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Infection and Immunity, March 2004, p. 1637-1644, Vol. 72, No. 3
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.3.1637-1644.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Blockade of Endogenous Leukotrienes Exacerbates Pulmonary Histoplasmosis

Alexandra I. Medeiros,1 Anderson Sá-Nunes,1 Edson G. Soares,2 Camila M. Peres,1 Célio L. Silva,3 and Lúcia H. Faccioli1*

Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto,1 Departamento de Patologia,2 Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo 14040-903, Brazil3

Received 10 March 2003/ Returned for modification 29 April 2003/ Accepted 21 November 2003

Leukotrienes are classical mediators of inflammatory response. New aspects of leukotriene function have recently been described. We examine here the previously unreported role that leukotrienes play in the regulation of cytokines in a murine model of histoplasmosis. We demonstrate that administration of MK 886, a leukotriene synthesis inhibitor, caused Histoplasma capsulatum-infected mice to die by the day 15 of infection, whereas the correlating death rate in untreated infected mice was 0%. Treating infected animals with MK 886 inhibited leukotriene synthesis but increased leukocyte recruitment to the lungs. Subsequent to this phenomenon, levels of tumor necrosis factor alpha, interleukin-1 (IL-1), IL-6, and KC chemoattractant cytokines and fungi in the lung parenchyma increased, as did inflammatory response. In contrast, IL-2, IL-5, IL-12, and gamma interferon cytokine levels actually decreased. Thus, murine response to pulmonary histoplasmosis may be leukotriene modulated. This finding may enable us to alter the course of the immune response and inflammation caused by histoplasmosis. The data from the present study suggest an important new strategy for immunologic or drug intervention in human patients.

* Corresponding author. Mailing address: Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo-Av. do Café, s/n Ribeirão Preto, São Paulo 14040-903, Brazil. Phone: 55-16-602-4303. Fax: 55-16-633-1936. E-mail: faccioli{at}fcfrp.usp.br.

Editor: T. R. Kozel

Infection and Immunity, March 2004, p. 1637-1644, Vol. 72, No. 3
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.3.1637-1644.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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