Simakajornboon Narong, Kuptanon Teeradej
Constance Kaufman Pediatric Pulmonary Research Laboratory, Department of Pediatrics, Tulane University School of Medicine, 1430 Tulane Ave., SL-37 New Orleans, LA, USA.
Respir Physiol Neurobiol. 2005 Nov 15;149(1-3):273-86. doi: 10.1016/j.resp.2005.05.005. Epub 2005 Jun 9.
The neuromodulator systems mediating the central component of the hypoxic ventilatory response (HVR) during development are complex and diverse. The early component of the HVR is mediated through N-methyl-D-aspartate (NMDA) glutamate receptors in the caudal brainstem. The intracellular downstream signal transductions of the NMDA receptors involve protein kinase C (PKC), neuronal nitric oxide synthase (nNOS) and tyrosine kinase (TK). Activation of NMDA receptors will also lead to activation of the early gene transcription factors including AP-1 (c-fos, c-jun) and NF-kappaB which may play a role in modulation of the subsequent response to hypoxia. NMDA receptors in the caudal brainstem play a critical role in the development of the HVR and increasing dependency on NMDA receptors emerges over time. Similarly, hypoxia-induced PKC, NOS and c-Fos activation in the caudal brainstem is relatively weak in the immature animals, but this activation increases with age and the strength of the response appears to increase concomitantly with the appearance of NMDA expression. Several neurotransmitters including adenosine, gamma-aminobutyric acid (GABA), serotonin and opioids are involved in the late component of the HVR. In addition, the late phase of the HVR is mediated in part through platelet-derived growth factor (PDGF)-beta receptors. PDGF-beta receptor activation is an important contributor of the hypoxic ventilatory depression at all postnatal ages, but its role is more critical in the developing animals. Maturation of these neuromodulators, especially the NMDA and PDGF-beta receptors-mediated pathways, occurs primarily during the early postnatal period. Perturbation of these developmental processes may result in short-term or sustained alterations to the HVR and may also affect neuronal survival during hypoxia.
在发育过程中，介导低氧通气反应（HVR）中枢部分的神经调节系统复杂多样。HVR的早期部分是通过延髓尾部的N-甲基-D-天冬氨酸（NMDA）谷氨酸受体介导的。NMDA受体的细胞内下游信号转导涉及蛋白激酶C（PKC）、神经元型一氧化氮合酶（nNOS）和酪氨酸激酶（TK）。NMDA受体的激活还会导致早期基因转录因子的激活，包括AP-1（c-fos、c-jun）和核因子κB，它们可能在调节随后对低氧的反应中发挥作用。延髓尾部的NMDA受体在HVR的发育中起关键作用，并且随着时间的推移，对NMDA受体的依赖性不断增加。同样，在未成熟动物中，低氧诱导的延髓尾部PKC、NOS和c-Fos激活相对较弱，但这种激活随着年龄增长而增加，反应强度似乎随着NMDA表达的出现而相应增加。包括腺苷、γ-氨基丁酸（GABA）、5-羟色胺和阿片类物质在内的几种神经递质参与了HVR的晚期部分。此外，HVR的晚期部分部分是通过血小板衍生生长因子（PDGF）-β受体介导的。PDGF-β受体激活是所有出生后年龄段低氧通气抑制的重要促成因素，但其作用在发育中的动物中更为关键。这些神经调节剂的成熟，尤其是NMDA和PDGF-β受体介导的途径，主要发生在出生后的早期阶段。这些发育过程的扰动可能导致HVR的短期或持续改变，也可能影响低氧期间的神经元存活。
