title: Treatment of Paracoccidioides brasiliensis-infected mice with a nitric oxide inhibitor prevents the failure of cell-mediated immune response.
abstract: The activation of the nitric oxide (NO) production system and its involvement in the control of the lung fungal burden and in immunosuppression mechanisms were studied during the course of Paracoccidioides brasiliensis-infected mice. Mice that had been infected with the fungus were treated daily with a specific inhibitor of NO synthesis, N omega-nitro-L-arginine, or with buffered saline (control); NO production was assessed on the basis of spontaneous NO2- production by bronchoalveolar and peritoneal macrophages (Mphi) and of serum NO3- levels. The infection coursed with an elevation of NO3- levels. The Mphi produced NO2- and released TNF-alpha only after stimulation with LPS. In addition, the immunoproliferative responses of spleen cells that had been stimulated with the fungus Ag or with Con A were depressed. An examination of the lungs of infected animals showed a progressive increase in the size of the lesions. Treatment of the animals, which resulted in an inhibition of NO2- production by Mphi and a reduction of serum NO3- levels, caused the spontaneous release of TNF-alpha from infected animals and prevented the failure of the lymphoproliferative capacity of spleen cells. Furthermore, the treatment resulted in less pulmonary damage despite the fact that the lung fungal burden increased. It was also demonstrated that the NO donors S-nitroso-acetyl penicillamine and 3-morpholino-sydnonimine-hydrochloride were able to inhibit the growth of P. brasiliensis in vitro. These results suggest that although NO is important for the killing of the fungi, the activation of NO production in P. brasiliensis infection contributes to the occurrence of the immunosuppression observed during the course of the infection.
authors.affiliation: Department of Pathology, Faculty of Medicine of Ribeirão Preto, São Paulo, Brazil.
authors.forename: A L
authors.initials: AL
authors.lastname: Bocca
authors.forename: E E
authors.initials: EE
authors.lastname: Hayashi
authors.forename: A G
authors.initials: AG
authors.lastname: Pinheiro
authors.forename: A B
authors.initials: AB
authors.lastname: Furlanetto
authors.forename: A P
authors.initials: AP
authors.lastname: Campanelli
authors.forename: F Q
authors.initials: FQ
authors.lastname: Cunha
authors.forename: F
authors.initials: F
authors.lastname: Figueiredo
mesh_terms: D000818:Animals; D002474:Cell-Free System; D004334:Drug Administration Schedule; D007111:Immunity, Cellular / Q000187:drug effects*; D007274:Injections, Intraperitoneal; D008168:Lung / Q000382:microbiology; D008174:Lung Diseases, Parasitic / Q000382:microbiology / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009573:Nitrites / Q000378:metabolism; D019335:Nitroarginine / Q000008:administration & dosage / Q000494:pharmacology*; D010228:Paracoccidioides / Q000187:drug effects / Q000254:growth & development / Q000276:immunology*; D010229:Paracoccidioidomycosis / Q000097:blood / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D009566:Nitrates; D009573:Nitrites; C110881:S-nitro-N-acetylpenicillamine; D014409:Tumor Necrosis Factor-alpha; D019335:Nitroarginine; D009569:Nitric Oxide; C002385:linsidomine; D008981:Molsidomine; D019001:Nitric Oxide Synthase; D010396:Penicillamine