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Experimental Chemotherapy in Paracoccidioidomycosis Using Ruthenium NO Donor

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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.

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Acknowledgments

The authors would like to acknowledge the financial support from Fundação Araucária/SETI-PR, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and Special Program for Research and Training in Tropical Diseases (TDR/WHO). Dr. A. Leyva provided English editing of the manuscript.

Conflict of Interest

The authors have no financial conflict of interest.

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Authors and Affiliations

  1. Department of Pathology Science, CCB, State University of Londrina-UEL, Londrina, PR, Brazil

    Wander Rogério Pavanelli, Carolina Panis, Ivete Conchon Costa, Maria Claudia Noronha Dutra de Menezes, Francisco José de Abreu Oliveira, Rubens Cecchini, Maria Angélica Ehara Watanabe & Eiko Nakagawa Itano

  2. Institute of Physics of São Carlos, University of São Paulo-USP, São Paulo, Brazil

    Jean Jerley Nogueira da Silva

  3. Department of Pharmacology, Faculty Medicine of Ribeirão Preto-USP, Ribeirão Preto, Brazil

    Thiago Mattar Cunha & Fernando de Queiroz Cunha

  4. Department of Organic and Inorganic Chemistry, Federal University of Ceará, Fortaleza, Brazil

    Luiz Gonzaga de França Lopes

  5. Universidade Estadual de Londrina-UEL-Rodovia Celso Garcia Cid, Campus Universitário, Cx. Postal 6001, Londrina, PR, 86051-990, Brazil

    Wander Rogério Pavanelli

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  1. Wander Rogério Pavanelli
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Correspondence to Wander Rogério Pavanelli.

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This paper is based on part of the post-doctoral work of WR Pavanelli.

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Pavanelli, W.R., da Silva, J.J.N., Panis, C. et al. Experimental Chemotherapy in Paracoccidioidomycosis Using Ruthenium NO Donor. Mycopathologia 172, 95–107 (2011). https://doi.org/10.1007/s11046-011-9416-8

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