Interaction of platelet activating factor, reactive oxygen species generated by xanthine oxidase, and leukocytes in the generation of hepatic injury after shock/resuscitation
Y. Yamakawa et al., Interaction of platelet activating factor, reactive oxygen species generated by xanthine oxidase, and leukocytes in the generation of hepatic injury after shock/resuscitation, ANN SURG, 231(3), 2000, pp. 387-398
Objective
To evaluate the putative relation of platelet activating factor (PAF), xant
hine oxidase, reactive oxidants, and leukocytes in the pathogenesis of hepa
tic injury after shock/resuscitation (S/R) in vivo.
Background
Reactive oxygen metabolites generated by xanthine oxidase at reperfusion ha
ve 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 bloo
d (anticoagulated with citrate-phosphate-dextrose) and crystalloid and obse
rved 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 allopuri
nol, antioxidant treatment with N-acetylcysteine, or severe leukopenia indu
ced 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 t
he small level of residual hepatocellular injury seen in leukopenic rats.
Conclusion
These findings suggest that reactive oxidants generated by xanthine oxidase
at reperfusion, stimulated by PAF, mediate hepatocellular injury by trigge
ring leukocyte accumulation, primarily within the centrolobular sinusoids.