Effect of Neonatal Hyperoxia on Alveolar Development and Infection

新生儿高氧对肺泡发育和感染的影响

• 批准号: 10246362
• 负责人: Michael A O'Reilly
• 金额: $ 53.66万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-10 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10246362
• 关键词: Adult; Affect; Air; Alveolar; Birth; Cartoons; Cell Death; Cell Proliferation; Cells; Cessation of life; Development; Environment; Environmental Risk Factor; Epigenetic Process; Epithelial Cells; Exposure to; Funding; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; Health; Heterochromatin; Histones; Hyperoxia; Hypersensitivity; Immune response; Infection; Inflammation; Influenza A Virus, H3N2 Subtype; Influenza A virus; Inherited; Knockout Mice; Label; Laboratories; Life; Lung; Lung diseases; Modeling; Mus; Neonatal Hyperoxic Injury; Oxidative Stress; Oxygen; Pathogenesis; Pathogenicity; Positioning Attribute; Premature Infant; Proliferating; Proliferation Marker; Proteins; Public Health; Pulmonary Fibrosis; Recombinants; Reporter; Research; Risk; Severities; Shapes; Structure; Testing; Virus Diseases; alveolar epithelium; cell injury; chromatin immunoprecipitation; daughter cell; experience; fetal; genetic information; genotoxicity; improved; influenza infection; influenza virus strain; lung development; model design; mouse model; next generation; novel; novel therapeutics; oxidative damage; postnatal; prenatal; self-renewal; therapy design; therapy design/development; transcriptome sequencing; tumor progression

PROJECT SUMMARY (ABSTRACT) There is growing appreciation that prenatal and postnatal environmental factors shape our health later in life. One of the most profound environmental factors that the developing lung will ever experience is oxygen as it transitions at birth from a fetal to air environment. While the term lung is prepared to breathe oxygen, the preterm lung transitions into air too soon and is often exposed to excess oxygen used to maintain appropriate oxygen saturations. This aberrant oxygen exposure at birth increases the risk for long-term lung disease through poorly understood mechanisms. Our laboratory developed and uses a unique mouse model designed to understand how high levels of oxygen at birth increases the severity of influenza A virus (IAV) infections in adults. Studies conducted during the previous funding period established that neonatal hyperoxia accelerates proliferation of alveolar epithelial type 2 cells (AEC2s), that these cells are slowly depleted when mice return to room air, and that the loss of AEC2s contributes to fibrotic lung disease when the mice are infected with IAV. This proposal builds on these findings by investigating how the oxygen-dependent depletion of AEC2s enhances the severity of IAV infections. Using genetic lineage studies, we found that neonatal hyperoxia depletes AEC2s by stimulating their differentiation into alveolar epithelial type 1 cells (AEC1s), neonatal hyperoxia enhances death of AEC1s during IAV infection, and that many AEC1s in adult mice exposed to neonatal hyperoxia express Ki67, a proliferation marker traditionally used to mark cancer progression. Recent studies however show Ki67 does not regulate cell proliferation but rather modifies gene expression via its ability to organize heterochromatin. Because proliferating cells are hypersensitive to the genotoxic effects of hyperoxia and damaged cells can transmit that experience thorough epigenetic inheritance, we will test the hypothesis that neonatal hyperoxia enhances sensitivity to IAV infection by inducing Ki67-dependent epigenetic changes in proliferating AEC2s that are maintained when they differentiate into AEC1s. Aim 1 uses novel Ki67-reporter and Ki67-null mice to determine whether AEC2s that proliferate during neonatal hyperoxia produce AEC1s that are marked by persistent Ki67 expression. Aim 2 infects these mice with recombinant strains of IAV-expressing fluorescent protein used to determine whether Ki67 modifies how AEC1s respond to IAV infection. Aim 3 uses cell-specific deep RNA sequencing and chromatin immunoprecipitation to determine whether Ki67 modifies a subset of oxygen-dependent changes in gene expression and that these changes help explain why AEC1s are susceptible to IAV infection. Understanding how neonatal hyperoxia shapes how AECs respond to IAV infection in mice is important because the scientific discoveries will stimulate development of therapies designed to improve the health of people born preterm.

