Niveles de sustancia P en sangre de cordón umbilical en neonatos a término

• Autores: Inmaculada Bueno Rodríguez
• Directores de la Tesis: Miguel Muñoz Sáez (dir. tes.), Antonio Pavón Delgado (dir. tes.), María Luisa Rosso González (dir. tes.), Juan Carlos Crespo de la Rosa (tut. tes.)
• Lectura: En la Universidad de Sevilla ( España ) en 2014
• Idioma: español
• Tribunal Calificador de la Tesis: Antonio Ayala Gómez (presid.), María Mercedes Cano Rodríguez (secret.), José Bernabéu Wittel (voc.), Nieves Respaldiza (voc.), J. A. Soult Rubio (voc.)
• Materias:
  • Ciencias médicas
    • Ciencias clínicas
      • Pediatría
• Texto completo no disponible (Saber más ...)
• Resumen

  • INTRODUCCIÓN La SP se une a receptores específicos RNK-1 y desarrolla funciones proinflamatorias, por lo que es esperable que desempeñe un papel relevante en la corioamnionitis, en el síndrome inflamatorio fetal, en la inducción del parto prematuro, la hipertensión en el embarazo y consecuentemente en la morbimortalidad neonatal asociada.

    Para iniciar el estudio de la intervención de este neuropéptido en dichos procesos, nos encontramos con el desconocimiento actual de los valores ¿normales¿ o ¿fisiológicos¿ en la sangre de cordón de neonatos a término sanos. El conocer los valores de SP en sangre en recién nacidos sanos nos permitiría tener una referencia con la que compararlos en caso de patología. La evaluación de antagonistas de SP/RNK-1 como agentes terapéuticos y el uso como marcador de la SP para monitorizar los procesos inflamatorios enfatizan la necesidad de contar con métodos exactos en la medición de la SP en plasma o en suero con un alto nivel de precisión, sensibilidad y reproductibilidad (Campbell DE et al. 2006).

    Los niveles de SP en sangre de cordón podrían utilizarse con ventajas sobre los de IL-6 en el diagnóstico precoz de la corioamnionitis y el síndrome inflamatorio fetal, ya que la activación de la SP se produce antes que la de la referida IL-6.

    En nuestro conocimiento, aún no ha sido abordado el estudio de los valores normales de SP en sangre de cordón del neonato mediante la técnica de enzimoinmunoanálisis (ELISA).

    En esta ocasión pretendemos determinarlos mediante la técnica de ELISA y en una muestra representativa que permita la obtención de valores fiables definitivos a partir de los cuales basar futuras investigaciones.

    La disponibilidad de antagonistas selectivos de los RNK-1, del tipo no peptídico, abre la posibilidad de bloquear los efectos de la SP en la práctica clínica, si se llegara a probar que esta juega un papel relevante en los procesos referidos.

    DESARROLLO TEÓRICO OBJETIVOS Determinar los niveles normales de SP en sangre de cordón umbilical de recién nacidos a término sanos y sin aparentes malformaciones. Estudio observacional descriptivo.

    POBLACIÓN DE ESTUDIO Recién nacidos sanos y sin aparentes malformaciones cuyo parto haya ocurrido a término (entre las 37 y 41 semanas de gestación), descartando corioamnionitis de la placenta por anatomía patológica, con el consentimiento previo otorgado por sus representantes legales y cuyos criterios de exclusión son los mencionados en el apartado de material biológico.

    ASPECTOS ÉTICOS DE LA INVESTIGACIÓN Estudio sujeto a los principios adoptados por la 18ª Asamblea Médica Mundial (Helsinki, 1964) y posteriores revisiones. Se han seguido las normas de Buena Práctica Clínica dictadas por la Conferencia Internacional de Armonización de Directrices sobre Buena Práctica Clínica y los requisitos de las Autoridades Sanitarias Españolas establecidos en el Real Decreto 711/2002 de 19 de Julio. El consentimiento informado de los sujetos o representantes legales fueron obtenidos, tras haber sido informados tanto por escrito como oralmente de los objetivos del estudio, procedimientos a seguir, derechos y responsabilidades. Los sujetos del estudio se identificaron mediante código único de manera confidencial. Se ha cumplido lo estipulado por la Ley Orgánica 15/1999 de 13 de diciembre de Protección de Datos de Carácter Personal.

    RECOGIDA DE MUESTRAS Las muestras de sangre se recogen de la placenta, de la cara fetal, inmediatamente después de su alumbramiento. Se realiza mediante punción y aspiración con jeringa de 5 ml de venas placentarias.

