CO2-evoked release of PGE2 modulates sighs and inspiration as demonstrated in brainstem organotypic culture
CO2-evoked release of PGE2 modulates sighs and inspiration as demonstrated in brainstem organotypic culture
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DOI：
10.7554/elife.14170
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发表时间：
2016-07-05
期刊：
影响因子：
7.7
通讯作者：
Herlenius, Eric
中科院分区：
文献类型：
--
作者：
Forsberg, David;Horn, Zachi;Herlenius, Eric
炎症诱导的前列腺素 E-2 (PGE(2)) 释放会改变呼吸模式和对 CO2 水平的反应。这可能会对新生儿产生致命的后果，并导致婴儿猝死。为了阐明潜在机制，我们提出了一种新型呼吸脑干器官型培养物，可产生节律性神经网络和运动活动 3 周。我们发现，增加的 CO2 会引发间隙连接依赖性 PGE(2) 释放。这改变了前博辛格节律生成复合体和化学敏感脑干呼吸区域的神经网络活动，从而增加叹气频率和吸气深度。我们使用缺乏类二十烷酸前列腺素 3 受体 (EP3R) 的小鼠、呼吸脑干器官切片和 EP3R(+/+) 细胞的光遗传学抑制来证明 EP3R 对于高碳酸血症的通气反应很重要。我们的研究确定了一条连接炎症和呼吸系统的新途径，对一生中的吸气和叹息以及呼吸衰竭时的自动复苏能力具有影响。
Inflammation-induced release of prostaglandin E-2 (PGE(2)) changes breathing patterns and the response to CO2 levels. This may have fatal consequences in newborn babies and result in sudden infant death. To elucidate the underlying mechanisms, we present a novel breathing brainstem organotypic culture that generates rhythmic neural network and motor activity for 3 weeks. We show that increased CO2 elicits a gap junction-dependent release of PGE(2). This alters neural network activity in the preBotzinger rhythm-generating complex and in the chemosensitive brainstem respiratory regions, thereby increasing sigh frequency and the depth of inspiration. We used mice lacking eicosanoid prostanoid 3 receptors (EP3R), breathing brainstem organotypic slices and optogenetic inhibition of EP3R(+/+) cells to demonstrate that the EP3R is important for the ventilatory response to hypercapnia. Our study identifies a novel pathway linking the inflammatory and respiratory systems, with implications for inspiration and sighs throughout life, and the ability to autoresuscitate when breathing fails.