Phosphodiesterase inhibitors prevent NSAID enteropathy independently of effects on TNF-alpha release

Although the ability of nonsteriodal anti-inflammatory drugs (NSAIDs) to injure the small intestine has been well established in humans and animals, the mechanism involved in this type of injury has yet to be elucidated. The cytokine tumor necrosis factor-alpha (TNF-alpha) has recently been demonstrated to play a critical role in the pathogenesis of NSAID-induced gastric damage. We therefore assessed the possibility that TNF-alpha is similarly involved in the pathogenesis of NSAID-induced small intestinal injury. Administration of multiple doses (n = 4) of diclofenac, but not a single dose, resulted in profound macroscopic damage in the intestine and significantly increased levels of TNF-alpha in intestinal tissue and bile. Pretreatment of rats with a phosphodiesterase inhibitor, pentoxifylline, theophylline, or rolipram, significantly attenuated the macroscopic intestinal ulceration produced by diclofenac administration. However, inhibition of TNF-alpha release with thalidomide or immunoneutralization with a polyclonal antibody directed against TNF-alpha failed to afford any protection. These results suggest that the cytokine TNF-alpha does not play a critical role in NSAID-induced small intestinal injury. Therefore, phosphodiesterase inhibitors mediate their protective effect through a mechanism independent of TNF-alpha synthesis inhibition.