Interaction of platelet activating factor, reactive oxygen species generated by xanthine oxidase, and leukocytes in the generation of hepatic injury after shock/resuscitation.
OBJECTIVE
To evaluate the putative relation of platelet activating factor (PAF), xanthine oxidase, reactive oxidants, and leukocytes in the pathogenesis of hepatic injury after shock/resuscitation (S/R) in vivo.


BACKGROUND
Reactive oxygen metabolites generated by xanthine oxidase at reperfusion have been found to trigger postischemic injury in many organs, including the liver. However, the precise linear sequence of the mechanism of consequent hepatic injury after S/R remains to be characterized.


METHODS
Unheparinized male rats were bled to a mean blood pressure of 45 +/- 3 mmHg. After 2 hours of shock, they were resuscitated by reinfusion of shed blood (anticoagulated with citrate-phosphate-dextrose) and crystalloid and observed for the next 6 or 24 hours.


RESULTS
S/R caused the oxidation of hepatic glutathione and generated centrolobular leukocyte accumulation at 6 hours, followed by predominantly centrolobular hepatocellular injury at 24 hours. Each of these components was attenuated by PAF inhibition with WEB 2170, xanthine oxidase inhibition with allopurinol, antioxidant treatment with N-acetylcysteine, or severe leukopenia induced by vinblastine. In each case, the degree of leukocyte accumulation at 6 hours correlated with the hepatocellular injury seen at 24 hours. However, xanthine oxidase inhibition with allopurinol failed to attenuate further the small level of residual hepatocellular injury seen in leukopenic rats.


CONCLUSIONS
These findings suggest that reactive oxidants generated by xanthine oxidase at reperfusion, stimulated by PAF, mediate hepatocellular injury by triggering leukocyte accumulation, primarily within the centrolobular sinusoids.
Yamakawa
Y
Y
Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-4685, USA.
Takano
M
M
Patel
M
M
Tien
N
N
Takada
T
T
Bulkley
G B
GB
D000818:Animals; D004195:Disease Models, Animal; D004347:Drug Interactions; D007962:Leukocytes / Q000378:metabolism*; D008099:Liver / Q000098:blood supply* / Q000378:metabolism; D008297:Male; D018384:Oxidative Stress / Q000502:physiology; D010972:Platelet Activating Factor / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015424:Reperfusion / Q000379:methods; D015427:Reperfusion Injury / Q000209:etiology* / Q000378:metabolism; D012151:Resuscitation / Q000009:adverse effects*; D012771:Shock, Hemorrhagic / Q000150:complications* / Q000378:metabolism; D013997:Time Factors; D014969:Xanthine Oxidase / Q000378:metabolism*
D010972:Platelet Activating Factor; D017382:Reactive Oxygen Species; D014969:Xanthine Oxidase