DEVELOPMENTAL REGULATION OF HYPERCAPNIC RESPONSES

摘要早产儿呼吸暂停是临床上的一大问题，其病理生理机制。 人们对此知之甚少。在早产儿中，特别是那些有呼吸暂停的婴儿， 对高碳酸血症的呼吸反应受损：初步数据 显示高碳酸血症导致呼气持续时间延长， 与出生后早期低氧暴露时观察到的情况相似 生活。高碳酸血症引起的呼吸延长可被以下药物逆转 在我们的新生动物模型中，在缺氧时阻断GABAA受体 肾上腺素能受体减弱α2诱发的频率降低 拮抗剂应用于脑干。我们已经证明了 新生儿茶酚胺阳性细胞对球脊髓神经元的支配 大鼠脑干和球脊髓吸气的一个亚群 神经元表达GABAA受体。这项提议检验了这一假设 高碳酸血症调节呼吸计时和 出生后早期的吸气和呼气肌肉行为 发展。我们进一步假设二氧化碳诱导了细胞的激活。 中枢抑制系统，如GABA能和α2肾上腺素能 通路负责这些反应的成熟变化。 我们将给予脑池内注射GABAA和α2肾上腺素能阻滞剂 神经抑制通路在二氧化碳诱导中的作用 成年大鼠幼鼠的呼气延长。我们将利用新生儿 CO_2对仔猪胸壁和喉部影响的实验研究 肌肉在调节喉部阻力中的反应 呼吸计时。微量注射GABAA和α2肾上腺素能 脑干延髓神经元识别部位的阻滞剂 将使我们能够确定这些神经抑制通路的作用 在调节仔猪的呼吸计时方面。跨神经标记法 技术将与免疫组织化学相结合来表征 成熟幼鼠延髓神经元的连通性。我们 将描述GABAA和Alpha2的表达和激动剂亲和力 脑干吸气球脊髓神经元上的肾上腺素能受体 检验受体过度表达或激动剂增加的假设 亲和力导致的有效期延长 生命早期的高碳酸血症。中央的刻画 导致受损高碳酸血症的神经化学途径 换气反应可能有助于我们对发病机制的理解。 治疗新生儿呼吸暂停，并为新的药物干预做出贡献。

Apnea of prematurity is a major clinical problem whose pathophysiology is poorly understood. In preterm infants, especially those with apnea, ventilatory responses to hypercapnia are impaired: preliminary data reveal that hypercapnia causes prolongation of expiratory duration, similar to that observed during hypoxic exposure in early postnatal life. Hypercapnia induced prolongation of expiration is reversed by blockade of GABAA receptors in our neonatal animal models, while hypoxia induced frequency decrease is attenuated alpha2 by adrenergic receptor antagonists applied to the brainstem. We have demonstrated that catecholamine containing cells innervate bulbospinal neurons in newborn rat brainstem and that a subpopulation of bulbospinal inspiratory neurons express GABAA receptors. This proposal tests the hypothesis that hypercapnia modulates respiratory timing and the balance of inspiratory and expiratory muscle behavior during early postnatal development. We further hypothesize that C02 induced activation of central inhibitory systems such as GABAergic and alpha2 adrenergic pathways is responsible for maturational changes in these responses. We will administer intracisternal GABAA and alpha2 adrenergic blockers to characterize the role of neuroinhibitory pathways in C02 induced expiratory prolongation in maturing rat pups. We will utilize newborn piglets to characterize the role Of C02 induced chest wall and laryngeal muscle responses in modulating laryngeal resistance during changes in respiratory timing. Microinjection of GABAA and alpha2 adrenergic blockers at sites where brainstem bulbospinal neurons are identified will allow us to characterize the role of these neuroinhibitory pathways in mediating respiratory timing in piglets. Transneural labeling techniques will be combined with immunohistochemistry to characterize the connectivity of neurons in the medulla of maturing rat pups. We will describe expression and agonist affinity of GABAA and alpha2 adrenergic receptors on brainstem inspiratory bulbospinal neurons to test the hypothesis that receptor overexpression or increased agonist affinity contributes to the prolongation of expiration induced by hypercapnia during early life. Characterization of central neurochemical pathways that contribute to impaired hypercapnic ventilatory responses may advance our understanding of the pathogenesis of neonatal apnea and contribute to novel pharmacologic interventions.