Laouafa Sofien, Perrin-Terrin Anne-Sophie, Jeton Florine, Elliot-Portal Elizabeth, Tam Rose, Bodineau Laurence, Voituron Nicolas, Soliz Jorge
Université Laval, Faculté de Médecine, Centre de Recherche Institut universitaire de cardiologie et de pneumologie de Québec, Département de Pédiatrie, Québec, QC, Canada; LEHNA, UMR CNRS 5023, Ecologie des Hydrosystèmes Naturels et Anthropisés, Université de Lyon, Université Lyon 1, ENTPE, 6 rue Raphael Dubois, 69622 Villeurbanne, France.
Université Paris 13, Sorbonne Paris Cité, UFR SMBH, Laboratoire "Hypoxie et poumons", EA 2363, 93017 Bobigny, France; Sorbonne Universités, UPMC Univ Paris 06, INSERM, UMR_S1158 Neurophysiologie Respiratoire Expérimentale et Clinique, F-75013, Paris, France.
Respir Physiol Neurobiol. 2017 Aug;242:73-79. doi: 10.1016/j.resp.2017.04.003. Epub 2017 Apr 8.
Cerebral erythropoietin (Epo) plays a crucial role for respiratory control in newborn rodents. We showed previously that soluble Epo receptor (sEpoR: an Epo antagonist) reduces basal ventilation and hypoxic hyperventilation at postnatal day 10 (P10) and in adult mice. However, at these ages (P10 and adulthood), Epo had no effect on central chemosensitivity. Nevertheless, it is known that the sensitivity to CO/H during the mammalian respiratory network maturation process is age-dependent. Accordingly, in this study we wanted to test the hypothesis that cerebral Epo is involved in the breathing stimulation induced by the activation of central CO/H chemoreceptors at earlier postnatal ages. To this end, en bloc brainstem-spinal cord preparations were obtained from P4 mice and the fictive breathing response to CO-induced acidosis or metabolic acidosis was analyzed. This age (P4) was chosen because previous research from our laboratory showed that Epo altered (in a dose- and time-dependent manner) the fictive ventilation elicited in brainstem-spinal cord preparations. Moreover, as it was observed that peripheral chemoreceptors determined the respiratory sensitivity of central chemoreceptors to CO, the use of this technique restricts our observations to central modulation. Our results did not show differences between preparations from control and transgenic animals (Tg21: overexpressing cerebral Epo; Epo-TAg: cerebral Epo deficient mice). However, when Tg21 brainstem preparations were incubated for 1h with sEpoR, or with inhibitors of ERK/Akt (thus blocking the activation of the Epo molecular pathway), the fictive breathing response to CO-induced acidosis was blunted. Our data suggest that variation of the Epo/sEpoR ratio is central to breathing modulation during CO challenges, and calls attention to clinical perspectives based on the use of Epo drugs at birth in hypoventilation cases.
脑源性促红细胞生成素（Epo）在新生啮齿动物的呼吸控制中起着关键作用。我们之前的研究表明，可溶性Epo受体（sEpoR：一种Epo拮抗剂）可降低出生后第10天（P10）和成年小鼠的基础通气量和低氧性通气过度。然而，在这些年龄段（P10和成年期），Epo对中枢化学敏感性没有影响。尽管如此，已知在哺乳动物呼吸网络成熟过程中对CO/H的敏感性是年龄依赖性的。因此，在本研究中，我们想检验这样一个假设，即脑源性Epo参与出生后早期由中枢CO/H化学感受器激活所诱导的呼吸刺激。为此，从P4小鼠获取了整体脑干 - 脊髓标本，并分析了对CO诱导的酸中毒或代谢性酸中毒的模拟呼吸反应。选择这个年龄（P4）是因为我们实验室之前的研究表明，Epo（以剂量和时间依赖性方式）改变了脑干 - 脊髓标本中诱发的模拟通气。此外，由于观察到外周化学感受器决定了中枢化学感受器对CO的呼吸敏感性，使用这种技术使我们的观察仅限于中枢调节。我们的结果未显示对照动物和转基因动物（Tg21：脑源性Epo过表达；Epo - TAg：脑源性Epo缺陷小鼠）的标本之间存在差异。然而，当将Tg21脑干标本与sEpoR或ERK/Akt抑制剂孵育1小时（从而阻断Epo分子途径的激活）时，对CO诱导的酸中毒的模拟呼吸反应减弱。我们的数据表明，在CO刺激期间，Epo/sEpoR比值的变化是呼吸调节的核心，并提请关注基于出生时在通气不足病例中使用Epo药物的临床前景。
