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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Modified Research Career Development Award (K04)
Project #
5K04AI001082-03
Application #
2057112
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Project Start
1992-08-01
Project End
1997-07-31
Budget Start
1994-08-01
Budget End
1995-07-31
Support Year
3
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Michigan State University
Department
Physiology
Type
Schools of Veterinary Medicine
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
Kaiser, Lana; Williams, Jeffrey F (2004) Dirofilaria immitis: worm burden and pulmonary artery proliferation in dogs from Michigan (United States). Vet Parasitol 124:125-9
Kaiser, L; Geary, T G; Williams, J F (1998) Dirofilaria immitis and Brugia pahangi: filarial parasites make nitric oxide. Exp Parasitol 90:131-4
Kaiser, L; Williams, J F (1998) Dirofilaria immitis: heartworm infection converts histamine-induced constriction to endothelium-dependent relaxation in canine pulmonary artery. Exp Parasitol 88:146-53
Maksimowich, D S; Bell, T G; Williams, J F et al. (1997) Effect of arsenical drugs on in vitro vascular responses of pulmonary artery from heartworm-infected dogs. Am J Vet Res 58:389-93
Mupanomunda, M; Williams, J F; Mackenzie, C D et al. (1997) Dirofilaria immitis: heartworm infection alters pulmonary artery endothelial cell behavior. J Appl Physiol 82:389-98
Maksimowich, D S; Mupanomunda, M; Williams, J F et al. (1997) Effect of heartworm infection on in vitro contractile responses of canine pulmonary artery and vein. Am J Vet Res 58:395-7
Kaiser, L; Mupanomunda, M; Williams, J F (1996) Brugia pahangi-induced contractility of bovine mesenteric lymphatics studied in vitro: a role for filarial factors in the development of lymphedema? Am J Trop Med Hyg 54:386-90
Mupanomunda, M; Williams, J F; Kaiser, L (1996) Effect of heartworm infection on fade of norepinephrine-induced constriction in canine pulmonary vein. Am J Vet Res 57:172-7
Maksimowich, D S; Williams, J F; Kaiser, L (1996) Thiacetarsamide depresses relaxation of canine pulmonary artery in vitro. Vet Parasitol 64:251-6
Tithof, P K; Schwartz, A J; Mupanomunda, M et al. (1994) Dirofilaria immitis: depression of endothelium-dependent relaxation of canine femoral artery seen in vivo does not persist in vitro. Exp Parasitol 79:159-65

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