Novel Anti-inflammatory Activities For ADAM8 In Pulmonary Emphysema

ADAM8 在肺气肿中的新型抗炎活性

• 批准号: 8386987
• 负责人: CAROLINE A OWEN
• 金额: $ 15.95万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8386987
• 关键词: Address; Affect; Alveolar wall; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Apoptotic; Binding; Blood; Bone Marrow; Cause of Death; Cell Death; Cells; Chronic Obstructive Airway Disease; Cigarette Smoker; Cigarette smoke-induced emphysema; Cytoplasmic Tail; Data; Death Rate; Development; Disease Progression; Disintegrins; Exposure to; Half-Life; Human; In Vitro; Incidence; Individual; Lentivirus Vector; Leukocytes; Link; Lung; Lung Inflammation; Measures; Mediating; Messenger RNA; Metalloproteases; Modeling; Mus; Pathway interactions; Patients; Peptide Hydrolases; Phagocytes; Plasma; Play; Proteins; Pulmonary Emphysema; Risk Factors; Rodent; Role; Sampling; Severity of illness; Source; Structure of parenchyma of lung; Surface; Testing; Therapeutic; Transgenic Mice; Tyrosine Kinase Inhibitor; United States; Wild Type Mouse; air filter; aspergillopepsin II; c-fms Proto-Oncogenes; cigarette smoke-induced; cigarette smoking; gain of function; improved; in vitro Assay; in vivo; insight; loss of function; macrophage; macrophage product; mortality; novel; overexpression; prevent; promoter; selective expression; src-Family Kinases; translational study; treatment strategy

DESCRIPTION (provided by applicant): COPD is associated with high mortality and there is an urgent need to develop new treatments that limit disease progression. Although much is known about how cigarette smoke (CS, the main risk factor for COPD) promotes COPD development, little is known about anti-inflammatory pathways that likely protect some cigarette smokers from developing COPD. Our novel data show that a proteinase with a disintegrin and a metalloproteinase (MP) domain-8 (Adam8) is robustly up-regulated in lung macrophages in wild type (WT) mice exposed to CS. However, CS-exposed Adam8-/- mice have higher lung macrophage counts and worse emphysema associated with decreased lung macrophage apoptosis than CS-exposed WT mice. We hypothesize that Adam8 has anti-inflammatory and protective activities in the CS-exposed murine lung by promoting macrophage apoptosis thereby reducing the half life of destructive macrophages in the lung. Although CS up-regulates anti-inflammatory Adam8 in lung macrophages in mice, ADAM8 levels are reduced in plasma and lung samples from COPD patients when compared to samples from control subjects. We hypothesize that reduced blood and plasma levels of ADAM8 in human COPD patients is linked to disease severity in human COPD via ADAM8 regulating macrophage survival in human lungs. We will test these hypotheses by pursuing the following Specific Aims: Aim 1: We will use a loss-of-function strategy (studies of WT vs. Adam8-/- mice in the CS exposure model) to test the hypothesis that Adam8 protects the CS-exposed murine lung from developing emphysema by promoting macrophage cell death. We will identify the mechanisms involved. We will also determine the critical cellular sources of anti-inflammatory Adam8 in the lung by generating and studying Adam8 bone marrow chimeric mice in the murine CS exposure model of emphysema. Aim 2: We will use gain-of-function strategies to confirm that Adam8 has anti-inflammatory activities in the CS-exposed murine lung by promoting lung macrophage apoptosis. We will generate transgenic mice that overexpress human Adam8 in an inducible fashion in lung macrophages. We will also use lentiviral vectors to selectively transduce murine lung macrophages with hADAM8 in a durable fashion. We will test whether these strategies prevent CS-induced emphysema and/or limit disease progression. Aim 3: We will test our hypothesis that COPD patients have reduced expression of ADAM8. We will measure ADAM8 protein and mRNA levels in blood and lung samples from COPD patients versus control subjects and correlate ADAM8 levels with disease severity, lung macrophage counts, and lung macrophage apoptosis. Significance: Our studies may provide novel insights into the mechanism(s) by which ADAM8 mediates its protective activities in the CS-exposed lung. Our studies may also identify ADAM8 as a novel target for developing therapeutic strategies to limit lung destruction and disease progression in patients with COPD.

描述（由申请人提供）：COPD与高死亡率相关，迫切需要开发新的治疗方法来限制疾病进展。尽管人们对吸烟（CS， COPD的主要危险因素）如何促进COPD的发展了解甚多，但对可能保护一些吸烟者不患COPD的抗炎途径知之甚少。我们的新数据表明，在暴露于CS的野生型（WT）小鼠的肺巨噬细胞中，一种具有崩解素和金属蛋白酶（MP）结构域8 （Adam8）的蛋白酶显著上调。然而，cs暴露的Adam8-/-小鼠比cs暴露的WT小鼠有更高的肺巨噬细胞计数和更严重的肺气肿，并伴有肺巨噬细胞凋亡减少。我们假设Adam8通过促进巨噬细胞凋亡从而减少肺中破坏性巨噬细胞的半衰期，在cs暴露的小鼠肺中具有抗炎和保护作用。虽然CS上调小鼠肺巨噬细胞中的抗炎Adam8，但与对照组相比，COPD患者血浆和肺样本中的Adam8水平降低。我们假设人类COPD患者血液和血浆ADAM8水平的降低通过ADAM8调节人肺巨噬细胞存活与人类COPD疾病严重程度相关。我们将通过追求以下具体目标来验证这些假设：目的1：我们将使用功能丧失策略（在CS暴露模型中WT与Adam8-/-小鼠的研究）来验证Adam8通过促进巨噬细胞死亡来保护CS暴露小鼠肺免受肺气肿的假设。我们将确定所涉及的机制。我们还将通过在小鼠CS暴露肺气肿模型中生成和研究Adam8骨髓嵌合小鼠，确定肺中抗炎Adam8的关键细胞来源。目的2：我们将使用功能获得策略来证实Adam8通过促进肺巨噬细胞凋亡在cs暴露的小鼠肺中具有抗炎活性。我们将以诱导方式在肺巨噬细胞中产生过表达人Adam8的转基因小鼠。我们还将使用慢病毒载体以持久的方式选择性地转导hADAM8小鼠肺巨噬细胞。我们将测试这些策略是否可以预防cs诱导的肺气肿和/或限制疾病进展。目的3：我们将验证COPD患者ADAM8表达降低的假设。我们将测量COPD患者与对照组血液和肺样本中的ADAM8蛋白和mRNA水平，并将ADAM8水平与疾病严重程度、肺巨噬细胞计数和肺巨噬细胞凋亡联系起来。意义：我们的研究可能为ADAM8在cs暴露肺中调节其保护活性的机制提供新的见解。我们的研究还可能确定ADAM8作为开发限制COPD患者肺破坏和疾病进展的治疗策略的新靶点。