RESUMO
The fetal lung is affected by maternal diabetes. Nuclear receptor PPARα regulates nitric oxide (NO) overproduction in different tissues. We aimed to determine whether fetal lung PPARα expression is altered by maternal diabetes, and if there are gender-dependent changes in PPARα regulation of NO production in the fetal lung. Fetal lungs from control and diabetic rats were explanted on day 21 of gestation and evaluated for PPARα expression and NO production. Fetuses were injected with the PPARα ligand LTB(4) on days 19, 20 and 21, and the fetal lung explanted on day 21 to evaluate PPARα and the inducible isoform of NO synthase (iNOS). Besides, pregnant rats were fed with olive oil- and safflower oil-supplemented diets, enriched in PPAR ligands, for evaluation of fetal lung NO production and PPARα expression. We found reduced PPARα concentrations only in the lung from male fetuses from the diabetic group when compared to controls, although maternal diabetes led to NO overproduction in both male and female fetal lungs. Fetal activation of PPARα led to changes in lung PPARα expression only in female fetuses, although this treatment increased iNOS expression in both male and female fetuses in the diabetic group. Diets supplemented with olive oil and not with safflower oil led to a reduction in NO production in male and female fetal lungs. In conclusion, there are gender-dependent changes in PPARα expression and signaling in the fetal lung from diabetic rats, although PPARα activation prevents maternal diabetes-induced lung NO overproduction in both male and female fetuses.
Assuntos
Diabetes Mellitus Experimental/metabolismo , Feto/metabolismo , Pulmão/metabolismo , Óxido Nítrico/metabolismo , PPAR alfa/metabolismo , Gravidez em Diabéticas/metabolismo , Animais , Glicemia , Dieta , Feminino , Sangue Fetal/metabolismo , Peso Fetal , Feto/efeitos dos fármacos , Feto/patologia , Regulação da Expressão Gênica no Desenvolvimento , Leucotrieno B4/administração & dosagem , Pulmão/patologia , Masculino , Troca Materno-Fetal , Azeite de Oliva , Tamanho do Órgão , PPAR alfa/genética , Óleos de Plantas/administração & dosagem , Gravidez , Fenômenos Fisiológicos da Nutrição Pré-Natal , Ratos , Ratos Wistar , Óleo de Cártamo/administração & dosagem , Fatores Sexuais , Transdução de Sinais , Triglicerídeos/sangueRESUMO
Histoplasmosis is a pulmonary disease characterised by chronic granulomatous and suppurative inflammatory reactions caused by Histoplasma capsulatum. Regarding new therapies to control fungal infections, the aim of this study was to investigate whether pulmonary administration of leukotriene B(4) (LTB(4))-loaded microspheres (MS) could confer protection to 5-lipoxygenase knockout (5-LO(-/-)) mice infected by H. capsulatum. In this study, MS containing LTB(4) were administered intranasally to mice infected by H. capsulatum. On Day 14 after the infection, fungal recovery from the lungs and histology were evaluated and inflammatory cytokines were measured. Pulmonary administration of LTB(4)-loaded MS was able to reduce fungal recovery from infected lungs. Production of important inflammatory cytokines related to host defence was augmented following MS administration to the lungs. Lung histology also showed that infected mice presented a clear reduction in the fungal burden following the pulmonary release of LTB(4) from MS. Our study provides evidence that the proposed biodegradable microparticulate system, which can release LTB(4) to the lungs, can be employed as therapy, enhancing the antimicrobial activity of host cells during histoplasmosis.
Assuntos
Histoplasma/efeitos dos fármacos , Histoplasmose , Leucotrieno B4/farmacologia , Microesferas , Administração Intranasal , Animais , Citocinas/imunologia , Citocinas/metabolismo , Glicolatos , Histoplasmose/tratamento farmacológico , Histoplasmose/imunologia , Histoplasmose/microbiologia , Histoplasmose/patologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/microbiologia , Ácido Láctico , Leucotrieno B4/administração & dosagem , Leucotrieno B4/imunologia , Lipoxigenase/genética , Pulmão/imunologia , Pulmão/microbiologia , Pulmão/patologia , Pneumopatias Fúngicas/tratamento farmacológico , Pneumopatias Fúngicas/imunologia , Pneumopatias Fúngicas/microbiologia , Pneumopatias Fúngicas/patologia , Masculino , Camundongos , Camundongos Knockout , Ácido Poliglicólico , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Resultado do TratamentoRESUMO
Leukotriene B(4) (LTB(4)) is a potent inflammatory mediator and stimulates the immune response. In addition, LTB(4) promotes leukocyte functions such as phagocytosis, chemotaxis and chemokinesis of polymorphonuclear leukocytes, as well as modulates cytokine release. However, some physicochemical characteristics of leukotrienes, such as poor solubility in water and chemical instability, make them difficult to administer in vivo. The aim of this study was to develop LTB(4)-loaded microspheres (MS) that prolong and sustain the in vivo release of this mediator. An oil-in-water emulsion solvent extraction-evaporation method was chosen to prepare the lipid-loaded MS. We determined their diameters, evaluated the in vitro release of LTB(4), using enzyme immunoassay and evaluated in vitro MS uptake by peritoneal macrophages. To assess the preservation of neutrophil chemoattractant activity, LTB(4)-loaded MS were tested in vitro (in a modified Boyden microchamber) and in vivo, after intratracheal administration.