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Rôle De La Phosphodiestérase Spécifique De L'ampc (PDE4) Dans

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Rôle De La Phosphodiestérase Spécifique De L'ampc (PDE4) Dans Faculté de pharmacie UMR-CNRS 7213 laboratoire de Biophotonique et de pharmacologie, Université de Strasbourg Département de Physiologie et Biophysique, Université de Sherbrooke Rôle de la pho sphodiestérase spécifique de l’AMPc (PDE4) dans deux modèles d’inflammation chronique : le lupus érythémateux disséminé et l’asthme . Thèse présentée à Ecole Doctorale des Sciences de la Vie et de la Santé de Strasbourg en vue de l’obtention du grade de docteur es science en pharmacologie moléculaire, et à la Faculté de médecine et des sciences de la santé en vue de l’obtention du grade de Philosophiae Doctor (Ph.D.) en Physiologie Par YOUGBARE Issaka 20 Décembre 2010 Composition du Jury : Présidente du Jury : Pr Valérie SCHINI-KERTH, Université de Strasbourg, France Rapporteurs externes : Pr Jean- Pierre SAVINEAU, Université Victor Ségalen Bordeaux 2, France Pr Manuel-Campos TOIMIL, Universidade de Santiago de Compostela, Espagne Co-directeurs de thèses : Dr Claire LUGNIER, co-directeur de thèse, Université de Strasbourg, France Pr Eric ROUSSEAU, Co-directeur de thèse, Université de Sherbrooke, Canada SOMMAIRE REMERCIEMENTS ................................................................................................................ 5 Listes des Manuscrits pour publications ................................................................................ 6 Listes des Communications à des congrès internationaux ................................................... 6 Liste des abréviations ............................................................................................................... 7 Préambule .............................................................................................................................. 10 I) INTRODUCTION .......................................................................................................... 13 I.1. La superfamille des phosphodiestérases des nucléotides cycliques............................... 13 I.1.1 Les nucléotides cycliques ............................................................................................ 13 I.1.1.1 L’AMPc et ces cibles intracellulaires ...................................................................... 15 I.1.1 .1.1 La protéine kinase A dépendante de l’AMPc ....................................................... 16 I.1.1.1.2 Les « Exchange Proteins Activated by cAMP » .................................................... 18 I.1.1.1.3 Les canaux ioniques régulés par les nucléotides cycliques.................................... 19 I.1.1.2 Le GMPc et ses cibles cellulaires ............................................................................. 20 I.1.1.2.1 Les Protéines kinases G ......................................................................................... 22 I.1.1.2.2 Les effets de la PKA et PKG sur la relaxation du muscle lisse ............................ 23 I.1.2 Les phosphodiestérases des nucléotides cycliques ...................................................... 24 I.1.2.1 Structures comparatives et nomenclature des PDEs ................................................. 25 I.1.2.2 Les différentes familles de PDEs et leurs rôles physiologiques. .............................. 29 I.1.2.2.1 La famille des phosphodiestérases de type 1 (PDE1) ............................................ 29 I.1.2.2.2 La famille des phosphodiestérases de types 2 (PDE2): ......................................... 32 I.1.2.2.3 La famille des PDE3: ............................................................................................. 33 I.1.2.2.4 La famille des PDE4 .............................................................................................. 34 I.1.2.2.4.1 Structure et activités hydrolytiques des PDE4s .................................................. 34 I.1.2.2.4.2 Compartimentalisation l’AMPc et intereactome des PDE4s .............................. 35 I.1.2.2.4.3 Inhibition des PDE4s et leurs régulations à court et long terme ......................... 37 I.1.2.2.4.4 Les inhibiteurs de PDE4s en cours de développement ....................................... 39 I.1.2.2.5 Les familles de PDE5 ............................................................................................. 41 I.1.2.2.6 Les familles de PDE6 à PDE11 ............................................................................. 41 I.2 Gén éralités sur l’inflammation chronique ....................................................................... 42 I.2.1 Revue de la littérature sur 2 modèles d’inflammations chroniques ............................. 45 I.2.1.1 Le lupus érythémateux disséminé (LED) ................................................................. 