Tnfa contributes to the pathogenesis of ethanol-induced gastric
damage in cirrhotic rats.
Ferraz, Jos Geraldo P., Allan W. Tigley, Caroline B. Appleyard &
John L. Wallace.
Intestinal Disease Research Unit, Faculty of Medicine, University
of Calgary, Calgary, Alberta T2N 4N1, Canada
APStracts 3:0228G, 1996.
Cirrhotic rats exhibit increased susceptibility to ethanol-induced
gastric damage, but the underlying mechanism for this phenomenon
remains unclear. Abnormalities of the gastric microcirculation have
been reported, which may contribute to the increased susceptibility
to damage. Decreased gastric synthesis of prostaglandins also likely
contributes to impaired mucosal defence in cirrhotic rats. TNFa has
been implicated in mucosal injury, and its synthesis can be inhibited
by prostaglandins. Therefore, we hypothesized that TNFa
synthesis/release is altered in cirrhotic rats and plays a role in
the pathogenesis of ethanol-induced gastric damage. Cirrhosis was
induced by bile duct ligation, while controls had sham-operation.
Topical application of 40% ethanol caused four times as much damage
in cirrhotic rats than controls. Basal plasma TNFa levels did not
differ between control and cirrhotic rats, although cirrhotic rats
exhibited significantly higher levels of gastric TNFa mRNA. Plasma
TNFa increased significantly in control and cirrhotic rats following
ethanol administration. Inhibition of TNFa synthesis/release with
pentoxifylline, thalidomide or dexamethasone, or immunoneutralization
of TNF(, (with anti-TNF() were found to significantly reduce the
severity of ethanol-induced gastric mucosal damage in cirrhotic rats.
We conclude that TNFa contributes to the pathogenesis of ethanol
-induced gastric damage in cirrhotic rats.
Received 19 April 1996; accepted in final form 25 September 1996.
APS Manuscript Number G130-6.
Article publication pending Am. J. Physiol. (Gastrointest. Liver
Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 5 November 1996