Nitric oxide and prostaglandins interact to prevent hepatic damage during murine endotoxemia.
Nitric oxide (NO) and prostaglandins (PG) both possess the ability to induce vasodilatation and prevent the aggregation of platelets. The synthesis of these substances is increased following in vivo lipopolysaccharide (LPS) infusion, but their function during sepsis is incompletely understood. We studied the role of NO and PG in a murine model of chronic hepatic inflammation (Corynebacterium parvum injection), which is known to progress to sudden hepatic necrosis after LPS injection. NO synthesis, which is induced in hepatocytes by C. parvum treatment and in nonparenchymal cells by LPS treatment, was inhibited using NG-monomethyl-L-arginine (L-NMMA). High-dose aspirin (ASA) was used to block PG synthesis. Treatment with L-NMMA or ASA alone, in the absence of LPS, resulted in no increase in hepatic injury. C. parvum-treated mice that received both L-NMMA and ASA without LPS developed marked hepatic damage as reflected by increased hepatocellular enzyme release (aspartate aminotransferase and L-ornithine carbamoyl-transferase). Marked hepatic damage was seen after LPS administration, and ASA pretreatment alone had no effect on the LPS-induced hepatic injury, whereas L-NMMA markedly increased the hepatic damage. The combination of L-NMMA and ASA after LPS resulted in the greatest hepatocellular enzyme release, characterized histologically by intravascular thrombosis with diffuse infarction and necrosis. Simultaneous treatment with either PGI2 or L-arginine partially prevented this injury. These data demonstrate that NO and PG function synergistically to maintain hepatocellular integrity; thus increased synthesis of these mediators protects the liver from the pathophysiological effects of LPS in this model.
Department of Surgery, University of Pittsburgh, Pennsylvania 15213.
B G
BG
Harbrecht
J
J
Stadler
A J
AJ
Demetris
R L
RL
Simmons
T R
TR
Billiar
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology; D004731:Endotoxins / Q000097:blood*; D005260:Female; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008107:Liver Diseases / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000502:physiology*; D011425:Propionibacterium acnes; D011453:Prostaglandins / Q000502:physiology*; D019323:omega-N-Methylarginine
D004731:Endotoxins; D011453:Prostaglandins; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D001120:Arginine; D001241:Aspirin