Worldwide, more than 200 million people and countless animals are infected by filarial parasites. Previously, the pathology associated with filarial diseases has been solely attributed to the physical presence of the adult wonns ancvor the host's immunologic response to the parasite. However, patients with low worm burdens and no distinct pattern of immunological reactivity often suffer severe and disabling symptoms. Despite the prevalence of filariasis, the pathogenesis remains poorly understood. This is due, in part, to the lack of experimental animal models of human filariasis. Fortunately, several filarial nematodes that infect animals are behaviorally, taxonomically, and metabolically similar to the human filarial pathogens. Using the filarial parasites Dirofilaria immitis and Brugia pahangi, we have developed a novel system for studying the pathogenesis of filariasis. Our studies have focused on the hypothesis that filarial parasites produce biologically active factors that circulate in the blood and alter mammalian endothelial cell metabolism and function. The role of endothelial cells in the control of vascular tone has been well documented. Furthermore, endothelial cell metabolism and function is altered in all cardiovascular diseases studied to date. It is the goal of this proposal to characterize the effects of filarial parasites on endothelium-dependent vascular and lymphatic reactivity. Our working hypothesis is that endothelium-mediated regulation of vascular and lymphatic smooth muscle are adversely affected, in vivo and in vitro, by biologically active factors released by filarial nematodes. We will test the following specific hypotheses: (I) Filarial parasites release a factor(s) that depresses endothelium-dependent relaxation and alters the mechanism of endothelium-dependent relaxation. (II) The factor is a filarial cyclooxygenase product. (III) Filarial parasites release a factor(s) that circulates in the blood and depresses endothelium-dependent relaxation. (IV) Spontaneous contractions of bovine mesenteric lymphatics are endothelium-dependent. Changes in isometric tension in response to vasoactive agents will be measured on in vitro vascular and lymphatic rings. Comparisons will be made between vessels from infected animals (dogs with D immitis and rats with B pahangi) and noninfected controls and between normal vessels exposed to adult parasites, filarial-conditioned media, or serum from infected humans and animals and their respective controls. We propose that filarial parasites release biologically active compounds that alter endothelial cell metabolism of vasoactive compounds. Interactions between filarial parasites, parasite products, and endothelial cells could be responsible, in part, for the clinical and pathological manifestations of chronic filarial diseases in humans and animals. These studies should provide insight into the pathogenesis of filariasis, as well as provide a framework for human studies.
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