Lipoxin-Mediated Inflammatory Resolution in Newborn Hyperoxic Lung Injury

描述(申请人提供)：支气管肺发育不良(BPD)，一种发生在早产儿的慢性肺部疾病，以炎症、水肿和肺泡化减少为特征。炎症是BPD发生的关键因素，肺内白细胞渗入增加是炎症介质的最大来源。脂氧素(Lx)是花生四烯酸衍生的脂类，已被证明通过减少中性粒细胞和巨噬细胞的浸润来介导炎症消退。阿司匹林是一种抗炎药物，它使COX-2乙酰化，并将COX-2的功能从环氧合酶改变为脂氧合酶，它会产生一种生物上更稳定、更有效的脂氧素，即15-表观脂氧素。脂氧素或15-表位脂氧素启动的分解途径包括与高亲和力脂氧素受体ALXR结合。一旦结合，这些配体就会减少促炎细胞因子和趋化因子的转录。我们的总体假设是，在新生儿高氧性损伤过程中给予脂氧素增强治疗将减轻炎症反应，改善肺结构和功能。在特定的目标I中，我们将检验一种假设，即在肺上皮细胞，特别是Clara细胞中，脂氧素或15-表脂氧素激活ALXR将通过核因子-kB和SOC-2介导的途径减少趋化因子和细胞因子的转录。在特定的目标II中，我们将检验给予阿司匹林会减少暴露在高氧下的新生小鼠的肺部炎症反应和白细胞浸润的假设。新生的小鼠将被阿司匹林或赋形剂处理，并暴露在&gt；95%02中。炎症标志物，特别是KC和MIP-2，将在小鼠肺组织中进行测量。最后，我们将使用肺形态计量学分析来验证这样的假设，即给暴露在高氧中的新生小鼠服用阿司匹林将改善与高氧损伤相关的肺结构缺陷。我们的目标是在一个新生儿模型中研究高氧损伤过程中增强炎症消退的效果。这些研究将有助于深入了解炎症在高氧性损伤的进展和BPD的发展中的作用。支气管肺发育不良(BPD)是一种慢性肺部疾病，每年影响50,000多名早产儿。消炎和改善肺部发育的治疗方法可以极大地提高受BPD影响的婴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.