    A continuación se transfieren a microtainers, sin EDTA y sin heparina de sodio, que contienen 500UI de aprotinina (agente hemostático que inhibe las proteasas) por cada ml de sangre de muestra fetal que se obtiene y posteriormente se centrifugan a 1500 rpm y 4ºC durante 15 minutos.

    Una vez obtenido el suero, se preparan en alícuotas de 250 ¿l en tubos de ependorff de 1,8 ml y tras su correcta identificación se mantienen congeladas a -80ºC hasta su procesamiento.

    MÉTODO DE PURIFICACIÓN DE LAS MUESTRAS DE SANGRE DE CORDÓN Acidificar las muestras Coger 250 ¿l de suero descongelado a temperatura ambiente y añadir ácido acético al 4% para diluirlo a ¿ consiguiendo un volumen total de 1000 ¿l, posteriormente homogeneizar la muestra vorteando durante un par de minutos e identificar la misma.

    Preparar, equilibrar, añadir y recoger las muestras a través de las columnas C 18 SPE 200 mg.

    Equilibrado de las columnas C18 SPE 200 mg Equilibrar las columnas C18 SPE 200 mg colocadas en la parte superior del Visiprep DL Disposable Liner Spe Vacuum Manifold además de los tubos de precipitado de cristal de 15 ml en la parte inferior del Visiprep. Hacer pasar a través de ellas 3 ml de acetonitrilo puro, seguido de 9 ml de ácido trifluoroacético al 1%. No dejar nunca secar las columnas C18 SPE 200 mg. Decantar el sobrenandante de los tubos de cristal de 15 ml y recolocarlos de nuevo en su mismo lugar.

    Verter la muestra previamente acidificada. Pasar lentamente los 1000 ¿l (volumen total) de la muestra ya acidificada por las C18 SPE 200 mg y añadir inmediatamente 3 ml de ácido Trifluoracético al 1% tres veces a través de las columnas sin dejarlas secar y dejar caer por gravedad, decantar nuevamente el sobrenadante de los tubos de cristal de 15 ml.

    Recogida del eluyente de las muestras. Cambiar los tubos de cristal de precipitado de 15 ml por criotubos de 3,6 ml en la parte inferior del Visiprep DL Disposable Liner Spe Vacuum Manifold para la recogida del eluyente de las columnas que se obtiene al pasar la mezcla de acetonitrilo y ácido trifluoracético al 1% (60/40), pasando de ml en ml hasta 2 ml en total.

    SECADO DE LAS MUESTRAS Las muestras ya eluidas en los criotubos de 3,6 ml pasan a ser secadas en el Evac-Orac system con flujo de nitrógeno a temperatura ambiente. Una vez secada la muestra se guarda a -80ºC hasta la elaboración del kit para SP por enzimoinmunoanálisis (ELISA).

    REALIZACIÓN DE ENZIMOINMUNOANÁLISIS (ELISA) Contenido del kit de elisa para determinación de SP - 1 vial para 100 determinaciones (dtn) de antisuero de SP.

    - 1 vial para 100 determinaciones de SP unida a acetilcolinesterasa.

    - 1 vial de SP en polvo para la curva estándar.

    - 2 viales de 10 ml de buffer para ELISA para concentración de 10X.

    - 1 vial de 5 ml de buffer de lavado de 400X.

    - 1 vial de 3 ml de Tween 20.

    - Placa de 96 pocillos cubiertos de anticuerpos Ig G contra conejo creado en ratón.

    - 1 cubre de placa de 96 pocillos.

    - 3 viales para 100 dtn de Reactivo Ellman¿s (sustrato de la acetilcolinesterasa).

    Descripción del enzimoinmunoanálisis de competición para la SP Este ensayo esta basado en un mecanismo de competición entre la SP libre y la SP marcada o conjugada con acetilcolinesterasa (SP AchE). Ambas compiten por el sitio de unión de los anticuerpos específicos contra la SP de conejo que se encuentran en los 96 pocillos.

    Mientras la concentración de SP conjugada se mantiene constante, la concentración de SP libre varia, la cantidad de SP conjugada que es capaz de unirse al antisuero de conejo, será inversamente proporcional a la concentración de SP libre que haya en el pocillo. El complejo antisuero de conejo-SP se une a los anticuerpos monoclonales de conejo hecho en ratón que se encuentran unido al fondo del pocillo. La placa es lavada para remover los reactivos no unidos y se añade el reactivo Ellman¿s (el cual contiene el sustrato de la acetilcolinesterasa) que es añadido al pocillo. El producto de esta reacción enzimática emite un color amarillo a una lectura de absorbancia de aproximadamente de 412 nm determinado espectrofotométricamente, la cuál es proporcional a la cantidad de SP conjugada con acetilcolinesterasa unida al pocillo e inversamente proporcional a la cantidad de SP libre presente en el pocillo (Ver figura 35).

