Estresse materno induzido por desnutrição altera o eixo neuroendócrino-imune da prole adulta: implicações na resposta inflamatória pulmonar aguda
Data
2022-02-24
Autores
Gil, Noemi Lourenço [UNIFESP]
Orientadores
Landgraf, Richardt Gama [UNIFESP]
Tipo
Tese de doutorado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
Objetivo: Este trabalho procurou investigar as influências da restrição alimentar
materna e o estresse materno sobre o eixo hipotálamo-pituitária-adrenal e resposta
inflamatória pulmonar aguda da prole adulta. Métodos: No primeiro dia de gestação,
ratas Wistar foram separadas em mães controles, mães que receberam 50 % de
restrição alimentar em comparação as controles e em mães que, além de receberem
50 % de restrição alimentar, foram tratadas com metirapona (0,5 mg/mL) v.o. durante
toda a gestação. Quando a prole de machos atingiram 12 semanas de idade, induziuse
a lesão pulmonar aguda, instilando-se lipopolissacarídeo i.n. (750 μg/mL).
Decorridas 6h após a instilação, os ratos foram eutanasiados e as amostras foram
coletadas para análise. Resultados: Mães que sofreram restrição alimentar
apresentaram concentrações elevadas de corticosterona, e apesar do tratamento com
metirapona reduzir as concentrações deste hormônio, tanto os filhotes de mães
restritas quanto os das restritas tratadas com o fármaco nasceram com baixo peso.
Ao se analisar a resposta inflamatória no contexto da lesão pulmonar aguda,
observou-se que a prole de mães restritas apresentaram um infiltrado neutrofílico
reduzido para os pulmões, acompanhado de um não aumento das citocinas próinflamatórias.
Já a prole oriunda de mães restritas, porém tratadas com metirapona,
apresentaram infiltrado neutrofílico e produção de citocinas semelhantes ao grupo
controle. Observou-se ainda que a prole de mães restritas apresentaram
hipercorticosteronemia, já os de mães tratadas, não apresentaram. As concentrações
dos hormônios corticosterona e adrenocorticotrófico após estímulo com
lipopolissacarídeo, indicaram que tanto a prole de mães restritas quanto os das
tratadas com metirapona, desenvolveram uma desregulação do eixo hipotálamopituitária-
adrenal, que pode ser tanto uma consequência da superexposição à
corticosterona materna, quanto do tratamento das mães com metirapona. Além disso,
a própria restrição alimentar provocou alterações estruturais e funcionais na glândula
adrenal da prole. Conclusões: Pode-se concluir com este estudo que tanto a restrição
alimentar materna quanto o estresse associado a esta condição prejudicam o
desenvolvimento fetal, entretanto, o estresse materno per se, pode provocar
alterações nos padrões de secreção da corticosterona da prole adulta, influenciando,
portanto, nos efeitos anti-inflamatórios do hormônio, alterando desta forma, a resposta
imunológica pulmonar frente a um estímulo infeccioso.
Objective: This work investigating the influences of maternal food restriction and maternal stress on the hypothalamic-pituitary-adrenal axis and acute pulmonary inflammatory response in adult offspring. Methods: On the first day of pregnancy, Wistar rats were separated into control mothers, mothers who received 50% food restriction compared to controls and in mothers who, in addition to receiving 50% food restriction, were treated with metyrapone (0.5 mg / mL) v.o. throughout gestation. The male offspring with12 weeks of age received lipopolysaccharide i.n. (750 µg / ml) to induce acute lung injury and 6 hours after instillation, the rats were euthanized and the samples were collected for analysis. Results: Food restricted mothers presented high levels of corticosterone, and although metyrapone treatment have reduced this hormone, both offspring of restricted and restricted mothers treated with the drug were born with low weight. Analyzing the inflammatory response in acute lung injury context, it was observed that the offspring of restricted mothers presented a reduced neutrophilic infiltrate into the lungs, accompanied by a non-increase in the pro-inflammatory cytokines. Offspring from restricted mothers, however treated with metyrapone, presented a neutrophilic count and production of cytokines similar to the control group. Restricted mothers offspring presented hypercorticosteronemia, whereas those of mothers treated with metyrapone presented normal corticosterone levels. The adrenocorticotropic and corticosterone hormones concentrations after stimulation with lipopolysaccharide indicated a hypothalamic-pituitary-adrenal axis dysregulation in both the offspring group: those of restricted mothers and mother treated with metyrapone, which supposedly is a consequence of overexposure to maternal corticosterone and the mothers treatment with metyrapone. In addition, maternal food restriction itself caused structural and functional changes in the offspring adrenal gland. Conclusion: This study show a impaired fetal development provoked by maternal food restriction and stress associated to this condition, however, maternal stress alone alters the corticosterone patterns secretions of adult offspring, influencing the corticosterone anti-inflammatory effects and, therefore, changing the lung immune response by infectious stimuli.
Objective: This work investigating the influences of maternal food restriction and maternal stress on the hypothalamic-pituitary-adrenal axis and acute pulmonary inflammatory response in adult offspring. Methods: On the first day of pregnancy, Wistar rats were separated into control mothers, mothers who received 50% food restriction compared to controls and in mothers who, in addition to receiving 50% food restriction, were treated with metyrapone (0.5 mg / mL) v.o. throughout gestation. The male offspring with12 weeks of age received lipopolysaccharide i.n. (750 µg / ml) to induce acute lung injury and 6 hours after instillation, the rats were euthanized and the samples were collected for analysis. Results: Food restricted mothers presented high levels of corticosterone, and although metyrapone treatment have reduced this hormone, both offspring of restricted and restricted mothers treated with the drug were born with low weight. Analyzing the inflammatory response in acute lung injury context, it was observed that the offspring of restricted mothers presented a reduced neutrophilic infiltrate into the lungs, accompanied by a non-increase in the pro-inflammatory cytokines. Offspring from restricted mothers, however treated with metyrapone, presented a neutrophilic count and production of cytokines similar to the control group. Restricted mothers offspring presented hypercorticosteronemia, whereas those of mothers treated with metyrapone presented normal corticosterone levels. The adrenocorticotropic and corticosterone hormones concentrations after stimulation with lipopolysaccharide indicated a hypothalamic-pituitary-adrenal axis dysregulation in both the offspring group: those of restricted mothers and mother treated with metyrapone, which supposedly is a consequence of overexposure to maternal corticosterone and the mothers treatment with metyrapone. In addition, maternal food restriction itself caused structural and functional changes in the offspring adrenal gland. Conclusion: This study show a impaired fetal development provoked by maternal food restriction and stress associated to this condition, however, maternal stress alone alters the corticosterone patterns secretions of adult offspring, influencing the corticosterone anti-inflammatory effects and, therefore, changing the lung immune response by infectious stimuli.