DESFERAL ATTENUATES TNF RELEASE FOLLOWING HEPATIC ISCHEMIA/REPERFUSION

Iron chelators have been shown to protect against oxygen free radical injury occurring in association with ischemia/reperfusion (I/R). Tumor necrosis factor alpha (TNF) represents a major mediator of the pulmonary and hepatic injury occurring after hepatic I/R since pretreatment with anti-TNF antibody results in significant protection against both the lung and liver injury following this insult. We were therefore interested in the possible association of the protective actions of deferoxamine (Desferal) following hepatic I/R and subsequent TNF release. A rat model of hepatic I/R was used to evaluate this; four experimental groups were studied. Animals in I/R underwent 90 min of hepatic ischemia with subsequent reperfusion. DES-I/R animals were pretreated with 200 mg of deferoxamine and VEH-I/R rats were given an equivalent amount of vehicle prior to hepatic I/R. SHAM animals underwent sham laparotomy alone. Plasma specimens were obtained and analyzed for TNF using a cytolytic bioassay based on the WEHI 164 subclone 13 cell line. Mean peak TNF levels following deferoxamine pretreatment was 110.38 +/- 24.68 pg/ml, as compared to mean peak TNF levels of 213.64 +/- 38.09 pg/ml in the VEH-I/R group (P < 0.01). Lung injury following hepatic I/R was evaluated by assessment of pulmonary microvascular permeability and by evaluation of pulmonary neutrophil infiltration as measured by pulmonary myeloperoxidase (MPO) content. Pretreatment with deferoxamine resulted in a significant decrease in lung leak as compared to animals pretreated with vehicle prior to I/R (DES-I/R = 0.192 +/- 0.013, VEH-I/R = 0.690 +/- 0.050; P < 0.005). Deferoxamine had a similar significant protective effect against neutrophil influx: DES-I/R MPO = 0.318 +/- 0.078 and VEH-I/R MPO = 0.600 +/- 0.060 (P < 0.005). Liver injury following I/R was measured with SGPT levels 24 hr postreperfusion and a significant protective effect was seen in animals receiving deferoxamine prior to hepatic I/R (DES-I/R = 1816 +/- 528, VEH-I/R = 7367 +/- 922; P < 0.001). Although deferoxamine's protective actions can be attributed to inhibition of oxygen free radical generation, these experiments also document a decrease in TNF release. The decrease in organ injury may be due to a combination of fewer toxic oxygen metabolites and less TNF. (C) 1994 Academic Press, Inc.