ABSTRACT
Leishmania chagasi, the cause of South American visceral leishmaniasis, must survive antimicrobial responses of host macrophages to establish infection. Macrophage oxidative responses have been shown to diminish in the presence of intracellular leishmania. However, using electron spin resonance we demonstrated that murine and human macrophages produce O2-during phagocytosis of opsonized promastigotes. Addition of the O2- scavenger 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl to cultures resulted in increased infection, suggesting that O2- enhances macrophage leishmanicidal activity. The importance of NO. produced by inducible NO synthase (iNOS) in controlling murine leishmaniasis is established, but its role in human macrophages has been debated. We detected NO. in supernatants from murine, but not human, macrophages infected with L. chagasi. Nonetheless, the iNOS inhibitor N(G)-monomethyl-L-arginine inhibited IFN-gamma-mediated intracellular killing by both murine and human macrophages. According to RNase protection assay and immunohistochemistry, iNOS mRNA and protein were expressed at higher levels in bone marrow of patients with visceral leishmaniasis than in controls. The iNOS protein also increased upon infection of human macrophages with L. chagasi promastigotes in vitro in the presence of IFN-gamma. These data suggest that O2- and NO. each contribute to intracellular killing of L. chagasi in human and murine macrophages.
Subject(s)
Leishmania infantum/immunology , Macrophages/metabolism , Macrophages/parasitology , Oxidative Stress/immunology , Phagocytosis/immunology , Animals , Bone Marrow Cells/enzymology , Bone Marrow Cells/pathology , Cells, Cultured , Cyclic N-Oxides/pharmacology , Electron Spin Resonance Spectroscopy , Free Radical Scavengers/pharmacology , Humans , Leishmania infantum/drug effects , Leishmania infantum/growth & development , Leishmaniasis, Visceral/enzymology , Leishmaniasis, Visceral/pathology , Macrophages/immunology , Mice , Monocytes/enzymology , Nitric Oxide/antagonists & inhibitors , Nitric Oxide/biosynthesis , Nitric Oxide/toxicity , Nitric Oxide Synthase/antagonists & inhibitors , Nitric Oxide Synthase/biosynthesis , Nitric Oxide Synthase/genetics , Nitric Oxide Synthase Type II , Nitrites/antagonists & inhibitors , Nitrites/metabolism , Oxidants/toxicity , RNA, Messenger/biosynthesis , Spin Labels , Superoxides/antagonists & inhibitors , Superoxides/metabolism , Superoxides/toxicity , omega-N-Methylarginine/pharmacologyABSTRACT
We retrospectively reviewed the cases of 51 patients with borderline ovarian tumors seen over a 9-year period. Half of these tumors were manifested by abdominal distention and pain; the remainder were found incidentally at the time of surgery planned for other reasons. Overall survival is excellent, but proper surgical staging reveals that approximately 15% of patients have metastasis beyond the ovaries, most commonly to the omentum, peritoneum, and retroperitoneal lymph nodes.
