Chemokine Blockade to Preserve Lung Development

趋化因子阻断以保护肺部发育

• 批准号: 6877731
• 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/6877731
• 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.

早产儿慢性肺病（CLD）可能影响多达50%的极低出生体重新生儿。CLD会增加神经发育异常的风险。早产儿对足够的抗氧化防御反应的炎症是导致CLD的肺损伤病理生理学的核心。目前的治疗包括糖皮质激素，它可能对肺、躯体和中枢神经系统的发育产生不利影响。靶向免疫治疗阻断早期炎症性肺损伤可能阻止CLD的发展并避免不良的类固醇效应。我们的假设是，在高氧暴露的啮齿动物模型中，阻断白细胞内流和/或功能将预防慢性肺部疾病。本研究将利用暴露在高氧环境下的新生啮齿动物作为CLD模型，研究炎症对肺发育的影响机制，以响应氧化应激。中性粒细胞和巨噬细胞内流/功能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。目的1将确定中性粒细胞和/或巨噬细胞内流/功能的哪个方面在高氧诱导的肺损伤开始时对新生儿肺部生化氧化应激贡献最大。目的1将确定中性粒细胞和/或巨噬细胞内流/功能的哪个方面在高氧诱导的肺损伤开始时对新生儿肺部生化氧化应激贡献最大。目的2将确定白细胞内流/功能对导致肺泡异常发育的DNA损伤、生长停滞和病理性细胞凋亡的具体贡献。目的3将确定在严重氧化应激恢复期间，阻断白细胞功能是否可以安全地保持正常的肺泡发育。

项目成果

Antimacrophage chemokine treatment prevents neutrophil and macrophage influx in hyperoxia-exposed newborn rat lung.

抗巨噬细胞趋化因子治疗可防止中性粒细胞和巨噬细胞流入高氧暴露的新生大鼠肺部。

• DOI: 10.1152/ajplung.00414.2002
• 发表时间: 2004
• 期刊: American journal of physiology. Lung cellular and molecular physiology
• 作者: Vozzelli,MichaelA;Mason,SNicholas;Whorton,MaryH;AutenJr,RichardL
• 通讯作者: AutenJr,RichardL

Airway smooth muscle relaxation is impaired in mice lacking the p47phox subunit of NAD(P)H oxidase.

缺乏 NAD(P)H 氧化酶 p47phox 亚基的小鼠气道平滑肌松弛受损。

• DOI: 10.1152/ajplung.00384.2007
• 发表时间: 2008
• 期刊: American journal of physiology. Lung cellular and molecular physiology
• 作者: Chitano,Pasquale;Wang,Lu;Mason,StanleyN;Auten,RichardL;Potts,ErinN;Foster,WilliamM;Sturrock,Anne;Kennedy,ThomasP;Hoidal,JohnR;Murphy,ThomasM
• 通讯作者: Murphy,ThomasM

Opposing effects of 60% oxygen and neutrophil influx on alveologenesis in the neonatal rat.

• DOI: 10.1164/rccm.200402-215oc
• 发表时间: 2004-12
• 期刊: American journal of respiratory and critical care medicine
• 影响因子: 24.7
• 作者: M. Yi;R. Jankov;R. Belcastro;Daryl Humes;I. Copland;Samuel Shek;N. Sweezey;M. Post;K. Albertine;R. Auten;A. Tanswell

Mast cells mediate hyperoxia-induced airway hyper-reactivity in newborn rats.

• DOI: 10.1203/pdr.0b013e3181e0cd97
• 发表时间: 2010-07
• 期刊: Pediatric research
• 影响因子: 3.6
• 作者: Schultz ED;Potts EN;Mason SN;Foster WM;Auten RL
• 通讯作者: Auten RL