TUMOR-NECROSIS-FACTOR-ALPHA REGULATES NITRIC-OXIDE SYNTHASE EXPRESSION IN PORTAL HYPERTENSIVE GASTRIC-MUCOSA OF RATS

Anti-tumor necrosis factor alpha (TNF-alpha) treatment decreases nitri c oxide (NO) synthesis and ameliorates the hyperdynamic circulation in portal hypertensive rats. We have recently demonstrated that nitric o xide synthase isoform 3 (NOS3) is overexpressed in portal hypertensive gastric mucosa and that resultant NO overproduction probably is respo nsible for the increased susceptibility of the mucosa to damage, In th e present study, we examined whether TNF-alpha is overexpressed in por tal hypertensive gastric mucosa and whether anti-TNF-alpha treatment a ffects gastric NOS3 messenger RNA (mRNA) and protein expression, We ex amined plasma concentrations of TNF-alpha and its protein expression i n gastric specimens from portal hypertensive and sham-operated rats us ing Western blotting and immunohistochemistry. We also measured gastri c mucosal blood flow, gastric expression of NOS3 mRNA and protein, and NOS3 enzyme activity in rats with and without TNF-alpha-neutralizing antibody treatment, The TNF-alpha protein levels in portal hypertensiv e stomachs were significantly increased by 57% compared with levels in sham-operated controls, TNF-alpha antibody treatment normalized gastr ic mucosal blood flow in portal hypertensive stomachs and significantl y reversed overexpression of gastric NOS3 mRNA, protein, and its enzym e activity in portal hypertensive rats by 48%, 45%, and 33%, respectiv ely. These results suggest that TNF-alpha may regulate NOS3 expression in the portal hypertensive stomach and that anti-TNF-alpha treatment may ameliorate the pathophysiological abnormalities of portal hyperten sive gastric mucosa.