Itraconazole in combination with neutrophil depletion reduces the expression of genes related to pulmonary fibrosis in an experimental model of paracoccidioidomycosis

Med Mycol. 2018 Jul 1;56(5):579-590. doi: 10.1093/mmy/myx087.


Itraconazole (ITC) is the drug of choice for treating paracoccidioidomycosis (PCM); nonetheless, patients with the chronic form of this mycosis develop fibrosis, a residual pulmonary abnormality, even after treatment. Recently, we observed that the depletion of neutrophils with a specific monoclonal antibody (mAb-anti-Ly6G) during the chronic stages of PCM was associated with a decrease in the fungal burden, the inflammatory response and a reduction of fibrosis. Herein, we aimed to evaluate the effect of ITC in combination with the mAb-anti-Ly6G in an experimental model of pulmonary PCM. BALB/c male mice were challenged with Paracoccidioides brasiliensis yeasts and treated with the mAb-anti-Ly6G and/or ITC at 4th week post-infection (p.i.) and then sacrificed at 12th week p.i. to assess neutrophil subpopulations, fungal load, collagen, expression of fibrosis- and pro-inflammatory-related genes and histopathology. We observed that combination of ITC/mAb-anti-Ly6G favored the control of infection and diminished the inflammatory response. Of note, such therapeutic strategy reduced the expression of IL-1β, IL-6, IL-17, IL-10, TNF-α, TGF-β1, TGF-β3, GATA-3, RORc, Ahr, MMP-1α, MMP-8 MMP-15, TIMP-1, and TIMP-2 genes in an additive manner compared to those mice treated with the mAb or ITC alone. Interestingly, ITC induced an increase of type-II neutrophils even in those mice treated with the mAb-anti-Ly6G. These results indicate that combination ITC/mAb-anti-Ly6G reduced the infection and pulmonary fibrosis through down-regulation of inflammatory and pro-fibrotic genes. Additionally, we confirmed the immunomodulatory properties of this antifungal in vivo. This work emphasizes the importance of exploring new potential combination treatments to treat fungal infections.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Antibodies, Monoclonal / therapeutic use*
  • Antifungal Agents / pharmacology
  • Antifungal Agents / therapeutic use
  • Collagen / genetics
  • Colony Count, Microbial
  • Disease Models, Animal*
  • Drug Therapy, Combination
  • Immunomodulation / drug effects
  • Inflammation / genetics
  • Itraconazole / pharmacology*
  • Itraconazole / therapeutic use*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Neutrophils / drug effects*
  • Paracoccidioides / drug effects
  • Paracoccidioides / growth & development
  • Paracoccidioides / pathogenicity
  • Paracoccidioidomycosis / drug therapy*
  • Paracoccidioidomycosis / immunology
  • Paracoccidioidomycosis / pathology
  • Pulmonary Fibrosis / drug therapy*
  • Pulmonary Fibrosis / immunology
  • Pulmonary Fibrosis / pathology
  • Transcription, Genetic / drug effects


  • Antibodies, Monoclonal
  • Antifungal Agents
  • Itraconazole
  • Collagen