45 I.2.1.1.1 Manifestations cliniques du LED ........................................................................... 45 I.2.1.1.2 Physiopathologie du lupus ..................................................................................... 46 I.2.1.2 Anatomie fonctionnelle et physiologie du système urinaire ..................................... 50 I.2.1.3 Les atteintes rénales au cours du lupus : ................................................................... 52 I.2.1.4 Collaboration scientique entre l’ équi pe de C. LUGNIER et E. ROUSSEAU ......... 54 I.2.2 L’asthme ...................................................................................................................... 55 I.2.2.1 Anatomie fonctionnelle de l’appareil respiratoire .................................................... 55 I.2.2.2 Les maladies inflammatoires chroniques des systèmes respiratoires : asthme, la .... 58 1 I.3 Justification de la problématique de recherche ............................................................... 61 I.4 But et objectifs de recherche ........................................................................................... 64 I.4.1 Objectifs spécifiques dans le cas du lupus ................................................................... 64 I.4.2 Objectifs spécifiques dans le cas de l’asthme .............................................................. 64 II) MATERIEL AND METHODES ..................................................................................... 65 II.1 Animaux et traitements .................................................................................................. 65 II.2 Préparation des extraits tissulaires (protéines) et des ARN totaux .............................. 66 II.3 Dosages radio-enzymatiques des activités PDEs .......................................................... 66 II.4 Techniques de Western blot .......................................................................................... 68 II.5 Techniques Real-Time PCR .......................................................................................... 69 II.6 Techniques d’immuno -histochimie ............................................................................... 70 II.7 Fractionnement subcellulaire du parenchyme ............................................................... 71 II.8 Protocole de test de prolifération de cellules A549 ...................................................... 71 II.9 Cultures cellulaires et cultures organoïdes des tissus pulmonaires ............................... 72 II.10 Cultures organoïdes des tissus pulmonaires. ............................................................... 74 II.11 Mesures de tension mécanique en bain d’o rgane isolé ................................................ 74 III) RESULTATS ................................................................................................................... 77 III.1 Manuscrit 1: Disease progression in MRL/lpr lupus-prone mice is reduced by a specific PDE4 inhibitor ........................................................................................................ 77 III.2 Manuscrit 2 : Effect of NCS 613, a specific PDE4 inhibitor, on cAMP, PDE4s regulations and on immune complexes in kidney from MRL/lpr lupus- prone mice. ....... 100 III.3 Manuscrit: Cyclic GMP catabolism up-regulation in MRL/lpr lupus prone mice is associated to organ remodeling. ......................................................................................... 129 III.4 Manuscrit 4 : NCS 613, a potent and specific PDE4 inhibitor, displays anti- inflammatory effects on human lung tissues (soumis AJP). .............................................. 154 III.5 Résultats complémentaires de manuscrit ................................................................... 182 III.5.1 Effets anti-inflammatoires du NCS 613 sur les PBMC. .......................................... 183 III.5.2 Effets antiprolifératifs du NCS 613 sur les cellules d’adénocarcinome A549 ........ 185 III.5.3 Effets anti-inflammatoires du NCS 613 sur les cellules A549 et les explants d’adénocarcinome pulmonaire humaine. ........................................................................... 188 III. 5.4 Bilan des résultats complémentaires ...................................................................... 189 IV. DISCUSSION GENERALE .......................................................................................... 190 IV.1 Implication des PDE4 dans l’inflammation chron ique. ............................................. 190 IV.2. Effets biologiques du traitement par le NCS 613: .................................................... 193 IV.2.1 Effets biologiques du NCS 613 au niveau systémique dans les PBMC. ................ 193 IV.2.2 Effets biologiques du NCS 613 au niveau tissulaire ..............................................
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