Evaluation of antifibrotic and antifungal combined therapies in experimental pulmonary paracoccidioidomycosis

Abstract

<jats:title>Abstract</jats:title> <jats:p>Paracoccidioidomycosis (PCM) is a systemic mycosis caused by the Paracoccidioides genus. Most of the patients with chronic form present sequelae, like pulmonary fibrosis, with no effective treatment, leading to impaired lung functions. In the present study, we aimed to investigate the antifibrotic activity of three compounds: pentoxifylline (PTX), azithromycin (AZT), and thalidomide (Thal) in a murine model of pulmonary PCM treated with itraconazole (ITC) or cotrimoxazole (CMX). BALB/c mice were inoculated with P. brasiliensis (Pb) by the intratracheal route and after 8 weeks, they were submitted to one of the following six treatments: PTX/ITC, PTX/CMX, AZT/ITC, AZT/CMX, Thal/ITC, and Thal/CMX. After 8 weeks of treatment, the lungs were collected for determination of fungal burden, production of OH-proline, deposition of reticulin fibers, and pulmonary concentrations of cytokines and growth factors. Pb-infected mice treated with PTX/ITC presented a reduction in the pulmonary concentrations of OH-proline, associated with lower concentrations of interleukin (IL)-6, IL-17, and transforming growth factor (TGF)-β1 and higher concentrations of IL-10 compared to the controls. The Pb-infected mice treated with AZT/CMX exhibited decreased pulmonary concentrations of OH-proline associated with lower levels of TGF-β1, and higher levels of IL-10 compared controls. The mice treated with ITC/Thal and CMX/Thal showed intense weight loss, increased deposition of reticulin fibers, high pulmonary concentrations of CCL3, IFN-γ and VEGF, and decreased concentrations of IL-6, IL-1β, IL-17, and TGF-β1. In conclusion, our findings reinforce the antifibrotic role of PTX only when associated with ITC, and AZT only when associated with CMX, but Thal did not show any action upon addition.</jats:p>

Combined Silymarin and Cotrimoxazole Therapy Attenuates Pulmonary Fibrosis in Experimental Paracoccidioidomycosis

“…For the intratracheal administration, mice were anesthetized intraperitoneally with ketamine (80 mg/kg) and xylazine (10 mg/kg). This experimental model was previously standardized to induce intense PF [ 11 ].…”

“…In recent years, our group has focused on the study of pulmonary sequelae in patients with CF-PCM, and our findings have shown pro-fibrotic alterations since diagnosis along with prolonged systemic and low-grade pro-inflammatory profiles during and after a complete and successful antifungal therapy [ 6 , 7 , 8 , 9 , 10 ]. In addition, we previously established a murine model of pulmonary PCM, in which BALB/c mice presented with intense pulmonary fibrosis (PF), and we evaluated antifibrotic drugs and combined antifungal therapies [ 11 ].…”

The Therapy of Pulmonary Fibrosis in Paracoccidioidomycosis: What Are the New Experimental Approaches?

“…Fungal burden, inflammatory response, PF IL-6, IL-9, GM-CSF, CXCL1, CXCL9, CCL5 [24,40] Fungal burden, inflammatory response; and PF if treatment was started an early time post-infection (4 wk.) Fungal burden, Inflammatory response, PF ITC + Thal PF IL-1β, IL-6, IL-10, IL-12, IL-17, TGF-β1, VEGF, IFN-γ, CCL3 [12] CMX + PTX PF, CCL3 IL-17, TGF-β1 [12] CMX + AZT Inflammatory response, hydroxyproline TGF-β1 TNF-α, IL-10…”

“…More recently, Finato et al [12] evaluated the antifibrotic and antifungal combined therapies in an experimental model of pulmonary PCM. Thus, these authors investigated the antifibrotic activity of PTX, AZT, and Thal in combination with the antifungals ITC or CMX in P. brasiliensis-infected mice at advanced stages of infection (week eight).…”

“…Additionally, infected mice treated with a combination of CMX + AZT also exhibited low levels of hydroxyproline and TGF-β with higher levels of IL-10. On the contrary, the combined treatment with ITC + Thal, CMX + Thal, and ITC + AZT was associated with the loss of body weight, the increased deposition of reticuline fibers, low levels of IL-1β, IL-6, and TGF-β, and higher concentrations of vascular endothelial growth factor (VEGF), interferon-gamma (IFN-γ), and CCL3 [12].…”