Lipoxin-Mediated Inflammatory Resolution in Newborn Hyperoxic Lung Injury

描述（由申请人提供）：支气管肺发育不良（BPD）是一种常见于早产儿的慢性肺部疾病，其特征是炎症、水肿和肺泡化减少。炎症是BPD发生的关键因素，而肺内白细胞浸润增加是炎症介质的最大来源。脂毒素（LX）是花生四烯酸衍生的脂质，已被证明通过减少中性粒细胞和巨噬细胞浸润来介导炎症消退。阿司匹林是一种消炎药物，它能使COX-2乙酰化，并将COX-2的功能从环加氧酶转变为脂加氧酶，它能产生一种生物上更稳定、更有效的脂毒素，即15-epi脂毒素。由脂毒素或15-epi脂毒素启动的溶解途径包括与高亲和力脂毒素受体ALXR的结合。结合后，这些配体减少促炎细胞因子和趋化因子的转录。我们的总体假设是，在新生儿高氧损伤过程中给予脂素增强治疗可以减轻炎症反应，改善肺结构和功能。在Specific Aim I中，我们将验证肺上皮细胞（特别是Clara细胞）中脂毒素或15-epi-脂毒素激活ALXR的假设，将通过NF-kB和SOC-2介导的途径减少趋化因子和细胞因子的转录。在Specific Aim II中，我们将验证阿司匹林会降低暴露于高氧环境下的新生小鼠幼崽的肺部炎症反应和白细胞浸润的假设。新生小鼠幼崽将用阿司匹林或载体治疗，并暴露于bbb95 % 02。炎症标志物，特别是KC和MIP-2，将在小鼠肺组织中测量。最后，我们将通过肺形态计量学分析来验证对暴露于高氧环境下的新生小鼠幼崽给予阿司匹林将改善与高氧损伤相关的肺结构缺陷的假设。我们的目的是研究在新生儿模型高氧损伤过程中增强炎症消退的影响。这些研究将有助于深入了解炎症对高氧损伤进展和BPD发展的贡献。支气管肺发育不良（BPD）是一种慢性肺部疾病，每年影响超过50,000名早产儿。缓解炎症和改善肺部发育的治疗可以大大提高BPD患儿的发病率和死亡率。

DESCRIPTION (provided by applicant): Bronchopulmonary Dysplasia (BPD), a chronic lung disease that occurs in preterm infants, is characterized by inflammation, edema, and decreased alveolarization. Inflammation is a key contributing factor to the development of BPD and increases in leukocyte infiltration into the lung is the greatest source of inflammatory mediators. Lipoxins (LX) are arachidonic acid derived lipids that have been shown to mediate inflammatory resolution by decreasing neutrophil and macrophage infiltration. Aspirin, an anti-inflammatory drug that acetylates COX-2 and changes COX-2 function from a cyclooxygenases to a lipoxygenase, generates a more biologically stable and potent form of lipoxins, 15-epi lipoxins. Resolution pathways initiated by lipoxins or 15-epi lipoxins include binding to the high affinity lipoxin receptor, ALXR. Upon binding, these ligands decrease transcription of pro-inflammatory cytokines and chemokines. Our overall hypothesis is that administration of lipoxin-enhancing therapies during the course of newborn hyperoxic injury will attenuate the inflammatory responses and improve lung structure and function. In Specific Aim I, we will test the hypothesis that activation of ALXR by lipoxins or 15-epi-lipoxins In lung epithelial cells, specifically Clara cells, will decrease the transcription of chemokines and cytokines through pathways mediated by NF-kB and SOC-2. In Specific Aim II, we will test the hypothesis that administration of aspirin will decrease pulmonary inflammatory responses and leukocyte infiltration in newborn mouse pups exposed to hyperoxia. Newborn mouse pups will be treated with aspirin or vehicle and exposed to >95% 02. Markers of inflammation, specifically KC and MIP-2, will be measured in mouse lung tissues. Finally, we will test the hypothesis that administration of aspirin to newborn mouse pups exposed to hyperoxia will improve the lung structural deficits associated with hyperoxic injury using lung morphometric analyses. Our goal is to investigate the effects of enhanced inflammatory resolution during the course of hyperoxic injury in a newborn model. These studies will provide insight into the contribution of inflammation to the progression of hyperoxic injury and development of BPD. Bronchopulmonary Dysplasia (BPD) is a chronic lung disease that affects over 50,000 premature infants a year. Therapies to resolve inflammation and improve the lung development could greatly improve the morbidity and mortality of infants affected by BPD.