Resolution of Diffuse Inflammatory Lung Injury in Neonatal Mice

新生小鼠弥漫性炎症性肺损伤的解决

基本信息

  • 批准号:
    8502861
  • 负责人:
  • 金额:
    $ 38.56万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-06-15 至 2017-04-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): In the United States pediatric acute lung injury (ALI) has a mortality rate of 22%, with 11% of children dying from ALI-related pneumonias. Although a high morbidity and mortality is associated with pediatric ALI-related pneumonias, little is known about the processes that cause acute lung injury and the mechanisms that lead to lung recovery. Furthermore, relatively less is known about the age-related changes that occur in the immune system from neonatal to adolescence life and how these age differences affect the lungs' response to ALI. Our preliminary studies suggest differences in macrophage-lymphocyte interactions in neonatal lung in response to an ALI, specifically a lack of MHC class II upregulation in alveolar macrophages in response to TLR4 activation. We believe that this may influence the initial inflammatory response and impair recruitment and proliferation of Tregs into areas of lung injury, thus promoting chronic lung inflammation. Tregs have been shown to be critical orchestrators of lung recovery in an experimental model of adult ALI. In our preliminary studies we found that adoptive transfer of Tregs, but not CD8+ cells or PBS (sham) from adult spleen of C57BL/6 congenic CD45.1 mice attenuated lung neutrophilia and weight loss in neonatal mice with LPS-induced ALI. Our preliminary studies also suggested that Tregs can modulate lung inflammation in the neonate with ALI. The primary goal of this project is to characterize the mechanisms and factors that modulate disease severity from ALI in the neonatal and juvenile lung. We have developed a model of ALI for neonatal mice in which we can deliver an agent into the lungs using a non-invasive intra-tracheal route. Using this model we will study the age related differences that occur in response to an ALI and the mechanisms that allow for recovery. We are also interested in identifying vulnerable periods during lung development in which lung injury can cause lasting changes in the adult lung. In this project we will specifically: (1) characterize age related differences in the early and late inflammatory response to ALI in neonatal (5 day old mice) and juvenile (12 day old mice) (2) study the role of T-regulatory cells in resolving lung inflammation and bacterial clearance in neonatal and juvenile ALI and (3) determine the impact of age on macrophage-lymphocyte interactions during acute lung injury and recovery. We believe that these studies will facilitate detailed examination of neonatal lung responses in a context that is relevant to clinical ALI and will highlight a role for supplemental Tregs as a possible adjuvant therapy in the treatment of neonatal ALI.
描述(由申请人提供):在美国,小儿急性肺损伤(ALI)的死亡率为22%,其中11%的儿童死于ALI相关肺炎。虽然高发病率和死亡率与小儿急性肺损伤相关的肺炎,很少有人知道的过程,导致急性肺损伤和机制,导致肺恢复。此外,对于从新生儿到青春期的免疫系统中发生的年龄相关变化以及这些年龄差异如何影响肺部对ALI的反应,我们所知相对较少。 我们的初步研究表明,新生儿肺巨噬细胞-淋巴细胞相互作用的差异,在急性肺损伤,特别是缺乏MHC II类上调肺泡巨噬细胞响应TLR 4激活。我们认为,这可能会影响最初的炎症反应,并损害招募和增殖的Tcl 3进入肺损伤的地区,从而促进慢性肺部炎症。在成人ALI的实验模型中,已证明TBI是肺恢复的关键协调剂。在我们的初步研究中,我们发现过继性转移来自C57 BL/6同源CD45.1小鼠的成年脾脏的TcB,而不是CD 8+细胞或PBS(假手术),减轻了患有LPS诱导的ALI的新生小鼠的肺嗜中性粒细胞和体重减轻。我们的初步研究还表明,TBP可以调节新生儿ALI的肺部炎症。 该项目的主要目标是描述新生儿和青少年肺ALI疾病严重程度的调节机制和因素。我们已经为新生小鼠开发了一种ALI模型,在该模型中,我们可以使用非侵入性气管内途径将药物递送到肺部。使用这个模型,我们将研究年龄相关的差异,发生在响应ALI和机制,允许恢复。我们也有兴趣确定肺发育过程中的脆弱时期,在此期间肺损伤可能导致成人肺的持久变化。在这个项目中,我们将具体:(1)表征新生儿ALI早期和晚期炎症反应的年龄相关差异,(5日龄小鼠)和幼龄小鼠(12日龄小鼠)(2)研究T调节细胞在解决新生儿和青少年ALI中的肺部炎症和细菌清除中的作用,以及(3)确定年龄对巨噬细胞的影响。急性肺损伤和恢复过程中淋巴细胞的相互作用。 我们相信,这些研究将有助于在与临床ALI相关的背景下详细检查新生儿肺反应,并将突出 补充TdR作为治疗新生儿ALI的一种可能的辅助疗法。

