Lipid peroxidation as molecular mechanism of liver cell injury during reperfusion after ischemia.
The pathophysiological importance of reactive oxygen species has been extensively documented in the pathogenesis of hepatic ischemia-reperfusion injury. Kupffer cells and neutrophils were identified as the dominant sources of the postischemic oxidant stress. To test the hypothesis that a direct free radical-mediated injury mechanism (lipid peroxidation; LPO) may be involved in the pathogenesis, highly sensitive and specific parameters of LPO, i.e., hydroxy-eicosatetraenoic acids (HETES), and F2-isoprostanes, were determined by gas chromatographic-mass spectrometric analysis in liver tissue and plasma during 45 min of hepatic ischemia and up to 24 h of reperfusion. A significant 60-250% increase of F2-isoprostane levels in plasma was found at all times during reperfusion; the HETE content increased only significantly at 1 h of reperfusion and in severely necrotic liver tissue at 24 h with increases between 90-320%. On the other hand, in a model of LPO-induced liver injury (infusion of 0.8 mumol tert-butylhydroperoxide/min/g liver), the hepatic HETE content increased two to fourfold over baseline values at 45 min, i.e., before liver injury. A further increase to 12- to 30-fold of baseline was observed during moderate liver injury. Based on these quantitative comparisons of LPO and liver injury, it seems highly unlikely that LPO is the primary mechanism of parenchymal cell injury during reperfusion, although it cannot be excluded that LPO may be important as a damaging mechanism in a limited compartment of the liver, e.g., endothelial cells, close to the sources of reactive oxygen, e.g., Kupffer cells and neutrophils.
Mathews
W R
WR
Upjohn Laboratories, Upjohn Company, Kalamazoo, MI 49001.
Guido
D M
DM
Fisher
M A
MA
Jaeschke
H
H
D000410:Alanine Transaminase / Q000097:blood; D000704:Analysis of Variance; D000818:Animals; D015237:Dinoprost / Q000097:blood; D008401:Gas Chromatography-Mass Spectrometry; D005978:Glutathione / Q000031:analogs & derivatives / Q000097:blood; D019803:Glutathione Disulfide; D007511:Ischemia / Q000097:blood / Q000378:metabolism*; D015227:Lipid Peroxidation; D008099:Liver / Q000098:blood supply*; D008297:Male; D010545:Peroxides / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D017382:Reactive Oxygen Species / Q000494:pharmacology; D015424:Reperfusion; D013997:Time Factors; D020122:tert-Butylhydroperoxide
D010545:Peroxides; D017382:Reactive Oxygen Species; D020122:tert-Butylhydroperoxide; D015237:Dinoprost; D000410:Alanine Transaminase; D005978:Glutathione; D019803:Glutathione Disulfide