Chemokine Blockade to Preserve Lung Development

早产儿慢性肺病（CLD）可能影响多达50%的极低出生体重儿。CLD增加了神经发育异常的风险。炎症反应在早产新生儿足够的抗氧化防御是核心的肺损伤导致CLD的病理生理学。目前的治疗包括糖皮质激素，其可不利地影响肺、躯体和中枢神经系统发育。靶向免疫治疗阻断早期炎症诱导的肺损伤可能会阻止CLD的发展，并避免不良的类固醇作用。我们的假设是，在高氧暴露的啮齿动物模型中，阻断白细胞流入和/或功能将预防慢性肺病。拟议的研究将使用高氧暴露的新生啮齿动物来研究炎症对肺发育的影响机制，以响应服务氧化应激，作为CLD的模型。将通过使用特异性抗趋化因子抗体和趋化因子受体拮抗剂来修饰神经元和巨噬细胞内流/功能。将在缺乏这些功能的基因敲除小鼠中研究关键中性粒细胞功能的贡献。目的1将确定哪一方面的中性粒细胞和/或巨噬细胞的流入/功能，最有助于生化氧化应激在新生儿肺在高氧诱导的肺损伤的开始。目的1将确定哪一方面的中性粒细胞和/或巨噬细胞的流入/功能，最有助于生化氧化应激在新生儿肺在高氧诱导的肺损伤的开始。目的2将确定白细胞流入/功能对DNA损伤、生长停滞和病理性细胞凋亡的具体贡献，这些贡献导致肺泡发育异常。目的3将确定阻断白细胞功能是否能安全地保护严重氧化应激恢复期间正常的肺泡发育。

Chronic lung disease in prematurity (CLD) may affect as many as 50% of very low birthweight newborns. CLD confers added risk for abnormal neurodevelopmental outcome. Inflammation in response to adequate antioxidant defenses in premature newborns is central to the pathophysiology of lung injury leading to CLD. Present therapy includes glucocorticoids which may adversely affect lung, somatic and central nervous system development.,. Targeted immunotherapy blocking early inflammatory-induced lung injury may prevent the development of CLD and avoid adverse steroid effects. Our hypothesis is that blocking leukocyte influx and/of function will prevent chronic lung disease in the hyperoxia-exposed rodent model. The proposed studies will use hyperoxia-exposed newborn rodents to study the mechanisms of inflammatory effects on lung development in response to serve oxidant stress, as a model of CLD. Neutrophil and macrophage influx/function will be modified by using specific anti- chemokine antibodies and chemokine receptor antagonists. The contribution of key neutrophil functions will e studied in gene knockout mice lacking these functions. Aim 1 will determine which aspect of neutrophil and/or macrophage influx/function contributes most to biochemical oxidant stress in newborn lung during initiation of hyperoxia-induced lung injury. Aim 1 will determine which aspect of neutrophil and/or macrophage influx/function contributes most to biochemical oxidant stress in newborn lung during initiation of hyperoxia-induced lung injury. Aim 2 will determine the specific contributions of leukocyte influx/function to DNA damage, growth arrest, and pathologic apoptosis, which contribute to abnormal alveolar development. Aim 3 will determine whether blockade of leukocyte function can safely preserve normal alveolar development during recovery from severe oxidant stress.