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Neonatal inflammation impairs control of breathing

新生儿炎症损害呼吸控制

基本信息

批准号：
10188613
负责人：
Adrianne Genest Huxtable
金额：
$ 36.58万
依托单位：
UNIVERSITY OF OREGON
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10188613
关键词：
Acute Adult Anti-Inflammatory Agents Astrocytes Behavior Breathing Cells Clinical Data Dose Female Financial compensation Functional disorder Gene Expression Genes Goals Health Healthcare High Prevalence Hippocampus (Brain)Human Immune Immune system Impairment Incidence Infant Infection Inflammation Inflammatory Inflammatory Response Knowledge Lead Learning Life Light Lipopolysaccharides Mental disorders Microglia Modeling Morbidity - disease rate Motor Neonatal Neuraxis Neurons Newborn Infant Obstructive Sleep Apnea Organism Outcome Pathology Pathway interactions Pharmaceutical Preparations Physiology Plethysmography Premature Infant Prostaglandin-Endoperoxide Synthase Rattus Respiratory System Spinal Cord Stimulus Structure of phrenic nerve Survival Rate Synaptic plasticity System Testing Viral Virus Diseases Work base cell type cognitive function critical developmental period disorder control experience immune function innovation interdisciplinary approach lung injury male mimetics mortality nerve injury neuroinflammation new therapeutic target relating to nervous system respiratory response sex sexual dimorphism stressor systemic inflammatory response therapy development transcriptome transcriptome sequencing treatment strategy virtual

项目摘要

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.

项目总结/文摘