Impacto de la deficiencia de hormonas tiroideas maternas en la gestaciĆ³n, sobre el proceso de astrogliosis reactiva frente a inflamaciĆ³n en la progenie
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2013
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es
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Universidad AndrƩs Bello
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Resumen
La deficiencia de hormonas tiroideas maternas en la gestaciĆ³n, tanto el hipotiroidismo
como la hipotiroxinemia, daƱa irreversiblemente el sistema nervioso central del feto
(SNC). Especificamente se ha observado daƱo en la maduraciĆ³n y diferenciaciĆ³n tanto de
las neuronas como de las cƩlulas gliales. Entre las cƩlulas gliales se encuentran los
astrocitos, cƩlulas que cumplen diversas funciones en el SNC. Una de las funciones de
los astrocitos es la astrogliosis reactiva frente a una respuesta inflamatoria. La
astrogliosis se caracteriza por aumento del tamaƱo del astrocito, del nĆŗmero de sus
proyecciones y de su proliferaciĆ³n. Las evidencias indican que la astrogliosis es un
proceso de protecciĆ³n frente al daƱo inflamatorio. La astrogliosis reactiva sea descrito en
enfermedades como la esclerosis mĆŗltiple (EM). La EM es una enfermedad autoinmune al
SNC cuya etiologĆa es desconocida, multifactorial y con una incidencia alta a nivel
mundial. La EM se caracteriza por presentar desmielinizaciĆ³n y degeneraciĆ³n neuronal,
consecuentemente la pƩrdida de la actividad motora y cognitiva del paciente. La EM se
estudia en gran medida en un modelo experimental de animales llamado encefalomielitis
autoinmune experimental (EAE). Evidencias de nuestro laboratorio han mostrado que
animales gestados bajo la deficiencia de hormonas tiroideas sufren de EAE mƔs severo
que los animales gestados en condiciones eutiroideas. Basados en los antecedentes
descritos anteriormente, sobre el rol de las hormonas tiroideas en la diferenciaciĆ³n de los
astrocitos proponemos las siguiente hipĆ³tesis: "La astrogliosis reactiva generada en
procesos inflamatorios, se encuentra disminuida en astrocitos provenientes de la
progenie gestada con dƩficit de hormonas tiroideas tanto como el hipotiroidismo o
la hipotiroxinemia". Con el objetivo de responder a esta hipĆ³tesis evaluamos la
astrogliosis en animales que sufren EAE y que se gestaron en madres con hipotiroidismo.
AdemƔs estudiamos el rol de factor tumoral de necrosis a (TNFa), molƩcula clave en el
desarrollo de EAE, sobre la astrogliosis reactiva en un modelo in vitro de astrocitos
provenientes de ratas gestadas en hipotiroxinemia. Los resultados obtenidos en esta
tesis, muestran que el hipotiroidismo gestacional produce astrogliosis reactiva sĆ³lo en
regiones especĆficas del SNC en que padecen EAE., Los resultados del estudio in vitro
mostraron una mayor expresiĆ³n de Ā”NOS principal molĆ©cula inflamatoria involucrada en el
daƱo durante la EM. En conclusiĆ³n, nuestros resultados indican que la deficiencia de
hormonas tiroideas durante la gestaciĆ³n genera una impronta en los astrocitos,
haciƩndolos mƔs inflamatorios pero disminuyendo su capacidad de astrogliosis reactiva.
