Resolution of Diffuse Inflammatory Lung Injury in Neonatal Mice

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%的儿童死于与ALI相关的肺炎。尽管小儿急性呼吸道感染相关肺炎的高发病率和死亡率相关，但对引起急性肺损伤的过程和导致肺恢复的机制知之甚少。此外，从新生儿到青春期，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急性肺损伤的反应，我们所知的相对较少。我们的初步研究表明，新生儿肺中巨噬细胞-淋巴细胞相互作用在ALI反应中存在差异，特别是在TLR4激活反应中肺泡巨噬细胞缺乏MHC II类上调。我们认为这可能会影响初始炎症反应，损害treg在肺损伤区域的募集和增殖，从而促进慢性肺炎症。在成人急性肺损伤的实验模型中，Tregs已被证明是肺恢复的关键协调者。在我们的初步研究中，我们发现从C57BL/6基因CD45.1小鼠的成年脾脏过继转移Tregs，而不是CD8+细胞或PBS（假），可以减轻lps诱导的ALI新生小鼠的肺中性粒细胞增多和体重减轻。我们的初步研究也表明Tregs可以调节ALI新生儿的肺部炎症。该项目的主要目标是表征调节新生儿和青少年肺部ALI疾病严重程度的机制和因素。我们已经为新生小鼠开发了一种ALI模型，我们可以通过非侵入性气管内途径将药物输送到肺部。使用这个模型，我们将研究ALI的年龄相关差异和恢复机制。我们也对确定肺发育过程中肺损伤可能导致成人肺持久变化的脆弱时期感兴趣。在这个项目中，我们将具体地：(1)表征新生儿（5日龄小鼠）和幼年（12日龄小鼠）对ALI早期和晚期炎症反应的年龄相关差异；(2)研究t调节细胞在新生儿和幼年ALI中解决肺部炎症和细菌清除中的作用；(3)确定年龄对急性肺损伤和恢复过程中巨噬细胞-淋巴细胞相互作用的影响。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，并将强调在以下方面的作用

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.