Respuesta pulmonar neonatal de las vías de prostaglandinas vasodilatadoras a melatonina en corderos crónicamente hipóxicos por altura
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Fecha
2016
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Facultad/escuela
Idioma
es
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Universidad Andrés Bello
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Licencia CC
Licencia CC
Resumen
La hipoxia crónica afecta a más de 140 millones de personas que viven sobre los 2500
metros de altitud. Esta condición induce respuestas cardiopulmonares en la vida perinatal, pudiendo
determinar un cuadro de hipertensión pulmonar del neonato (HPN). HPN se caracteriza por
presentar una respuesta vasoconstrictora alta, una disminuida función vasodilatadora, una
proliferación de células musculares lisas (SMC) y un engrosamiento de la matriz extracelular en la
circulación pulmonar. Se ha propuesto que uno de los mecanismos responsables dado por la hipoxia
es la generación excesiva de especies reactivas de oxigeno (ROS) y la presencia de estrés oxidativo.
A partir de estos antecedentes, se han propuesto tratamientos pre y postnatales con melatonina,
debido a que esta hormona tiene propiedades antioxidantes a través de la neutralización de ROS,
la activación de enzimas antioxidantes, la modulación negativa de agentes prooxidantes y como
agente vasodilatador.
Las prostaglandinas derivan del metabolismo del ácido araquidónico (AA) y son
importantes reguladores del tono vascular pulmonar, habiendo vías vasoconstrictoras como
tromboxano (TXA2) y vasodilatadoras como prostaciclina (PGI2). A la fecha, se desconoce si estas
vías responden a un tratamiento con melatonina en el pulmón neonatal. Por lo tanto, en este trabajo
se analizó las vías vasodilatadoras de las prostaglandinas, enfocándose en las ciclooxigenasas
(COX), prostaglandina sintasas D2, E2 y I2, y en los receptores DP1, EP2,4 y IP, que poseen
diversas funciones fisiológicas, entre las cuales está la vasodilatación vascular pulmonar.
La hipótesis experimental es que melatonina pre y post natal aumentará las vías de
prostaglandinas vasodilatadoras en pulmón de corderos crónicamente hipóxicos por altitud. Como
modelo experimental se utilizaron ovejas gestadas y nacidas en altura (3600 m de altitud), en
hipoxia crónica separadas en tres grupos con diferentes tratamientos: melatonina prenatal (último
tercio de gestación a la oveja gestante), melatonina postnatal (primeros 10 días al recién nacido), y
el grupo control con tratamiento de vehículo. Se evaluó tejido pulmonar neonatal para determinar
el patrón de expresión de las prostaglandinas mencionadas, además de la inmuno–localización de
los receptores prostanoides vasodilatadores más relevantes.
Este estudio demostró que existe un aumento de prostanoides vasodilatadores con el
tratamiento pre natal, y en menor medida con la administración post natal de melatonina. Este
estudio es un aporte en la búsqueda de un tratamiento para prevenir o tratar la HPN.
Chronic hypoxia affects more than 140 million people living on the 2,500 meters. This condition induces cardiopulmonary responses in perinatal life that can determine a frame of pulmonary hypertension of the newborn (HPN). HPN is characterized by a high vasoconstrictor response, a diminished vasodilator function, a proliferation of smooth muscle cells (SMC) and a thickening of the extracellular matrix in the pulmonary circulation. It has been proposed that one of the mechanisms responsible during hypoxia is the excessive generation of reactive oxygen species (ROS) and the presence of oxidative stress. Therefore, it has been proposed pre and postnatal treatments with melatonin, considering that this hormone has potent antioxidant properties through neutralization of ROS, activation of antioxidant enzymes, a negative modulation of pro-oxidants and as a vasodilator agent. Prostaglandins are derived from the metabolism of arachidonic acid (AA) and are important regulators of the pulmonary vascular tone, having vasoconstrictor pathways such as thromboxane (TX) and vasodilator mechanisms such as prostacyclin (PGI2). Currently, it is unknown whether these pathways respond to a treatment with melatonin in the neonatal lung. Therefore, in this work, the vasodilator prostaglandins pathways were analyzed, focusing on cyclooxygenases (COX), prostaglandin synthases D2, E2 and I2, and the receptors DP1, EP2,4 and IP, which have various physiological functions, among them vascular pulmonary vasodilation. The hypothesis is that pre and post natal administration of melatonin increases prostaglandin pulmonary pathways tending vasodilatation in chronically hypoxic lambs at altitude. The experimental model were sheep gestated and born at high altitude (3600 m) chronic hypoxia, divided into three groups with different treatments: prenatal melatonin (last third of gestation to pregnant sheep), postnatal melatonin (first 10 days of life), and control (vehicle treated group). Neonatal lung tissue was evaluated for the expression of the mentioned prostaglandins-associated proteins, plus immuno-localization of the relevant vasodilator synthases and receptors. This study shows that there is an increase in the prostanoids vasodilator pathway in the pre natal treatment with melatonin. However, the effects of postnatal administration of melatonin are milder. This study is a contribution in the search for a treatment to prevent or treat HPN.
Chronic hypoxia affects more than 140 million people living on the 2,500 meters. This condition induces cardiopulmonary responses in perinatal life that can determine a frame of pulmonary hypertension of the newborn (HPN). HPN is characterized by a high vasoconstrictor response, a diminished vasodilator function, a proliferation of smooth muscle cells (SMC) and a thickening of the extracellular matrix in the pulmonary circulation. It has been proposed that one of the mechanisms responsible during hypoxia is the excessive generation of reactive oxygen species (ROS) and the presence of oxidative stress. Therefore, it has been proposed pre and postnatal treatments with melatonin, considering that this hormone has potent antioxidant properties through neutralization of ROS, activation of antioxidant enzymes, a negative modulation of pro-oxidants and as a vasodilator agent. Prostaglandins are derived from the metabolism of arachidonic acid (AA) and are important regulators of the pulmonary vascular tone, having vasoconstrictor pathways such as thromboxane (TX) and vasodilator mechanisms such as prostacyclin (PGI2). Currently, it is unknown whether these pathways respond to a treatment with melatonin in the neonatal lung. Therefore, in this work, the vasodilator prostaglandins pathways were analyzed, focusing on cyclooxygenases (COX), prostaglandin synthases D2, E2 and I2, and the receptors DP1, EP2,4 and IP, which have various physiological functions, among them vascular pulmonary vasodilation. The hypothesis is that pre and post natal administration of melatonin increases prostaglandin pulmonary pathways tending vasodilatation in chronically hypoxic lambs at altitude. The experimental model were sheep gestated and born at high altitude (3600 m) chronic hypoxia, divided into three groups with different treatments: prenatal melatonin (last third of gestation to pregnant sheep), postnatal melatonin (first 10 days of life), and control (vehicle treated group). Neonatal lung tissue was evaluated for the expression of the mentioned prostaglandins-associated proteins, plus immuno-localization of the relevant vasodilator synthases and receptors. This study shows that there is an increase in the prostanoids vasodilator pathway in the pre natal treatment with melatonin. However, the effects of postnatal administration of melatonin are milder. This study is a contribution in the search for a treatment to prevent or treat HPN.
Notas
Tesis (Magíster en Biotecnología)
Proyectos Fondecyt 1110595, 1130801, 1151119.
Proyectos Fondecyt 1110595, 1130801, 1151119.
Palabras clave
Anoxia en Animales, Melatonina, Corderos, Enfermedades