    Absorbancia = Sustancia P conjugada con acetilcolinesterasa unida = 1/ sustancia P libre Preparación de los reactivos Preparación de la solución Buffer del ELISA. Diluir todo el contenido del vial del Buffer para conseguir una dilución a concentración 10X, añadiendo a dicho vial, 90 ml de agua ultrapura, homogenizar el vial y evitar que precipiten sales en el fondo del mismo.

    Preparación del Buffer de lavado. Diluir el vial de 5 ml de lavado a concentración 400X, hasta un total de 2 l con agua ultrapura y añadir 1 ml de Tween 20.

    Preparación del reactivo de Ellman. Reconstituirlo inmediatamente antes de su uso. Añadir 20 ml de agua ultrapura al vial del reactivo cantidad suficiente para los 96 pocillos.

    Preparación curva de SP estándar. Reconstituir la SP estándar con 2 ml de Buffer para ELISA. La concentración de esta disolución será de 5 ng/ml. Conservar esta solución a 4ºC y permanecerá estable durante 6 semanas. Para preparar la curva estándar hay que coger 8 tubos limpios y numerarlos del 1 al 8. Alicuotar 900 ¿l del buffer de ELISA para el tubo 1 y 500 ¿l para los tubos del 2 al 8. Transferir 100 ¿l del tubo matriz o madre al tubo 1 y mezclar enérgicamente, diluir seriadamente el estándar, coger 500 ¿l del tubo 1 y añadirlo al tubo 2 mezclar enérgicamente y repetir de nuevo el proceso cogiendo 500 ¿l del tubo 2 y añadirlo al tubo 3, mezclar enérgicamente y repetir este proceso hasta el tubo 8 (último de la curva estándar).

    Preparación de la SP conjugada con acetilcolinesterasa. Reconstituir con 6 ml de buffer para ELISA para placas de 96 pocillos.

    Preparación del antisuero SP para ELISA. Reconstituir con 6 ml de buffer para ELISA para placas de 96 pocillos Reconstituir las muestras con buffer para ELISA. Reconstituir con buffer para ELISA con un volumen igual al volumen de la muestra original, es decir, con 250 ¿l y vortear enérgicamente para homogenizar las muestras antes del montaje de la placa.

    DESCRIPCIÓN DEL MONTAJE DE LA PLACA Cada placa debe contener dos pocillos con blanco (blank), dos pocillos de unión no especifica (NSB), dos pocillos de máxima unión (B0), uno de total actividad (TA) y cada puntos de la curva estándar por duplicado (Std), dos controles internos, control 1(Ctrl 1) correspondiente al valor de SP del estándar 1 y el control 2 corresponde al valor de SP del estándar 3 según indicaciones del fabricante. Cada muestra analizada debe ser realizado doblemente y diluida al medio con el buffer del ensayo.

    ADICIÓN DE LOS REACTIVOS Y DE LAS MUESTRAS A LA PLACA Añadir 100 ¿l del buffer del ensayo a los pocillos de unión no especifica (NSB). Añadir 50 ¿l del mismo buffer a los pocillos de máxima unión (Bo). Añadir 50 ¿l del tubo 8 (el punto de mas baja concentración del estándar) comenzando por abajo de la placa y por duplicado (S8), según tabla del montaje mas arriba expuesto y repetir el proceso con cada punto del estándar.

    Usar la misma punta de pipeta para alicuotar todos los puntos del estándar en la placa, asegurándose en cada punto una adecuada calibración de la pipeta.

    Añadir 50 ¿l de cada muestra a analizar por pocillo realizándolo por duplicado y cada muestra debe ser ensayada con un mínimo de una dilución y cada dilución debe ser ensayada por duplicado.

    Añadir 50 ¿l de SP conjugada con colinesterasa a cada pocillo excepto al de total actividad (TA) y a los pocillos blancos (Blk). Añadir 50 ¿l de antisuero de SP excepto al de total actividad (TA), a los de la unión no especifica (NSB) y a los blancos (Blk).

    Cubrir la placa con tapa de plástico e incubar a 4ºC sobre una placa orbital toda la noche.

