The influence of brain death on liver function.
BACKGROUND
In this study, we investigated the influence of brain death on inflammatory response and the effects of brain death on liver function both directly after explantation and after reoxygenation.


METHODS
The influence of brain death on liver function was studied in rats using a brain death model and the liver slice model to mimic reoxygenation. Liver function was assessed by measuring the ATP content and the ATP-driven urea synthesis. The activation of non-parenchymal cells was studied by measuring mRNA levels of IL-10, cytokine production (IL-10 and IL-1 beta) and inducible nitric oxide synthases (iNOS) upregulation (mRNA) and protein level.


RESULTS
Brain death had no direct influence on the ATP content of the liver. However, it led to induction of several cytokines because of activation of non-parenchymal cells, which led to upregulation of iNOS and to nitric oxide metabolites production. It is known that cytokine production may influence the drug metabolism capacity; however, no influence of brain death on drug metabolism was observed. An explanation may be the relatively short experimental period.


CONCLUSIONS
Kupffer cells seem to be activated during the onset of brain death induction; however, they become quiescent when liver slices of brain dead rats were reoxygenated during incubation. Other non-parenchymal cells, possibly the endothelial cells, remain activated during incubation and reoxygenation in slices from brain death donors but not in slices from control livers. Future experiments in our rat liver transplantation model need to elucidate the implications of these findings.
Olinga
Peter
P
GUIDE (Groningen University Institute for Drug Studies), Department of Pharmacokinetics and Drug Delivery, University Centre for Pharmacy, 9713 AV Groningen, The Netherlands. P.Olinga@farm.rug.nl
van der Hoeven
Joost A B
JA
Merema
Marjolijn T
MT
Freund
Rennie L
RL
Ploeg
Rutger J
RJ
Groothuis
Geny M M
GM
D000255:Adenosine Triphosphate / Q000096:biosynthesis*; D000818:Animals; D001926:Brain Death / Q000378:metabolism* / Q000473:pathology; D002470:Cell Survival; D003374:Coumarins / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D007728:Kupffer Cells / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009589:Nitrogen Oxides / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D011914:Rats, Inbred BN; D014468:Umbelliferones / Q000378:metabolism; D014508:Urea / Q000378:metabolism
D003374:Coumarins; D016207:Cytokines; D009589:Nitrogen Oxides; D011506:Proteins; D012333:RNA, Messenger; D014468:Umbelliferones; C017299:7-ethoxycoumarin; C031477:7-hydroxycoumarin; D000255:Adenosine Triphosphate; D014508:Urea; D003577:Cytochrome P-450 Enzyme System; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat