Efficacy of TNF inhibitor treatment in a model of heart failure and resulting cachexia

Abstract

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] The aim this dissertation was to explore the efficacy of tumor necrosis factor (TNF) inhibitors in attenuating increases in both anorexia and the ubiquitin proteasome pathway transcripts in cardiac cachexia, a potentially lethal condition that responds poorly to current treatments. Right heart failure and subsequent cardiac cachexia was rapidly induced with monocrotaline injection in Sprague-Dawley rats and either soluble TNF receptor-1 or the general inhibitor of TNF production, pentoxifylline, was given to diminish TNF action upon the first indication of cachexia. Ubiquitin proteasome pathway transcripts and western blotting were analyzed in skeletal muscle. Both soluble TNF receptor-1 and pentoxifylline attenuated losses in both body weight and skeletal muscle mass and also reduced the transcriptional activation of the ubiquitin proteasome pathway. The action of soluble TNF receptor-1 was partly through reversal of reduced food consumption, while the effects pentoxifylline were independent of food intake. The following dissertation shows that not only does soluble TNF receptor-1 treatment attenuate anorexia in monocrotaline-induced cardiac cachexia, but that this anti-anorectic effect is responsible for attenuating the induction of some ubiquitin proteasome pathway transcripts as well as preserving body weight and skeletal muscle mass. Though further investigation is needed, sTNFR1 may have clinical efficacy in combating cachectic states brought on by heart failure.