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Modulation Du Chémoréflexe Et De La Stabilité Respiratoire Par Les Récepteurs Nucléaires Et Membranaires De La Progestérone

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Modulation Du Chémoréflexe Et De La Stabilité Respiratoire Par Les Récepteurs Nucléaires Et Membranaires De La Progestérone Modulation du chémoréflexe et de la stabilité respiratoire par les récepteurs nucléaires et membranaires de la progestérone Thèse Ryma Boukari Doctorat en médecine expérimentale Philosophiæ doctor (Ph. D.) Québec, Canada © Ryma Boukari, 2018 Résumé La progestérone stimule le chémoréflexe ventilatoire et réduit l’occurrence des apnées. En revanche, ses mécanismes d’actions sont peu élucidés. Les récepteurs nucléaires (nPR) et les récepteurs membranaires (mPRs) de la progestérone de type α et β sont exprimés dans les centres respiratoires au niveau du tronc cérébral. En premier, nous avons postulé que la délétion des nPR chez la souris femelle (PRKO) affecte le chémoréflexe ventilatoire et augmente la fréquence des apnées durant le sommeil. Nos résultats ont montré que les nPR stimulent la réponse ventilatoire à l’hypercapnie et réduisent la fréquence des apnées post- soupirs durant le sommeil calme. Ensuite, nous avons postulé que le mPRα et le mPRβ modulent le chémoréflexe et la stabilité ventilatoire chez la souris adulte. La réduction de l’expression des récepteurs mPRβ ou le mPRα exprimés au niveau des centres de contrôle ventilatoire de la médulla oglongata a mis en évidence que ces récepteurs contribuent à la régulation du chémoréflexe ventilatoire. De plus, le mPRβ contribue à la stabilité respiratoire chez la souris adulte mâle et femelle. Enfin, nous avons postulé que la réduction de l’expression des nPR, mPRα ou le mPRβ dans le système nerveux central affecte le chémoréflexe et la stabilité ventilatoire chez des rats de 10 jours de vie. Nos résultats ont indiqué que le nPR et le mPRβ contribuent à la stabilité du patron ventilatoire chez le nouveau-né. Nous concluons que la progestérone signale par les récepteurs nPR, mPRα et le mPRβ pour réguler le chémoréflexe ventilatoire chez l’adulte. En outre, le nPR et le mPRb contribuent à la stabilité ventilatoire à la fois chez la souris adulte et le rat nouveau-né. Ces deux récepteurs pourraient être de nouvelles cibles thérapeutiques pour le traitement de l’apnée du sommeil chez l’adulte et l’apnée du nouveau-né. iii Abstract Progesterone stimulates the ventilatory chemorefelx and reduces the occurrence of apnea, but the mechanisms are not well understood. The nuclear (nPR) and membrane progesterone receptors (mPRs) sutypes α and β are expressed in the respiratory centers of the brainstem. First, we postulated that the nPR deletion in female mice (PRKO) affects ventilatory chemoreflex and increases the frequency of apnea during the quiet sleep. Our results showed that the nPR stimulate the ventilatory response to hypercapnia and reduce the frequency of post-sigh apneas during the quiet sleep. Next, we postulated that the mPRα and mPRβ modulate chemoreflex and ventilatory stability in adult mice. The reduction of the expression of the mPRβ or the mPRα, expressed at the level of the ventilatory control centers at the level of the medulla oblongata, has demonstrated that these receptors contribute to the regulation of the ventilatory chemoreflex. In addition, mPRβ contributes to respiratory stability in male and female adult mice. Finally, we have postulated that reduced expression of the nPR, mPRα, or mPRβ in the central nervous system affects chemoreflex and ventilatory stability in 10-day-old rats. Our results indicated that the nPR and mPRβ contribute to the stability of the ventilatory pattern in neonates. We conclude that progesterone signals via nPR receptors, mPRα and mPRβ to regulate ventilatory chemorefelx in adults. In addition, nPR and mPR contribute to ventilatory stability in both adult mice and neonatal rats. These two receptors could be new therapeutic targets for the treatment of sleep apnea in adults and apnea of the newborn. iv Tables des matières Résumé .............................................................................................................................................. iii Abstract .............................................................................................................................................. iv Tables des matières ............................................................................................................................. v Liste des figures ................................................................................................................................... x Liste des tableaux ............................................................................................................................. xiii Liste des abréviations et des sigles .................................................................................................... xiv Remerciements ................................................................................................................................xvii Avant-propos .................................................................................................................................... xix ................................................................................................................ 1 Introduction ............................................................................................................ 1 Introduction générale ................................................................................................ 2 La fonction respiratoire chez les mammifères ............................................................ 4 La fonction respiratoire .................................................................................................4 La ventilation pulmonaire....................................................................................................... 4 Échanges gazeux et circulation ............................................................................................... 5 La respiration cellulaire .......................................................................................................... 6 La physiologie du chémoréflexe ventilatoire chez les mammifères ...............................8 Le chémoréflexe périphérique ................................................................................................ 8 Le chémoréflexe central ....................................................................................................... 14 Les mécanorécepteurs ................................................................................................. 21 Intégration centrale et genèse de la commande ventilatoire motrice ......................... 21 Intégration des afférences sensorielles respiratoires ............................................................ 21 Genèse du rythme et de la commande ventilatoire motrice .................................................. 24 La physiopathologie de l’apnée du sommeil chez l’adulte ....................................... 26 Définition de l’apnée du sommeil (AS) ........................................................................ 26 Les types de l’AS .......................................................................................................... 28 L'apnée obstructive du sommeil (AOS) ................................................................................. 28 L'apnée centrale du sommeil (ACS) ...................................................................................... 28 L’apnée mixte ...................................................................................................................... 31 Épidémiologie et le dimorphisme sexuel de l’AS ......................................................... 31 Conséquences pathologiques de l’AS .......................................................................... 32 Les mécanismes physiopathologiques de l’AS ............................................................. 33 Obstruction des voies aériennes supérieures (VAS) .............................................................. 34 Mécanisme de l’apnée centrale ............................................................................................ 44 Les approches thérapeutiques disponibles .................................................................. 51 L’impact de la progestérone sur la fonction respiratoire chez les mammifères ....... 52 Généralités sur la progestérone .................................................................................. 52 Définition de la progestérone ............................................................................................... 52 Les voies de la biosynthèse et le métabolisme de la progestérone ........................................ 53 v Le lieu de la biosynthèse de la progestérone ........................................................................ 53 Taux de la progestérone chez le mâle et la femelle (humains et rongeurs) : .......................... 56 Actions pléiotropiques de la progestérone ........................................................................... 58 Effet de la progestérone sur le contrôle ventilatoire chez l’adulte .............................. 58 La ventilation chez la femelle et le mâle : Le dimorphisme sexuel ......................................... 58 Impact de la progestérone sur la fonction respiratoire.......................................................... 60 Les mécanismes expliquant les effets respiratoires de la progestérone ................................. 65 La pathophysiologie de l’apnée du nouveau-né ....................................................... 75 La définition de l’apnée du nouveau-né .....................................................................
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