TUMOR-NECROSIS-FACTOR-ALPHA REGULATES IN-VIVO NITRIC-OXIDE SYNTHESIS AND INDUCES LIVER-INJURY DURING ENDOTOXEMIA

Tumor necrosis factor-alpha is a principal mediator of the pathophysiological effects of endotoxemia and endotoxin shock. Tumor necrosis factor-alpha also contributes to the stimulation of nitric oxide synthesis by the induction of the enzyme nitric oxide synthase in a variety of tissues. Although the importance of tumor necrosis factor-alpha in the induction of nitric oxide synthase activity in vitro is well known, its role in in vivo nitric oxide synthesis has not been convincingly established. We were interested in determining whether tumor necrosis factor-alpha plays a significant role in the in vivo induction of nitric oxide synthesis. In Corynebacterium parvum-primed mice, lipopolysaccharide injection resulted in elevated serum tumor necrosis factor-alpha levels early and increased hepatic enzyme release (641 +/- 80 IU AST/L; 22.7 +/- 1.9 IU ornithine carbamoyltransferase per liter) and plasma nitrite and nitrate (804 +/- 84 mu mol/L) 5 hr after lipopolysaccharide injection. Polyclonal rabbit anti-mouse anti-tumor necrosis factor-alpha reduced in vivo tumor necrosis factor alpha-levels (1 hr, 7,332 +/- 1,492 U tumor necrosis factor-alpha per milliliter) and reduced nitric oxide synthesis as measured by plasma nitrite and nitrate (352 +/- 69 mu mol/L). Polyclonal rabbit anti-mouse anti-tumor necrosis factor-alpha also reduced lipopolysaccharide-induced hepatic enzyme release (428 +/- 33 IU AST/L; 16.0 +/- 2.5 IU ornithine carbamoyltransferase per liter). N-G-monomethyl-L-arginine, a competitive inhibitor of nitric oxide synthesis, also decreased plasma nitrite and nitrate (104 +/- 9 mu mol/L) but increased the lipopolysaccharide induced hepatic injury (797 +/- 66 IU AST/L; 33.1 +/- 2.1 IU ornithine carbamoyltransferase per liter). These results show that tumor necrosis factor-alpha not only acts as an in vivo signal for the induction of nitric oxide synthesis but also acts as a mediator of the lipopolysaccharide-induced hepatic injury. The mechanism by which tumor necrosis factor-alpha exerts its damaging effect on hepatic cells has not been determined but appears to be independent of its induction of nitric oxide synthesis.