Increased peripheral blood TCD4+ counts and serum SP-D levels in patients with chronic paracoccidioidomycosis, during and after antifungal therapy

Venturini, James; Cavalcante, R. S.; Sylvestre, Tatiane Fernanda; Santos, Rodolfo Ferreira dos; Moris, Daniela Vanessa; Carvalho, Lídia Raquel de; Arruda, Maria Sueli Parreira de; Golim, Márjorie de Assis; Mendes, Rinaldo Pôncio

doi:10.1590/0074-02760170046

Cited by 5 publications

(2 citation statements)

References 27 publications

(38 reference statements)

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“…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 ].…”

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confidence: 99%

Combined Silymarin and Cotrimoxazole Therapy Attenuates Pulmonary Fibrosis in Experimental Paracoccidioidomycosis

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et al. 2022

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Paracoccidioidomycosis (PCM), which mainly affects rural workers, is a systemic mycosis caused by the Paracoccidioides genus that induces pulmonary sequelae in most adult patients, causing serious disability and impairing their quality of life. Silymarin is herbal medicine with an effective antifibrotic activity. Considering that in PCM, antifibrotic treatment is still not available in pulmonary fibrosis, we aimed to evaluate combined silymarin and cotrimoxazole (CMX) therapy via the intratracheal route in BALB/c mice infected with P. brasiliensis yeast. After 12 weeks of treatment, the lungs were collected for the determination of fungal burden, production of OH-proline, deposition of collagen fibers, pulmonary concentrations of cytokines, and expression of fibronectin, α-SMA, MMP-2, MMP-9, and TIMP-2. Spleen cell cultures were also performed. Our results showed that infected mice treated with combined silymarin/CMX showed lower deposition of collagen fibers in the lungs and lower pulmonary concentrations of hydroxyproline than the placebo groups. Decreased levels of TGF-β1 and fibronectin and high levels of MMP-2 and IFN-γ were also observed in this group of mice. Collectively, our findings indicate that the combination of antifungal treatment with silymarin has a potent antifibrotic effect associated with an immunomodulatory effect that potentializes the antifungal immune response.

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confidence: 99%

Combined Silymarin and Cotrimoxazole Therapy Attenuates Pulmonary Fibrosis in Experimental Paracoccidioidomycosis

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“…The clinical aspects of PCM PS have rarely been studied [ 5 , 30 ], and although fibrogenesis in PCM is recognized as an early process [ 31 – 34 ], the molecular mechanisms involved in these sequela are still unknown. Our group has observed several immunological alterations in these patients even after successful antifungal treatment, including increased levels of pro-inflammatory cytokines and growth factor [ 35 ], high counts of CD14 + CD16 ++ monocyte subsets [ 34 ], high counts of peripheral blood TCD4 + [ 35 ], increased counts of peripheral blood plasmacytoid dendritic cells [ 36 ], and enhanced inflammasome activation [ 37 ]. These findings highlights the complexity of a sequelae in these patients along with systemic repercussion.…”

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confidence: 99%

Proteomic analysis of serum samples of paracoccidioidomycosis patients with severe pulmonary sequel

et al. 2021

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Background Pulmonary sequelae (PS) in patients with chronic paracoccidioidomycosis (PCM) typically include pulmonary fibrosis and emphysema. Knowledge of the molecular pathways involved in PS of PCM is required for treatment and biomarker identification. Methodology/Principal findings This non-concurrent cohort study included 29 patients with pulmonary PCM that were followed before and after treatment. From this group, 17 patients evolved to mild/ moderate PS and 12 evolved severe PS. Sera from patients were evaluated before treatment and at clinical cure, serological cure, and apparent cure. A nanoACQUITY UPLC-Xevo QT MS system and PLGS software were used to identify serum differentially expressed proteins, data are available via ProteomeXchange with identifier PXD026906. Serum differentially expressed proteins were then categorized using Cytoscape software and the Reactome pathway database. Seventy-two differentially expressed serum proteins were identified in patients with severe PS compared with patients with mild/moderate PS. Most proteins altered in severe PS were involved in wound healing, inflammatory response, and oxygen transport pathways. Before treatment and at clinical cure, signaling proteins participating in wound healing, complement cascade, cholesterol transport and retinoid metabolism pathways were downregulated in patients with severe PS, whereas signaling proteins in gluconeogenesis and gas exchange pathways were upregulated. At serological cure, the pattern of protein expression reversed. At apparent cure pathways related with tissue repair (fibrosis) became downregulated, and pathway related oxygen transport became upregulated. Additionally, we identified 11 proteins as candidate biomarkers for severe PS. Conclusions/Significance Development of severe PS is related to increased expression of proteins involved in glycolytic pathway and oxygen exchange), indicative of the greater cellular activity and replication associated with early dysregulation of wound healing and aberrant tissue repair. Our findings provide new targets to study mechanisms of PS in PCM, as well as potential biomarkers.

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Evaluation of antifibrotic and antifungal combined therapies in experimental pulmonary paracoccidioidomycosis

et al. 2019

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Abstract 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.

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Increased peripheral blood TCD4+ counts and serum SP-D levels in patients with chronic paracoccidioidomycosis, during and after antifungal therapy

Cited by 5 publications

References 27 publications

Combined Silymarin and Cotrimoxazole Therapy Attenuates Pulmonary Fibrosis in Experimental Paracoccidioidomycosis

Combined Silymarin and Cotrimoxazole Therapy Attenuates Pulmonary Fibrosis in Experimental Paracoccidioidomycosis

Proteomic analysis of serum samples of paracoccidioidomycosis patients with severe pulmonary sequel

Evaluation of antifibrotic and antifungal combined therapies in experimental pulmonary paracoccidioidomycosis

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