Chemokine Blockade to Preserve Lung Development

趋化因子阻断以保护肺部发育

• 批准号: 6731187
• 负责人: RICHARD L AUTEN
• 金额: $ 30.8万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6731187
• 关键词: DNA damage; NAD(P)H dehydrogenase; alveolar macrophages; apoptosis; cell proliferation; chemokine; chemokine receptor; chronic obstructive pulmonary disease; genetically modified animals; histogenesis; hyperoxia; immunocytochemistry; immunotherapy; inflammation; laboratory mouse; leukocyte activation /transformation; leukocyte oxidative burst; lung; lung development; monocyte chemoattractant protein 1; neutrophil; oxidative stress; premature infant animal; proliferating cell nuclear antigen; respiratory distress syndrome of newborn; respiratory function; respiratory oxygen; terminal nick end labeling

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.

多达 50% 的极低出生体重新生儿可能患有慢性早产儿肺病 (CLD)。 CLD 会增加神经发育结果异常的风险。早产儿对足够的抗氧化防御反应而产生的炎症是导致慢性肺病的肺损伤病理生理学的核心。目前的治疗包括糖皮质激素，其可能对肺、躯体和中枢神经系统发育产生不利影响。阻断早期炎症引起的肺损伤的靶向免疫疗法可以预防慢性肺病的发展并避免类固醇的不良反应。我们的假设是，阻断白细胞流入和/或功能将预防高氧暴露的啮齿动物模型中的慢性肺病。拟议的研究将使用暴露于高氧的新生啮齿动物来研究炎症对肺部发育的影响机制，以响应氧化应激，作为慢性肺病的模型。中性粒细胞和巨噬细胞的流入/功能将通过使用特定的抗趋化因子抗体和趋化因子受体拮抗剂来改变。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。目标 1 将确定在高氧引起的肺损伤开始期间，中性粒细胞和/或巨噬细胞流入/功能的哪个方面对新生肺中的生化氧化应激贡献最大。目标 1 将确定在高氧引起的肺损伤开始期间，中性粒细胞和/或巨噬细胞流入/功能的哪个方面对新生肺中的生化氧化应激贡献最大。目标 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，这些因素导致肺泡发育异常。目标 3 将确定白细胞功能的阻断是否可以在从严重氧化应激恢复期间安全地保持正常的肺泡发育。