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Abstract
Equine laminitis is debilitating and life-threatening disease that affects horses worldwide. This condition is exteremely painful and is associated with a variety of systemic diseases. Although the mechanisms responsible for development of laminitis remain to be determined, the most prominent hypothesis regarding the pathogenesis of the condition focuses on the development of local inflammatory changes in the foot and alterations in digital hemodynamics. The studies described in this dissertation were performed to determine the vasoactive properties of prostanoids and isoprostanes in order to determine the possible role of these inflammatory mediators in the selective venoconstriction that occurs during onset of the condition, and to evaluate alterations in gene expression in laminar tissues at three time points during the onset of the disease. Vascular constrictive effects of thromboxane, prostaglandin F2, prostaglandin E2 and the isoprostanes were compared using laminar arteries and veins from healthy horses and horses with the earliest signs of acute laminitis induced by administration of black walnut heartwood extract (BWHE). The results of these studies provide convincing evidence that genes associated with inflammation; activation and extravasation of leukocytes; antimicrobial activities; and destruction of the lamellar basement membrane, are induced in response to administration of BWHE. Using microarray techniques, proinflammatory genes were up-regulated as early as 1.5 hours after BWHE administration, and transcripts for endogenous antioxidants were expressed at Obel grade 1 laminitis. Furthermore, increases in plasma concentrations of prostanoids and laminar tissue concentrations of isoprostanes were identified after administration of BWHE, and were associated with venoconstriction and impairment of vasodilatory pathways identified in the in vitro studies performed with the laminar vessels. Collectively, these findings add credence to the results of recent studies indicating that inflammation and venoconstriction occur concurrently during the prodromal stages of equine laminitis, and suggest that prostanoids and isoprostanes contribute to the development of laminitis by increasing post-capillary resistance in the laminar dermis.