项目摘要(摘要) 人们越来越认识到，出生前和出生后的环境因素会在以后塑造我们的健康 在生活中。发育中的肺将经历的最深刻的环境因素之一是氧气。 因为它在出生时从胎儿环境过渡到空气环境。当术语肺准备呼吸氧气时， 早产儿肺过早地转换到空气中，经常暴露在过量的氧气中，以保持适当的 氧气饱和。出生时这种异常的氧气暴露会增加患长期肺部疾病的风险。 通过鲜为人知的机制。我们实验室开发并使用了一种独特的小鼠模型 为了了解出生时高水平的氧气如何增加儿童甲型流感病毒(IAV)感染的严重性 成年人。在上一次资助期间进行的研究证实，新生儿高氧加速 肺泡上皮2型细胞(AEC2)的增殖，当小鼠回到正常状态时，这些细胞会慢慢耗尽 当小鼠感染IAV时，AEC2的丢失会导致纤维化的肺部疾病。 这一建议建立在这些发现的基础上，通过调查AEC2的氧气依赖耗竭如何 增加了IAV感染的严重程度。利用遗传谱系研究，我们发现新生儿高氧血症 通过刺激AEC2分化为1型肺泡上皮细胞(AEC1s)来耗尽AEC2，新生儿 高氧增加IAV感染过程中AEC1的死亡，以及暴露于 新生儿高氧血症表达Ki67，这是一种传统上用于标记癌症进展的增殖标记物。近期 然而，研究表明Ki67并不调节细胞增殖，而是通过其基因表达调节基因表达 组织异染色质的能力。因为增殖细胞对基因毒性作用非常敏感 高氧和受损细胞可以通过表观遗传传递，我们将测试 新生儿高氧血症通过诱导Ki67依赖性增强对IAV感染敏感性的假说 增殖中的AEC2的表观遗传学变化，当它们分化为AEC1时保持不变。目标 1使用新的Ki67报告基因和Ki67缺失的小鼠来确定AEC2在新生儿期间是否增殖 高氧产生的AEC1以持续的Ki67表达为标志。AIM 2感染这些小鼠 用表达IAV荧光蛋白的重组菌株来确定Ki67是否改变 AEC1对IAV感染有反应。AIM 3使用细胞特定的深度RNA测序和染色质 免疫沉淀法确定Ki67是否改变了基因中氧依赖改变的一个子集 这些变化有助于解释为什么AEC1对IAV感染易感。理解 新生儿高氧血症如何影响小鼠血管内皮细胞对IAV感染的反应是重要的，因为科学 这些发现将刺激旨在改善早产儿健康的疗法的发展。

项目成果

Neonatal hyperoxia leads to persistent alterations in NK responses to influenza A virus infection.

• DOI: 10.1152/ajplung.00233.2014
• 发表时间: 2015
• 期刊: American journal of physiology. Lung cellular and molecular physiology
• 作者: Emma C. Reilly;K. Martin;G. Jin;Min Yee;M. O’Reilly;B. Lawrence

Neonatal hyperoxia impairs adipogenesis of bone marrow-derived mesenchymal stem cells and fat accumulation in adult mice.

• DOI: 10.1016/j.freeradbiomed.2021.03.005
• 发表时间: 2021-05-01
• 期刊: Free radical biology & medicine
• 影响因子: 7.4
• 作者: Woeller CF;Lim SA;Roztocil E;Yee M;Beier EE;Puzas JE;O'Reilly MA
• 通讯作者: O'Reilly MA

Neonatal hyperoxia increases sensitivity of adult mice to bleomycin-induced lung fibrosis.

新生儿高氧会增加成年小鼠对博来霉素诱导的肺纤维化的敏感性。

• DOI: 10.1165/rcmb.2012-0238oc
• 发表时间: 2013
• 期刊: American journal of respiratory cell and molecular biology
• 影响因子: 6.4
• 作者: Yee,Min;Buczynski,BradleyW;Lawrence,BPaige;O'Reilly,MichaelA
• 通讯作者: O'Reilly,MichaelA

Effect of neonatal hyperoxia followed by concentrated ambient ultrafine particle exposure on cumulative learning in C57Bl/6J mice.

• DOI: 10.1016/j.neuro.2018.06.006
• 发表时间: 2018-07
• 期刊: Neurotoxicology
• 影响因子: 3.4
• 作者: Morris-Schaffer K;Sobolewski M;Allen JL;Marvin E;Yee M;Arora M;O'Reilly MA;Cory-Slechta DA
• 通讯作者: Cory-Slechta DA

Cumulative neonatal oxygen exposure predicts response of adult mice infected with influenza A virus.

新生小鼠的累积氧气暴露量可预测感染甲型流感病毒的成年小鼠的反应。

• DOI: 10.1002/ppul.23063
• 发表时间: 2015
• 期刊: Pediatric pulmonology
• 影响因子: 3.1
• 作者: Maduekwe,EchezonaT;Buczynski,BradleyW;Yee,Min;Rangasamy,Tiruamalai;Stevens,TimothyP;Lawrence,BPaige;O'Reilly,MichaelA
• 通讯作者: O'Reilly,MichaelA