项目成果

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Sharon Ann McGrath-Morrow其他文献

Sharon Ann McGrath-Morrow的其他文献

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{{ truncateString('Sharon Ann McGrath-Morrow', 18)}}的其他基金

Multidisciplinary Training Program in Pediatric Lung Diseases
小儿肺部疾病多学科培训计划
  • 批准号:
    10332256
  • 财政年份:
    2022
  • 资助金额:
    $ 38.56万
  • 项目类别:
Multidisciplinary Training Program in Pediatric Lung Diseases
小儿肺部疾病多学科培训计划
  • 批准号:
    10594441
  • 财政年份:
    2022
  • 资助金额:
    $ 38.56万
  • 项目类别:
Resolution of Diffuse Inflammatory Lung Injury in Neonatal Mice
新生小鼠弥漫性炎症性肺损伤的解决
  • 批准号:
    8680365
  • 财政年份:
    2013
  • 资助金额:
    $ 38.56万
  • 项目类别:
Resolution of Diffuse Inflammatory Lung Injury in Neonatal Mice
新生小鼠弥漫性炎症性肺损伤的解决
  • 批准号:
    9769845
  • 财政年份:
    2013
  • 资助金额:
    $ 38.56万
  • 项目类别:
Resolution of Diffuse Inflammatory Lung Injury in Neonatal Mice
新生小鼠弥漫性炎症性肺损伤的解决
  • 批准号:
    9613428
  • 财政年份:
    2013
  • 资助金额:
    $ 38.56万
  • 项目类别:
Resolution of Diffuse Inflammatory Lung Injury in Neonatal Mice
新生小鼠弥漫性炎症性肺损伤的解决
  • 批准号:
    10226540
  • 财政年份:
    2013
  • 资助金额:
    $ 38.56万
  • 项目类别:
Resolution of Diffuse Inflammatory Lung Injury in Neonatal Mice
新生小鼠弥漫性炎症性肺损伤的解决
  • 批准号:
    10245317
  • 财政年份:
    2013
  • 资助金额:
    $ 38.56万
  • 项目类别:
NIGHTTIME HYPOXEMIA IN TEENAGERS WITH ATAXIA TELANGIECTASIA
毛细血管扩张性共济失调青少年的夜间低氧血症
  • 批准号:
    7604677
  • 财政年份:
    2006
  • 资助金额:
    $ 38.56万
  • 项目类别:
Multidisciplinary Training Program in Pediatric Pulmonary
小儿肺科多学科培训计划
  • 批准号:
    9068331
  • 财政年份:
    2003
  • 资助金额:
    $ 38.56万
  • 项目类别:
REGULATION OF GROWTH ARREST IN HYPEROXIC NEONATAL LUNG
高氧新生儿肺生长停滞的调节
  • 批准号:
    2027141
  • 财政年份:
    1997
  • 资助金额:
    $ 38.56万
  • 项目类别:

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