Neonatal inflammation impairs control of breathing

项目摘要/摘要 细菌引起的感染和炎症是新生儿常见的临床问题，随着 随着卫生保健水平的提高，更多的婴儿(包括早产儿)得以存活。我们最近才知道 开始了解新生儿炎症对成人生理的持久影响。具体来说， 了解新生儿炎症对成人呼吸的影响，这是一种重要的稳态行为，在很大程度上是 未被开发，这是本提案的重点。基于令人兴奋的初步数据，我们假设 新生儿炎症严重损害了成年后的呼吸控制网络。三个具体的 假说将被检验以促进我们在这个发展中的领域的理解：1)新生儿炎症 取消成人呼吸运动可塑性的多种已知途径；2)成人阈值下炎症 挑战对新生儿炎症后的呼吸控制有刺激特异性的影响；3)新生儿 炎症不同地改变了脊髓中的成人小胶质细胞和星形胶质细胞的炎症反应。一个 创新的、多学科的方法将被用来检验这些假设。实验方法包括： 麻醉大鼠的膈神经记录、非麻醉大鼠的体积描记和转录组 来自呼吸相关中枢神经系统(CNS)区域的分离细胞的图谱。在细菌诱导后 新生儿炎症，初步数据显示成人呼吸运动可塑性(AN)严重缺陷 对肺或神经损伤的补偿至关重要的学习和适应的重要形式)。有趣的是， 成人新生儿炎症后抗炎药物的急性治疗可不同程度地恢复 呼吸运动可塑性的两条主要途径，提示成人持续炎症是其结果 新生儿发炎的症状。由于生物体在生命中很少只经历一次炎症挑战， 我们正在测试成人呼吸系统对随后的低水平、无害的炎症的脆弱性 挑战。我们的初步数据显示成年男性呼吸控制网络的脆弱性增加 (可塑性、化学敏感性和死亡率)对新生儿炎症后其他无害的细菌刺激， 与男性成人病理发病率的增加有关。由于病毒感染在成年人中很常见， 我们还将调查新生儿细菌性炎症+成人病毒性炎症对两性的影响。 在机制水平上，我们发现两种类型的中枢神经系统细胞--星形胶质细胞对新生儿炎症反应相反。 和小胶质细胞。星形胶质细胞是中枢神经系统中的大多数细胞，它显示出炎症基因的增加。 表达持续到成年期，而小胶质细胞(中枢神经系统常驻免疫细胞)表现为钝化或不变 基因反应。这些研究的结果将极大地促进我们对新生儿的理解 炎症诱导的损伤持续到成年，并揭示了呼吸系统的敏感性 控制新生儿炎症的网络。这种理解对于确定新的治疗靶点是必要的。 并为患有呼吸控制障碍的成年人开发新的治疗策略。

PROJECT SUMMARY/ABSTRACT Bacterial-induced infections and inflammation in newborns are common clinical problems, and with continued health care improvements, more infants (including those born preterm) are surviving. We have only recently begun to understand the lasting impact of neonatal inflammation on adult physiology. Specifically, understanding the impact of neonatal inflammation on adult breathing, a vital homeostatic behavior, is largely unexplored, and is the focus of this proposal. Based on exciting preliminary data, we hypothesize that neonatal inflammation significantly impairs the respiratory control network in adulthood. Three specific hypotheses will be tested to advance our understanding in this developing field: 1) Neonatal inflammation abolishes multiple known pathways to adult respiratory motor plasticity; 2) Adult subthreshold inflammatory challenges have stimulus-specific effects on respiratory control following neonatal inflammation; 3) Neonatal inflammation differentially alters adult microglial and astrocytic inflammatory responses in the spinal cord. An innovative, multidisciplinary approach will be used to test these hypotheses. Experimental approaches include: phrenic nerve recordings in anesthetized rats, plethysmography in unanesthetized rats, and transcriptome profiling in isolated cells from respiratory-related central nervous system (CNS) regions. After bacterial-induced neonatal inflammation, preliminary data indicate severe deficits in adult respiratory motor plasticity (an important form of learning and adaptability critical for compensation to lung or neural injury). Interestingly, acute treatment with anti-inflammatory drugs in adults after neonatal inflammation differentially restores one of two main pathways to respiratory motor plasticity, suggesting persistent adult inflammation as a consequence of the neonatal inflammation. Since organisms rarely experience only a single inflammatory challenge in life, we are testing the vulnerability of the adult respiratory system to subsequent low-level, innocuous inflammatory challenges. Our preliminary data indicate increased vulnerability of the adult male respiratory control network (plasticity, chemosensitivity, and mortality) to otherwise innocuous bacterial stimuli after neonatal inflammation, correlating with increased incidence of adult pathology in males. Since viral infections are common in adults, we will also investigate the effects of neonatal bacterial inflammation + adult viral inflammation in both sexes. At a mechanistic level, we find opposing responses to neonatal inflammation in two CNS cell types, astrocytes and microglia. Astrocytes, which compose the majority of cells in the CNS, show increased inflammatory gene expression lasting into adulthood, while microglia (CNS resident immune cells) display a blunted or unchanged gene response. Results from these studies will significantly advance our understanding of neonatal inflammation-induced impairments persisting into adulthood, and shed light on the sensitivity of the respiratory control network to neonatal inflammation. This understanding is necessary to identify new therapeutic targets and to develop new treatment strategies for adults with ventilatory control disorders.