The maternal thyroid hormone deficiency during pregnancy, both hypothyroidism and hypothyroxinemia, irreversibly damage the fetal central nervous system (CNS) of the offspring. Damage has been observed specifically in the maturation and differentiation of both the neurons and glial cells. Astrocytes are glial cells that play several functions in the CNS. One of the functions of astrocytes is reactive astrogliosis against an inflammatory response. Reactive astrogliosis is characterized for astrocyte enlargement, an increase at the number of projections and their proliferation. Evidence indicates that astrogliosis is a process of protection against inflammatory damage. The reactive astrogliosis is described in diseases such as multiple sclerosis (MS). MS is a CNS autoimmune disease whose etiology is unknown and it has high incidence worldwide. MS is characterized by demyelination and neuronal degeneration, consequently the patient loss cognitive and motor activity. The experimental model to study EM is the experimental autoimmune encephalomyelitis (EAE). Evidence from our laboratory has shown that animals gestated under thyroid hormone deficiency suffer from more severe EAE than animals gestated in euthyroid conditions. Based on the evidences described above about the role of thyroid hormones in the differentiation of astrocytes we propose the following hypothesis: "The reactive astrogliosis generated in inflammatory processes is decreased in astrocytes from the progeny gestated under thyroid hormone deficiency like hypothyroidism or hypothyroxinemia". Aiming to evaluate this hypothesis, mice gestated under hypothyroidism were subjected to EAE. We analyzed the expression of GFAP and iNOS at the spinal cord and brain. We analyzed the role of tumor necrosis factor a (TNFa), a key molecule in the development of EAE, over reactive astrogliosis in a primary cell culture of astrocytes gestated in hypothyroxinemia. The results obtained in this thesis show that reactive astrogliosis occurs only in specific regions of the CNS of animals gestated under hypothyroidism that suffer. From the astrocyte primary cell culture we found an increase expression of iNOS, main molecule involved in the inflammatory damage in MS. In conclusion, our results indicate that thyroid hormone deficiency during pregnancy creates an imprint in astrocytes, making them more inflammatory but decreasing their ability to generate reactive astrogliosis.
The maternal thyroid hormone deficiency during pregnancy, both hypothyroidism and hypothyroxinemia, irreversibly damage the fetal central nervous system (CNS) of the offspring. Damage has been observed specifically in the maturation and differentiation of both the neurons and glial cells. Astrocytes are glial cells that play several functions in the CNS. One of the functions of astrocytes is reactive astrogliosis against an inflammatory response. Reactive astrogliosis is characterized for astrocyte enlargement, an increase at the number of projections and their proliferation. Evidence indicates that astrogliosis is a process of protection against inflammatory damage. The reactive astrogliosis is described in diseases such as multiple sclerosis (MS). MS is a CNS autoimmune disease whose etiology is unknown and it has high incidence worldwide. MS is characterized by demyelination and neuronal degeneration, consequently the patient loss cognitive and motor activity. The experimental model to study EM is the experimental autoimmune encephalomyelitis (EAE). Evidence from our laboratory has shown that animals gestated under thyroid hormone deficiency suffer from more severe EAE than animals gestated in euthyroid conditions. Based on the evidences described above about the role of thyroid hormones in the differentiation of astrocytes we propose the following hypothesis: "The reactive astrogliosis generated in inflammatory processes is decreased in astrocytes from the progeny gestated under thyroid hormone deficiency like hypothyroidism or hypothyroxinemia". Aiming to evaluate this hypothesis, mice gestated under hypothyroidism were subjected to EAE. We analyzed the expression of GFAP and iNOS at the spinal cord and brain. We analyzed the role of tumor necrosis factor a (TNFa), a key molecule in the development of EAE, over reactive astrogliosis in a primary cell culture of astrocytes gestated in hypothyroxinemia. The results obtained in this thesis show that reactive astrogliosis occurs only in specific regions of the CNS of animals gestated under hypothyroidism that suffer. From the astrocyte primary cell culture we found an increase expression of iNOS, main molecule involved in the inflammatory damage in MS. In conclusion, our results indicate that thyroid hormone deficiency during pregnancy creates an imprint in astrocytes, making them more inflammatory but decreasing their ability to generate reactive astrogliosis.
Notas
Tesis (BioquĆmico, MagĆster en BioquĆmica)
Este trabajo de tesis se realizĆ³ con el financiamiento de Fondecyt # 1100926, el Instituto Milenio de InmunologĆa e Inmunoterapia (MII) P09-01 6-F NĆŗcleo UNAB DI-209-12/N, y el proyecto ECOS-Conicyt C11503.
Este trabajo de tesis se realizĆ³ con el financiamiento de Fondecyt # 1100926, el Instituto Milenio de InmunologĆa e Inmunoterapia (MII) P09-01 6-F NĆŗcleo UNAB DI-209-12/N, y el proyecto ECOS-Conicyt C11503.
Palabras clave
Hormonas Tiroideas, Embarazadas, Astrogliosis