    Posteriormente vaciar los pocillos y enjuagarlos 5 veces con el buffer de lavado. Luego reconstituir el reactivo Ellman¿s inmediatamente antes de su uso con 20 ml de agua ultrapura y añadir 200 ¿l de este reactivo a cada pocillo con la pipeta multicanal (como se muestra en la figura 37) y 5 ¿l de SP conjugada al pocillo de total actividad (TA). Cubrir nuevamente la placa con el film de plástico e incubar en la oscuridad sobre una placa orbital durante 90-120 minutos y leer la absorbancia a 405-420 nm con un espectrofotómetro. La reacción será optima cuando la absorbancia de los pocillos de máxima unión (Bo) menos la absorbancia del blanco (Blank) esté entre 0,3-1 UA (unidades de absorbancia) y en ese momento debe ser leída.

    La SP es el mediador y desencadenante principal de la repuesta inflamatoria, por lo que al conocer los valores normales en sangre, podríamos tener una referencia para valorar si están alterados dichos valores y usarlo para el diagnóstico precoz de los procesos patológicos de la gestación y el tratamiento apropiado de esta patología con la utilización de antagonistas de los RNK-1.

    El diagnóstico de corioamnionitis podría realizarse más precozmente si se llegara a conocer la activación de los mediadores que intervienen en el inicio propiamente del proceso inflamatorio. Por estos motivos, es importante conocer los niveles sanguíneos de SP en RN sin patología y en RN a término para que sirvan de referencia para la patología fetal y perinatal, ya que se ha demostrado en repetidos estudios que la SP se halla elevada en los procesos inflamatorios de diversa causa.

    La asociación significativa de la corioamnionitis clínica o histológica con la parálisis cerebral, sugiere que las estrategias clínicas para prevenir o reducir la corioamnionitis daría lugar a una reducción de la parálisis cerebral (Shatrov JG et al. 2010) y una mejor comprensión de los mecanismos de la lesión cerebral perinatal permitirá descubrimientos de nuevos agentes neuroprotectores y mejores resultados tras el parto prematuro (Burd I et al. 2012).

    Muñoz y colaboradores (2010a, 2013b) demostraron la expresión y distribución de la SP y de su RNK-1 en tejido placentario humano a término mediante técnicas inmunohistoquímicas, por lo que se demuestra que tanto la SP como su RNK-1 podrían estar implicados en diversos procesos fisiopatológicos relacionados con la placenta, como la corioamnionitis o la preeclampsia con los riesgos que estas patologías conllevan para el desarrollo adecuado del feto.

    Nosotros proponemos a la SP como biomarcador en la inflamación ya que la SP estimula la producción de interleuquinas a través de distintas vías, como la IL-6 y regula los procesos inflamatorios. Es el mediador principal de la inflamación peptidérgica, es decir, la inflamación neurogénica y la no neurogénica. Dentro del interés que suscita la molécula como posible iniciador y mediador inflamatorio, habría que destacar la disponibilidad de diferentes antagonistas selectivos de los RNK-1, del tipo no peptídico, los cuales son candidatos idóneos para bloquear los efectos de la SP en la práctica clínica, si se llegara a demostrar más adelante que efectivamente ésta desempeña un papel importante en los procesos inflamatorios que llevan al desencadenamiento del parto.

    CONCLUSIONES 1- La SP está presente en todas las muestras estudiadas en sangre de cordón de RN a término.

    2- El método ELISA es fiable para la determinación de la SP ya que no hay diferencias significativas entre los valores de dos muestras del mismo individuo en cincuenta casos.

    3- Los niveles de SP en sangre de cordón de RN a término se hallan en concentraciones pg/ml. Oscilando entre 264,14 pg/ml ± 86,93 (196 pmol/L ± 64,50) y 256,88 pg/ml ± 84,25 (190,90 pmol/L ± 62,51).

    4- Los niveles normales de SP en sangre de cordón de RN a término establecen las bases para estudiar las posibles correlaciones de los mismos con las diferentes patologías del neonato.

    5- En base a las implicaciones fisiopatológicas de la SP, en un futuro se podrá utilizar la misma en la práctica clínica como un biomarcador precoz de inflamación e infección y cuadros hipertensivos y más concretamente en la patología del embarazo.

    6- El posible uso de la SP como biomarcador, incluiría la posibilidad del uso de los antagonistas de los RNK-1 como intervención terapéutica. Debido a que la SP al unirse al RNK-1 regula múltiples funciones fisiopatológicas, al contrario, los antagonistas de los RNK-1 bloquean dichas funciones fisiopatológicas. Por lo tanto, se amplia el concepto de biomarcador clásico pues también incluiría el uso de estos como dianas terapéuticas al poder actuar sobre la SP, sobre las enzimas que la degradan y sobre el receptor RNK-1.

    7- Los niveles normales de SP en sangre de cordón ayuda a la comprensión de los fenómenos fisiológicos donde se halla implicada la SP. Y establece las bases para un futuro abordaje de la fisiopatología en los que está involucrada la SP.

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