Effects of the Prostaglandin Analogue Misoprostol on TNF-alpha Release by Activated Equine Leukocytes by

BUCHHEIT, TERESA MARIE. Effects of the Prostaglandin Analogue Misoprostol on TNFAlpha Release by Activated Equine Leukocytes. (Under the direction of Dr. Samuel Jones). The magnitude of LPS-induced equine health problems cannot be over-estimated since endotoxemia is intimately involved in the pathogenesis of gastrointestinal disorders that cause colic, the leading cause of death in adult horses, and bacterial septicemia, the major killer of foals less than 7 days of age. These diseases lead to huge economic losses to the horse industry. The morbidity and mortality associated with sepsis in horses are primary attributable to the endogenous mediators released during the host’s response to bacterial LPS. Antimicrobials do not mitigate the effects of endotoxin and many current pharmacological therapies, such as non-steroidal inflammatory drugs (NSAIDs), only affect part of the inflammatory cascade, making this a difficult condition to manage effectively. The optimal therapy likely involves methods to alter the generation of inflammatory mediators. The capacity to neutralize TNF-α production remains a critical goal for investigating novel drugs for use in diseases associated with systemic inflammation. In other species, the prostaglandin analogue misoprostol has been shown to inhibit LPS-induced TNF-α synthesis due to its ability to increase cAMP levels within leukocytes. Given the capacity of misoprostol to inhibit TNF-α release from immune cells in other species and its clinical use in horses for protection against NSAID-induced gastrointestinal ulcers, the objective of the study reported here was to evaluate the effects of misoprostol on production of TNF-α by LPS-stimulated equine leukocytes. The hypothesis of this study was that misoprostol would suppress LPS-induced secretion of TNF-α by equine peripheral blood leukocytes. The results presented in this study show that addition of LPS to equine leukocytes induced TNF-α secretion and misoprostol effectively blunted this response. Thus, misoprostol may be useful as an immunomodulator of inflammatory cytokine production in SIRS/sepsis. Further in vivo investigation is warranted.