title: Experimental chemotherapy in paracoccidioidomycosis using ruthenium NO donor.
abstract: Paracoccidioidomycosis (PCM) is a granulomatous disease caused by a dimorphic fungus, Paracoccidioides brasiliensis (Pb). To determine the influence of nitric oxide (NO) on this disease, we tested cis-[Ru(bpy)2(NO)SO3](PF6), ruthenium nitrosyl, which releases NO when activated by biological reducing agents, in BALB/c mice infected intravenously with Pb 18 isolate. In a previous study by our group, the fungicidal activity of ruthenium nitrosyl was evaluated in a mouse model of acute PCM, by measuring the immune cellular response (DTH), histopathological characteristics of the granulomatous lesions (and numbers), cytokines, and NO production. We found that cis-[Ru(bpy)2(NO)SO3](PF6)-treated mice were more resistant to infection, since they exhibited higher survival when compared with the control group. Furthermore, we observed a decreased influx of inflammatory cells in the lung and liver tissue of treated mice, possibly because of a minor reduction in fungal cell numbers. Moreover, an increased production of IL-10 and a decrease in TNF-α levels were detected in lung tissues of infected mice treated with cis-[Ru(bpy)2(NO)SO3](PF6). Immunohistochemistry showed that there was no difference in the number of VEGF- expressing cells. The animals treated with cis-[Ru(bpy)2(NO)SO3](PF6) showed high NO levels at 40 days after infection. These results show that NO is effectively involved in the mechanism that regulates the immune response in lung of Pb-infected mice. These data suggest that NO is a resistance factor during paracoccidioidomycosis by controlling fungal proliferation, influencing cytokine production, and consequently moderating the development of a strong inflammatory response.
authors: Department of Pathology Science, CCB, State University of Londrina-UEL, Londrina, PR, Brazil. wanderpavanelli@uel.br
authors: Wander Rogério
authors: WR
authors: Pavanelli
authors: Jean Jerley Nogueira
authors: JJ
authors: da Silva
authors: Carolina
authors: C
authors: Panis
authors: Thiago Mattar
authors: TM
authors: Cunha
authors: Ivete Conchon
authors: IC
authors: Costa
authors: Maria Claudia Noronha Dutra
authors: MC
authors: de Menezes
authors: Francisco José de Abreu
authors: FJ
authors: Oliveira
authors: Luiz Gonzaga de França
authors: LG
authors: Lopes
authors: Rubens
authors: R
authors: Cecchini
authors: Fernando de Queiroz
authors: Fde Q
authors: Cunha
authors: Maria Angélica Ehara
authors: MA
authors: Watanabe
authors: Eiko Nakagawa
authors: EN
authors: Itano
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage*; D015169:Colony Count, Microbial; D004195:Disease Models, Animal; D005260:Female; D006651:Histocytochemistry; D008168:Lung / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000008:administration & dosage*; D010228:Paracoccidioides / Q000187:drug effects / Q000302:isolation & purification; D010229:Paracoccidioidomycosis / Q000188:drug therapy* / Q000473:pathology; D012376:Rodent Diseases / Q000188:drug therapy; D017975:Ruthenium Compounds / Q000008:administration & dosage*; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000935:Antifungal Agents; D017975:Ruthenium Compounds; D009569:Nitric Oxide