IFN-γ Mediated Signaling Improves Fungal Clearance in Experimental Pulmonary Mucormycosis.

We established three immunocompetent murine models of pulmonary mucormycosis to determine the involvement of the adaptive immune response in host resistance in pulmonary mucormycosis, a rapidly fatal disease caused mainly by Rhizopus spp. Immunocompetent inbred (C57BL/6, BALB/c) and outbred (Swiss) strains of mice were inoculated with R. oryzae via the intratracheal route. The inoculation resulted in a disseminated infection that spread to the brain, spleen, kidney, and liver. After 7 and 30 days of R. oryzae infection, BALB/c mice showed the lowest fungal load and highest production of IFN-γ and IL-2 by splenocytes. Swiss mice showed a higher fungal load 30 days p.i. and was associated with a weak development of the Th-1 profile. To confirm our findings, R. oryzae-infected IFN-γ-/- mice were evaluated after 60 days, where the mice still showed viable fungi in the lungs. This study showed, for the first time, that pulmonary mucormycosis in three widely used mouse strains resulted in an acute fungal dissemination without immunosuppression whose outcome varies according to the genetic background of the mice. We also identified the partial role of IFN-γ in the efficient elimination of R. oryzae during pulmonary infection.

The relevance of the optional use of fasting in laboratory measurements that make up the lipid profile: A systematic literature review.

The objective of this study was to evaluate the impact of fasting easing on laboratory measurements of the lipid profile, in order to contribute to the fidelity of interpretation of laboratory results. Starting in October 2022, a Systematic Literature Review (SRL) was carried out, using articles indexed in the electronic databases PubMed/MEDLINE, EMBASE, Scopus, LILACS and Cochrane Library, following the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes Group (PRISMA). This RSL was registered with PROSPERO, under registration number CRD42022370007. For inclusion, articles had to be original and developed in humans. After evaluating the methodological quality and analyzing the risk of bias, we obtained 16 articles published between 1994 and 2021, providing data on a total of 398,709 individuals, aged between 3 and 93 years. According to the selected studies, lipid profile measurements performed with flexible fasting, in addition to bringing benefits to patients and the pre-analytical system of the clinical laboratory, are more suitable for determining cardiovascular risk, mainly through the assessment of values obtained in the determination of triglycerides. It is therefore concluded that the optional use of fasting must be established through medical advice. In addition, laboratory methods and readings must be readjusted to this reality, informing through the report the parameters related to the lipid profile with and without the use of a 12-hour fast.

Combined Silymarin and Cotrimoxazole Therapy Attenuates Pulmonary Fibrosis in Experimental Paracoccidioidomycosis.

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-ß1 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.

Exoantigens of Paracoccidioides spp. Promote Proliferation and Modulation of Human and Mouse Pulmonary Fibroblasts.

Paracoccidioidomycosis (PCM) is a systemic granulomatous fungal infection caused by thermally dimorphic fungi of the genus Paracoccidioides. Endemic in Latin America, PCM presents with high incidence in Brazil, Colombia, and Venezuela, especially among rural workers. The main clinical types are acute/subacute (AF) form and chronic form (CF). Even after effective antifungal treatment, patients with CF usually present sequelae, such as pulmonary fibrosis. In general, pulmonary fibrosis is associated with dysregulation wound healing and abnormal fibroblast activation. Although fibrogenesis is recognized as an early process in PCM, its mechanisms remain unknown. In the current study, we addressed the role of Paracoccidioides spp. exoantigens in pulmonary fibroblast proliferation and responsiveness. Human pulmonary fibroblasts (MRC-5) and pulmonary fibroblasts isolated from BALB/c mice were cultivated with 2.5, 5, 10, 100, and 250 µg/ml of exoantigens produced from P. brasiliensis (Pb18 and Pb326) and P. lutzii (Pb01, Pb8334, and Pb66) isolates. Purified gp43, the immunodominant protein of P. brasiliensis exoantigens, was also evaluated at concentrations of 5 and 10 µg/ml. After 24 h, proliferation and production of cytokines and growth factors by pulmonary fibroblasts were evaluated. Each exoantigen concentration promoted a different level of interference of the pulmonary fibroblasts. In general, exoantigens induced significant proliferation of both murine and human pulmonary fibroblasts (p < 0.05). All concentrations of exoantigens promoted decreased levels of IL-6 (p < 0.05) and VEGF (p < 0.05) in murine fibroblasts. Interestingly, decreased levels of bFGF (p < 0.05) and increased levels of TGF-ß1 (p < 0.05) and pro-collagen I (p < 0.05) were observed in human fibroblasts. The gp43 protein induced increased TGF-ß1 production by human cells (p = 0.02). In conclusion, our findings showed for the first time that components of P. brasiliensis and P. lutzii interfered in fibrogenesis by directly acting on the biology of pulmonary fibroblasts.