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 pathophysio logical effects of endotoxemia and endotoxin shock. Tumor necrosis fac tor-alpha also contributes to the stimulation of nitric oxide synthesi s by the induction of the enzyme nitric oxide synthase in a variety of tissues. Although the importance of tumor necrosis factor-alpha in th e induction of nitric oxide synthase activity in vitro is well known, its role in in vivo nitric oxide synthesis has not been convincingly e stablished. We were interested in determining whether tumor necrosis f actor-alpha plays a significant role in the in vivo induction of nitri c oxide synthesis. In Corynebacterium parvum-primed mice, lipopolysacc haride injection resulted in elevated serum tumor necrosis factor-alph a levels early and increased hepatic enzyme release (641 +/- 80 IU AST /L; 22.7 +/- 1.9 IU ornithine carbamoyltransferase per liter) and plas ma nitrite and nitrate (804 +/- 84 mu mol/L) 5 hr after lipopolysaccha ride injection. Polyclonal rabbit anti-mouse anti-tumor necrosis facto r-alpha reduced in vivo tumor necrosis factor alpha-levels (1 hr, 7,33 2 +/- 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 fac tor-alpha also reduced lipopolysaccharide-induced hepatic enzyme relea se (428 +/- 33 IU AST/L; 16.0 +/- 2.5 IU ornithine carbamoyltransferas e per liter). N-G-monomethyl-L-arginine, a competitive inhibitor of ni tric oxide synthesis, also decreased plasma nitrite and nitrate (104 /- 9 mu mol/L) but increased the lipopolysaccharide induced hepatic in jury (797 +/- 66 IU AST/L; 33.1 +/- 2.1 IU ornithine carbamoyltransfer ase per liter). These results show that tumor necrosis factor-alpha no t only acts as an in vivo signal for the induction of nitric oxide syn thesis but also acts as a mediator of the lipopolysaccharide-induced h epatic injury. The mechanism by which tumor necrosis factor-alpha exer ts its damaging effect on hepatic cells has not been determined but ap pears to be independent of its induction of nitric oxide synthesis.