Chemokine Blockade to Preserve Lung Development

早产儿慢性肺部疾病(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结局的风险。在早产儿中，对足够的抗氧化剂防御反应的炎症是导致慢性阻塞性肺疾病的肺损伤的病理生理学的中心。目前的治疗方法包括糖皮质激素，它可能对肺、躯体和中枢神经系统的发育产生不利影响。阻断早期炎症性肺损伤的靶向免疫治疗可以防止慢性阻塞性肺疾病的发展，避免类固醇的不良反应。我们的假设是，在高氧暴露的啮齿动物模型中，阻断白细胞的内流和/或功能可以预防慢性肺部疾病。这项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，以应对氧化应激，作为CLD的模型。中性粒细胞和巨噬细胞的流入/功能将通过使用特异性的抗趋化因子抗体和趋化因子受体拮抗剂来改变。关键的中性粒细胞功能的贡献将在缺乏这些功能的基因敲除小鼠中进行研究。目的1确定在高氧性肺损伤启动过程中，中性粒细胞和/或巨噬细胞内流/功能的哪个方面对新生儿肺内生化氧化应激的影响最大。目的1确定在高氧性肺损伤启动过程中，中性粒细胞和/或巨噬细胞内流/功能的哪个方面对新生儿肺内生化氧化应激的影响最大。目的2将确定白细胞流入/功能在DNA损伤、生长停滞和病理性细胞凋亡中的具体作用，这些都是导致肺泡发育异常的原因。目的3将确定在严重的氧化应激恢复期间，阻断白细胞功能是否能安全地保护正常的肺泡发育。

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.