• Langue : Français
• Discipline : Pédiatrie
• Identifiant : 2017LIL2S003
• Type de thèse : Doctorat
• Date de soutenance : 20/03/2017

Résumé en langue originale

L’adaptation à la vie extra-utérine requiert la résorption rapide du liquide pulmonaire, la création de la capacité fonctionnelle résiduelle (FRC), ainsi que l’augmentation du débit pulmonaire. Bien que ces mécanismes aient été largement étudiés, leurs cinétiques restent mal connues faute de méthode d’étude non invasive in vivo. L’échec de l’adaptation cardiorespiratoire à la naissance est la principale cause de mortalité et de morbidité de la période néonatale, malgré l’utilisation de stratégie préventive comme la corticothérapie anténatale, et l’amélioration des techniques de réanimation néonatale. Les acides gras polyinsaturés oméga 3 (AGPI n3) que l’on retrouve dans les huiles de poisson ont des effets cardiovasculaires et respiratoires qui pourraient améliorer la transition périnatale. Par ailleurs, leurs propriétés anti-inflammatoires peuvent réduire les conséquences des effets iatrogènes des techniques de réanimation dont la mise en oeuvre est nécessaire en cas de maladaptation cardiorespiratoire à la naissance. Les objectifs de ce travail ont été de : Mettre au point et valider une méthode d’exploration de la cinétique de réabsorption du liquide pulmonaire à la naissance par résonnance magnétique nucléaire Etudier les effets des AGPI n3 sur : l’adaptation ventilatoire à la naissance la circulation pulmonaire périnatale la prévention des lésions pulmonaires induites par une hyperoxie prolongée Les études ont été réalisées sur les modèles expérimentaux de foetus de brebis et de ratons nouveau-nés exposés à une hyperoxie prolongée. Nous montrons que la technique par IRM permet d’évaluer la cinétique de clairance du liquide pulmonaire in vivo en situations physiologique et pathologique. Alors que les AGPI n3 améliorent la circulation pulmonaire, ils n’ont pas d’effet sur la clairance du liquide pulmonaire. Par contre, ils réduisent les lésions pulmonaires induites par l’oxygène. Ces résultats expérimentaux suggèrent que les AGPI n3 pourraient prévenir les échecs d’adaptation cardiorespiratoire à la naissance et ses conséquences à long terme.

Résumé traduit

Perinatal transition requires clearance of pulmonary fluid, creation of functional respiratory capacity (FRC), and the multiplication of pulmonary blood flow by ten, to ensure gas exchange and blood oxygenation. Physiology of perinatal transition has been broadly studied but the kinetics of its evolution is less known. The aim of our study was to assess the kinetics of the respiratory transition. Besides, we supposed that polyunsaturated fatty-acids omega 3 (n3 PUFA) would improve this transition. To study the kinetic of respiratory transition, we used the MRI in 3 groups of lambs: premature group (Preterm) with a term of 122-124 days, two groups of late preterm lambs (134-136 days), including one group who received antenatal steroids (Late preterm + steroids), and a group without steroids (Late preterm). Surprisingly, we observed a rapid increase of lung fluid in preterm lambs reaching 30% at the end of the experimentation. Creation of FRC was also impaired in this group. In the Late preterm group, clearance of pulmonary fluid was slowed down with a moderate fall of 10%, whereas, in the Late preterm + steroids group, lung fluid dropped by 50% (p<0.05). Similarly, FRC in the Late preterm + steroids group was higher than the other 2 groups (p <0.05). Respiratory functions were closely related to lung fluid content and to FRC. We hypothesized that n3 PUFA would improve perinatal transition using two models: - An acute model: in a chronically instrumented model, catheters were introduced in the jugular and the carotid vessels of lamb fetuses at 122 days of gestation. Lamb fetuses received either Omegaven (n3 PUFA), or Intralipide (n6 PUFA), or isotonique physiological serum (SSI) for 4 days. Respiratory transition was explored by MRI. There was no significant difference between these three groups. Total lung fluid increased by about 20% in Omegaven group and 18% in SSI group (p> 0.05). - A model of Bronchopulmonary dysplasia: pups were exposed to hyperoxia for 10 days, and feeding rats received supplementation by either n3 PUFA (Omacor), n6 PUFA (sunflower oil), or SSI, with control groups that received the same feeding supply but which were exposed to air. Histological studies showed bronchopulmonary dysplasia lesions in the Hyperoxia groups, characterized by decrease of alveolar number, decrease in the number of secondary alveolar septa, and widening of the interstitial space. These lesions were similar in SSI and n6 PUFA groups, whereas n3 PUFA improved these lesions (p <0.05). To assess the effects of n3 PUFA in pulmonary vascular resistances (PVR), we studied their effects on fetal circulation characterized by elevated RVP using a chronically instrumented experimental model of lamb fetus. Lamb fetuses received either n3 PUFA (Omegaven), or n6 PUFA (Intralipid). We then explored the action mechanisms of n3 PUFA: 1) NO pathway using L-Nitro Argenine (LNA), 2) potassium channels pathway using Tetraethylamonium (TEA) and 3) epoxides produced by cytochrome P450 using MS-PPOH. Finally, we investigated the effect of Eicosapentaenoic Acid (EPA) perfusion, or Docosahexaenoic Acid (DHA) perfusion in pulmonary circulation. We showed that, unlike Intralipid, Omegaven induced pulmonary vasodilation, and an increase in pulmonary flow. An identical effect was reproduced by EPA infusion, while DHA did not modify PVR. This response was not modified by LNA. But it was reduced by MS-PPOH, and abolished by TEA. These results indicate that n3 PUFA induced pulmonary vasodilation, mediated by epoxides which act on potassium channels. To conclude, we demonstrated that respiratory transition in preterm lambs even in late preterm ones is altered with the presence of pulmonary edema. n3 PUFA did not improve lung fluid clearance but should be considered in the tretment of pulmonary hypertension, and in the prevention of brochopulmonary dysplasia of the newborns.