Effects of lipopolysaccharide on TNF-alpha production, hepatic NOS2 activity, and hepatic toxicity in rats with cirrhosis.
OBJECTIVE
Septic shock results in high mortality in patients with cirrhosis. Nitric oxide synthase 2 (NOS2) is induced by bacterial lipopolysaccharides (LPS) and plays a major role in the inflammatory response to bacterial infections. Little is known about the regulation of NOS2 in cirrhosis under septic conditions. Thus, the aim of this study was to determine tissue NOS2 activity, serum nitrate and tumor necrosis factor (TNF-alpha) levels and hepatic toxicity in cirrhotic rats after LPS administration.


METHODS
Serum nitrates, TNF-alpha and transaminases were determined after LPS-administration in rats with secondary biliary cirrhosis and in sham-operated rats. Liver, lung, aortic and peritoneal macrophage NOS2 activities were determined by converting L[14C] arginine into L[14C] citrulline in a calcium free medium. Nitrate and TNF-alpha production were determined in a culture medium of peritoneal macrophages after in vivo LPS administration.


RESULTS
LPS (1.5 mg/kg) induced 50% mortality in cirrhotic rats and no mortality in sham-operated rats. After LPS, TNF-alpha, nitrate and transaminase levels were significantly higher in cirrhotic rats compared to sham-operated rats. After LPS administration, there were no differences in NOS2 activity in the aorta, lungs, or peritoneal macrophages of the two groups, whereas NOS2 activity was significantly higher in the cirrhotic liver compared to the normal liver.


CONCLUSIONS
In rats with cirrhosis, LPS administration induces higher mortality, hepatic toxicity, hepatic NOS2 activation and TNF-alpha release than in sham-operated rats. These results confirm the harmful role of septic shock in liver disease.
Heller
J
J
Laboratoire d'Hémodynamique Splanchnique et de Biologie Vasculaire, INSERM U-481, 3Service de Biochimie, Hôpital Beaujon, Clichy, France.
Sogni
P
P
Barrière
E
E
Tazi
K A
KA
Chauvelot-Moachon
L
L
Guimont
M C
MC
Bories
P N
PN
Poirel
O
O
Moreau
R
R
Lebrec
D
D
D000818:Animals; D008070:Lipopolysaccharides / Q000494:pharmacology* / Q000506:poisoning* / Q000633:toxicity; D008099:Liver / Q000187:drug effects* / Q000201:enzymology*; D008103:Liver Cirrhosis / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009566:Nitrates / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D017207:Rats, Sprague-Dawley; D000637:Transaminases / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000096:biosynthesis*
D008070:Lipopolysaccharides; D009566:Nitrates; D014409:Tumor Necrosis Factor-alpha; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D000637:Transaminases