Opposite effects of prostaglandin D2 and prostaglandin E2 in immune response during experimental infection by Histoplasma capsulatum.

Author(s)

Priscilla Aparecida Tartari Pereira

• Document type: Doctoral Thesis
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC)
• Defense date: 2013-10-30

Examining board members

Lucia Helena Faccioli; Claudia Farias Benjamim; Marcelo Torres Bozza; Cristina Ribeiro de Barros Cardoso; Sonia Jancar Negro

• Advisor: Lucia Helena Faccioli

Abstract

Histoplasma capsulatum is a pathogenic dimorphic fungus and responsible for severe pulmonary lesions. Infection is acquired by inhalation of conidia and posterior conversion to yeasts in the alveoli and bronchioles, in which they are phagocyted by resident alveolar macrophages and leukocytes that migrate to the local infection. Recently, we demonstrate that mice infected by H. capsulatum and treated with inhibitor of prostaglandins synthesis presented a decrease in fungal burden in lungs and spleen, increase in nitrite production and uptake of yeasts by alveolar macrophages, and more survival, when compared with animals only infected. However, in this study, it was not determined what subtypes of prostaglandins participate in pathogenesis of histoplasmosis. Many research groups have demonstrated that PGD2 and PGE2 can have different biological effects regarding to microorganisms elimination in the host. Thus, it is primordial the understanding about the role of PGD2 and PGE2 on effector mechanisms of macrophages in host defense, especially in histoplasmosis. Therefore, the aim of this study was to investigate the role of PGD2 and PGE2 on experimental infection by H. capsulatum. So, we verify that PGD2 increased the uptake and microbicidal mechanisms of alveolar macrophages infected in vitro by H. capsulatum. 15dPGJ2, a PGD2 metabolite, increased only the phagocytosis, and PGE2 inhibited the effector mechanisms of macrophages. Among these results, we showed an increase of BLT1 expression on alveolar macrophages after addition of PGD2, and a possible binding of this mediator to BLT1, and of LTB4 to DP2. Later, as tool of therapeutic investigation, we used PGD2 encapsulation in biodegradable polymer, PLGA, in order to preserve its stability. Size, zeta potential and morphology were adequate for a possible intranasal treatment and uptake by alveolar macrophages. MS-PGD2 were phagocyted and able to activate NF-B, and consequently, to modulate nitrite, IL-1, TNF-, IL-6 and TGF- production. In this context, we purpose a treatment of the infection with MS-PGD2, in comparison to treatment with PGE2. MS-PGD2 were administrated via intranasal in infected mice, treated or not with celecoxib. We verify a decrease of fungal burden in lungs and spleen, less cellular infiltrate and decrease of some inflammatory cytokines. In contrast, after treatment of MS-PGE2, we observed greater fungal burden in the lungs and spleen, and an increase of the tissue inflammation and production of IL-10. Furthermore, we show that on day 21 after infection, referring to the 7th day after the treatment with MS-PGD2, fungal burden remained reduced in the lungs, thus proving the effectiveness of the treatment. Subsequently, using specific inhibitors, HQL-79 and CAY10526, respectively show the protective role of PGD2 and in deleterious to PGE2 in histoplasmosis. Together, our data contribute to the understanding of the antagonistic functions of PGD2 and PGE2 in this mycosis. (AU)

• FAPESP's process: 09/05106-6 - Evaluation of the role of the PGD2 and PGE2 in the efectors mechanisms of in vitro infection alveolar macrophages with Histoplasma capsulatum and in the immune response during in vivo experimental infection.
• Grantee: Priscilla Aparecida Tartari Pereira
• Support Opportunities: Scholarships in Brazil - Doctorate