Recovery of hepatocellular ATP and "pericentral apoptosis" after hemorrhage and resuscitation.
Progressive liver dysfunction contributes significantly to the development of multiple organ failure after trauma/hemorrhage. This study tested the relative impact of necrotic and apoptotic cell death in a graded model of hemorrhagic shock (mean arterial blood pressure=35+/-5 mmHg for 1, 2, or 3 h, followed by 2 h, 1 h, or no resuscitation, respectively) in rats. Prolonged periods of hemorrhagic hypotension (3 h) were paralleled by a profound decrease of hepatic ATP levels and occurrence of pericentral necrosis. Resuscitation after shorter periods of hemorrhagic hypotension resulted in restoration of tissue ATP whereas hepatocellular function as assessed by indocyanine green clearance remained depressed (49.9+/-1.6 mL/(min x kg) at baseline, 28.8+/-1.2 mL/(min x kg) after 2 h of resuscitation; P<0.05). Under these conditions, induction of caspase activity and DNA fragmentation were observed in pericentral hepatocytes that could be prevented by the radical scavenger tempol. Pretreatment with z-Val-Ala-Asp(O-methyl)-flouromethylketone prevented de novo expression of caspase-generated cytokeratin 18, DNA fragmentation, and depression of hepatocellular indocyanine green clearance. These data suggest that prolonged low flow/hypoxia induces ATP depletion and pericentral necrosis and restoration of oxygen supply and ATP levels after shorter periods of low flow ischemia propagate programmed cell death or "pericentral apoptosis."
Paxian
Markus
M
Department of Anesthesiology and Critical Care Medicine, University of the Saarland, D-66421 Homburg, Germany.
Bauer
Inge
I
Rensing
Hauke
H
Jaeschke
Hartmut
H
Mautes
Angelika E M
AE
Kolb
Stefan A
SA
Wolf
Beate
B
Stockhausen
Andre
A
Jeblick
Silke
S
Bauer
Michael
M
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis; D061945:Caspase Inhibitors; D003497:Cyclic N-Oxides / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D022781:Hepatocytes / Q000473:pathology; D007022:Hypotension / Q000503:physiopathology; D007208:Indocyanine Green / Q000032:analysis; D007511:Ischemia / Q000473:pathology; D008099:Liver / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D009336:Necrosis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012151:Resuscitation; D012771:Shock, Hemorrhagic / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D013113:Spin Labels
D000590:Amino Acid Chloromethyl Ketones; D000975:Antioxidants; D061945:Caspase Inhibitors; D003497:Cyclic N-Oxides; D015853:Cysteine Proteinase Inhibitors; D013113:Spin Labels; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D000255:Adenosine Triphosphate; D007208:Indocyanine Green; C001803:tempol