DESENVOLVIMENTO DA FIBROSE PULMONAR NA PARACOCCIDIOIDOMICOSE MURINA DURANTE O TRATAMENTO COM COTRIMOXAZOL

Abstract

Paracoccidioidomycosis (PCM) is a systemic mycosis caused by fungi of the genus Paracoccidioides. Its main clinical forms are acute/subacute and chronic (CF). The disease is endemic in Latin America, with a high incidence in Brazil, Colombia, and Venezuela. The antifungal treatment for PCM is prolonged, with itraconazole being the first-choice drug, except for cases involving the central nervous system. In Brazil, cotrimoxazole (CMX) is widely used due to its effectiveness, availability, and broader distribution. However, most CF patients develop sequelae, such as pulmonary fibrosis (PF), even after successful antifungal treatment. Due to its high disabling potential, PCM is the cause of the withdrawal of rural workers with CF from their professions, causing social, economic and psychological problems, which are still underestimated. Although fibrogenesis in PCM is known to be an early process, the underlying mechanisms are not fully understood and the PF has no cure. Therefore, this study aims to evaluate the pulmonary tissue changes and immunological aspects related to PF development in mice infected with Paracoccidioides brasiliensis (Pb) during the cotrimoxazole treatment. Male BALB/c mice were intratracheally inoculated with Pb yeast. Four weeks after infection, treatment with CMX by gavage was initiated at a single dose per day. Pulmonary fungal burden, histopathological aspects of the lungs, production of inflammatory cytokines by alveolar macrophages (AM), distribution of total leukocytes, subpopulations of blood monocytes, and splenic dendritic cells were assessed at 4, 10, and 20 weeks of treatment. Our results demonstrated that CMX treatment in the initial phase led to increased production of H2O2 and TNF-α by AM compared to control treated with saline (CTL), enhanced tissue expression of F4/80, Collagen I and III in the lungs compared to Pb-infected group. After 20 weeks of treatment, fungal clearance was observed, along with normalization of H2O2 and TNF-α levels compared to CTL, and significant collagen deposition in alveolar septum in areas distant from residual granulomas in CMX-treated mice. Furthermore, even after fungal clearance, the CMX-treated mice exhibited a high percentage of inflammatory monocytes in the blood and increased MHC-II expression in myeloid dendritic cells compared to CTL. In conclusion, our results indicate that CMX treatment enhances the immune response against the fungus in the initial phase. However, this immune response profile appears to contribute to an imbalance between the immune response and tissue repair throughout the treatment, resulting in permanent pulmonary fibrosis accompanied by systemic repercussions.