The induced prostaglandin E2 pathway is a key regulator of the respiratory response to infection and hypoxia in neonates
The induced prostaglandin E2 pathway is a key regulator of the respiratory response to infection and hypoxia in neonates
复制标题
DOI：
10.1073/pnas.0611468104
复制
发表时间：
2007-06-05
影响因子：
11.1
通讯作者：
Herlenius, Eric
中科院分区：
文献类型：
--
作者：
Hofstetter, Annika O.;Saha, Sipra;Herlenius, Eric
新生儿期的感染通常会引起呼吸暂停发作，促炎细胞因子IL-1 β可能是这些事件之间的关键介质。为了确定IL-1 β抑制呼吸的机制，我们在新生小鼠和人类新生儿中检测了前列腺素E-2（PGE（2））依赖性途径。IL-1 β和短暂缺氧可快速诱导新生小鼠脑干特异性微粒体前列腺素E-2合酶-1（mPGES-1）活性。此外，IL-1 β在mPGES-1野生型小鼠中降低了高氧期间的呼吸频率，并抑制了缺氧喘息和自动复苏，但在mPGES-1敲除小鼠中没有。在野生型小鼠中，PGE（2）在体内诱导呼吸暂停和不规则呼吸模式，在体外抑制脑干呼吸节律的产生。缺乏PGE（2）的EP 3受体（EP 3R）的小鼠表现出较少的呼吸暂停和持续的脑干呼吸活动，表明PGE（2）通过EP 3R发挥其呼吸作用。在人类新生儿中，感染性标志物C-反应蛋白与脑脊液中PGE（2）升高相关，中枢PGE（2）升高与呼吸暂停频率增加相关。我们的结论是，IL-1 β通过mPGES-1激活和PGE（2）与脑干EP 3受体结合，对呼吸及其控制产生不利影响，导致呼吸暂停频率增加和缺氧诱导的死亡率。
Infection during the neonatal period commonly induces apnea episodes, and the proinflammatory cytokine IL-1 beta may serve as a critical mediator between these events. To determine the mechanism by which IL-1 beta depresses respiration, we examined a prostaglandin E-2, (PGE(2))-dependent pathway in newborn mice and human neonates. IL-1 beta and transient anoxia rapidly induced brainstem-specific microsomal prostaglandin E-2 synthase-1 (mPGES-1) activity in neonatal mice. Furthermore, IL-1 beta reduced respiratory frequency during hyperoxia and depressed hypoxic gasping and autoresuscitation in mPGES-1 wild-type mice, but not in mPGES-1 knockout mice. In wild-type mice, PGE(2) induced apnea and irregular breathing patterns in vivo and inhibited brainstem respiratory rhythm generation in vitro. Mice lacking the EP3 receptor (EP3R) for PGE(2) exhibited fewer apneas and sustained brainstem respiratory activity, demonstrating that PGE(2) exerts its respiratory effects via EP3R. In human neonates, the infectious marker C-reactive protein was correlated with elevated PGE(2) in the cerebrospinal fluid, and elevated central PGE(2) was associated with an increased apnea frequency. We conclude that IL-1 beta adversely affects breathing and its control by mPGES-1 activation and PGE(2) binding to brainstem EP3 receptors, resulting in increased apnea frequency and hypoxia-induced mortality.