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).(ABSTRACT TRUNCATED AT 250 WORDS)
Colletti
L M
LM
Department of Surgery, University of Michigan Medical Center, Ann Arbor 48109.
Remick
D G
DG
Campbell
D A
DA
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D003676:Deferoxamine / Q000494:pharmacology*; D004195:Disease Models, Animal; D008099:Liver / Q000098:blood supply*; D008107:Liver Diseases / Q000097:blood / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control*; D008171:Lung Diseases / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D010539:Permeability / Q000187:drug effects; D009195:Peroxidase / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000150:complications / Q000378:metabolism / Q000517:prevention & control*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism*
D014409:Tumor Necrosis Factor-alpha; D009195:Peroxidase; D000410:Alanine Transaminase; D003676:Deferoxamine