M. Ohta et al., TUMOR-NECROSIS-FACTOR-ALPHA REGULATES NITRIC-OXIDE SYNTHASE EXPRESSION IN PORTAL HYPERTENSIVE GASTRIC-MUCOSA OF RATS, Hepatology, 27(4), 1998, pp. 906-913
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.