lew
  • Reperfusion Injury / etiology*
  • Reperfusion Injury / prevention & control*
  • Thiocarbamates / pharmacology*
  • Transaminases / blood
  • Tumor Necrosis Factor-alpha / genetics

Substances

  • Antioxidants
  • Interleukin-1
  • NF-kappa B
  • RNA, Messenger
  • Thiocarbamates
  • Tumor Necrosis Factor-alpha
  • prolinedithiocarbamate
  • Proline
  • Heme Oxygenase (Decyclizing)
  • Heme Oxygenase-1
  • Transaminases