Neonatal inflammation impairs control of breathing

项目总结/摘要 新生儿细菌性感染和炎症是常见的临床问题， 随着医疗保健的改善，更多的婴儿（包括早产儿）存活下来。我们最近才 开始了解新生儿炎症对成人生理的持久影响。具体地说， 了解新生儿炎症对成人呼吸的影响，这是一种重要的自我平衡行为， 未开发的，这是该提案的重点。基于令人兴奋的初步数据，我们假设， 新生儿炎症显著损害成年期的呼吸控制网络。三个具体 假设将被测试，以促进我们在这个发展中的领域的理解：1）新生儿炎症 消除成人呼吸运动可塑性的多种已知途径; 2）成人阈下炎性 挑战对新生儿炎症后的呼吸控制具有刺激特异性影响; 3）新生儿 炎症不同地改变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 将采用创新的多学科方法来检验这些假设。实验方法包括： 麻醉大鼠的膈神经记录、未麻醉大鼠的体积描记和转录组 在分离的细胞中的分析，所述分离的细胞来自与肿瘤相关的中枢神经系统（CNS）区域。细菌诱导后 新生儿炎症，初步数据表明成人呼吸运动可塑性严重缺陷（ 对于肺或神经损伤补偿至关重要的学习和适应性的重要形式）。有趣的是， 新生儿炎症后成人的抗炎药物急性治疗可不同程度地恢复 呼吸运动可塑性的两个主要途径，表明持续的成人炎症的结果 新生儿的炎症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表明，成年男性呼吸控制网络的脆弱性增加， （可塑性，化疗敏感性和死亡率），否则无害的细菌刺激新生儿炎症后， 与男性成年病理发生率增加相关。由于病毒感染在成年人中很常见， 我们还将研究新生儿细菌性炎症+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CNS细胞类型（星形胶质细胞）对新生儿炎症的反应相反， 和小胶质细胞。星形胶质细胞是中枢神经系统中的主要细胞， 表达持续到成年期，而小胶质细胞（CNS驻留免疫细胞）显示出钝化或不变的表达。 基因反应这些研究的结果将大大促进我们对新生儿的理解。 炎症引起的损伤持续到成年期，并阐明了呼吸系统的敏感性， 新生儿炎症的控制网络。这种理解对于确定新的治疗靶点是必要的 并为患有强迫性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.