Activation of Kupffer cells and neutrophils for reactive oxygen formation is responsible for endotoxin-enhanced liver injury after hepatic ischemia.
The potential role of reactive oxygen species generated by Kupffer cells and neutrophils was investigated in a model of endotoxin-enhanced liver injury after hepatic ischemia. Male Fischer rats were subjected to 20 min ischemia and reperfusion of up to 24 h; .5 mg/kg Salmonella enteritidis endotoxin was injected at 30 min of reperfusion. The animals developed severe liver injury resulting in 50% hepatocellular necrosis at 24 h. Isolated Kupffer cells and neutrophils from the postischemic liver generated 10-fold more superoxide than cells from control livers. Treatment with gadolinium chloride (GdCl3) selectively reduced the capacity of Kupffer cells to generate superoxide by 65% and attenuated liver injury by 73% at 4 h and 58-69% at 24 h. Monoclonal antibodies against neutrophil adhesion molecules (CD11/CD18) had no effect on the early injury but reduced hepatocellular necrosis by 90-95% at 24 h. The antioxidant Trolox and the iron-chelator deferoxamine attenuated liver injury by 71 and 80%, respectively. It is concluded that Kupffer cells are mainly responsible for the initial injury, and neutrophils are the dominant cytotoxic cell type during the later phase. Reactive oxygen generated by both cell types is critical for this pathogenesis.
Drug Metabolism Research, Upjohn Company, Kalamazoo, Michigan 49001.
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P
Liu
G M
GM
McGuire
M A
MA
Fisher
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A
Farhood
C W
CW
Smith
H
H
Jaeschke
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D018845:CD11 Antigens / Q000276:immunology / Q000502:physiology; D002839:Chromans / Q000627:therapeutic use; D003676:Deferoxamine / Q000627:therapeutic use; D005682:Gadolinium / Q000494:pharmacology / Q000627:therapeutic use; D007511:Ischemia / Q000378:metabolism / Q000473:pathology*; D007728:Kupffer Cells / Q000502:physiology*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008833:Microcirculation; D009102:Multiple Organ Failure / Q000209:etiology / Q000473:pathology; D009336:Necrosis; D009504:Neutrophils / Q000502:physiology*; D051381:Rats; D011916:Rats, Inbred F344; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control; D016897:Respiratory Burst / Q000502:physiology; D012772:Shock, Septic / Q000150:complications / Q000503:physiopathology* / Q000628:therapy; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors
D000911:Antibodies, Monoclonal; D018845:CD11 Antigens; D002839:Chromans; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; C036757:lipopolysaccharide B; D013481:Superoxides; D005682:Gadolinium; D003676:Deferoxamine; C038958:gadolinium chloride; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid