Combined itraconazole-pentoxifylline treatment promptly reduces lung fibrosis induced by chronic pulmonary paracoccidioidomycosis in mice

Tonny W. Naranjo, Damaris E. Lopera, Lucy R. Diaz-Granados, Jhon J. Duque, Angela Restrepo M, Luz E. Cano

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    34 Scopus citations

    Abstract

    Fibrosis is a severe and progressive sequel of many pulmonary diseases, has no effective therapy at present and, consequently, represents a serious health problem. In Latin America, chronic pulmonary paracoccidioidomycosis (PCM) is one of the most important, prevalent and systemic fungal diseases that allows the development of lung fibrosis, with the additional disadvantage that this sequel may appear even after an apparently successful course of antifungal therapy. In this study, was propose the pentoxifylline as complementary treatment in the pulmonary PCM due to its immunomodulatory and anti-fibrotic properties demonstrated in vitro and in vivo in liver, skin and lung. Our objective was to investigate the possible beneficial effects that a combined antifungal (Itraconazole) and immunomodulatory (Pentoxifylline) therapy would have in the development of fibrosis in a model of experimental chronic pulmonary PCM in an attempt to simulate the naturally occurring events in human patients. Two different times post-infection (PI) were chosen for starting therapy, an "early time" (4 weeks PI) when fibrosis was still absent and a "late time" (8 weeks PI) when the fibrotic process had started. Infected mice received the treatments via gavage and were sacrificed during or upon termination of treatment; their lungs were then removed and processed for immunological and histopathologic studies in order to assess severity of fibrosis. When pulmonary paracoccidioidomycosis had evolved and reached an advanced stage of disease before treatment began (as normally occurs in many human patients when first diagnosed), the combined therapy (itraconazole plus pentoxifylline) resulted in a significantly more rapid reduction of granulomatous inflammation and pulmonary fibrosis, when compared with the results of classical antifungal therapy using itraconazole alone.

    Original languageEnglish
    Pages (from-to)81-91
    Number of pages11
    JournalPulmonary Pharmacology and Therapeutics
    Volume24
    Issue number1
    DOIs
    StatePublished - Feb 2011

    Bibliographical note

    Funding Information:
    This work was supported by COLCIENCIAS, Bogotá, Colombia (Project No. 2213-04-16439 and 2213-408-20412), the Corporación para Investigaciones Biológicas (CIB) and the University of Antioquia (UdeA), Medellin, Colombia. The authors thank the Laboratório de Patologia, Instituto Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, Brazil for their assistance with Grocott histological stain and scanning microscopy, and to Bacteriologist Laura Echeverry for her technical assistance.

    Keywords

    • Cytokines
    • Itraconazole
    • Lung fibrosis
    • Paracoccidioides brasiliensis
    • Paracoccidioidomycosis
    • Pentoxifylline

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