Apoptosis and defective repair in COPD

COPD 中的细胞凋亡和修复缺陷

• 批准号: 8204528
• 负责人: PETER M HENSON
• 金额: $ 68.82万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8204528
• 关键词: Address; Alveolar; Alveolar Cell; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Apoptotic; Biological Markers; Blood; Cause of Death; Cells; Chronic Obstructive Airway Disease; Cigarette smoke-induced emphysema; Clinical; Coupled; Data; Defect; Disease Progression; Epidemiologic Studies; Excision; Generations; Growth Factor; Homeostasis; In Vitro; Inflammation Mediators; Inflammatory Response; Injury; Intervention Studies; Label; Lead; Lovastatin; Lung; Monitor; Mononuclear; Mus; Outcome; Pathway interactions; Patients; Peptide Hydrolases; Phagocytes; Process; Pulmonary Emphysema; Risk; Rodent; Safety; Sampling; Smoker; Structure; System; United States; base; cell injury; cigarette smoking; cigarette smoking; disability; human subject; improved; lung repair; non-smoker; non-smoking; prevent; repaired; response; statistics; tissue repair; uptake

DESCRIPTION (provided by applicant): The central thesis of this project is that normal alveolar cell homeostasis is dysregulated in COPD. Increased apoptosis of alveolar cells, coupled with the defective ability to recognize, clear and replace these cells, is suggested to lead to loss of alveolar structure and emphysema. Recognition of apoptotic cells is a highly regulated process that results not only in their removal but also in generation of anti-inflammatory mediators, anti-proteases and growth factors, all of which are decreased in COPD. We further suggest that these processes involve activation of the Wnt/catenin pathways - also presumptively altered in COPD. Here we will compare these putative defective responses in smokers and COPD patients to non-smoking controls. In addition, evidence of defective cell replication and ¿-catenin responses will be similarly examined and correlated with the altered response to, and clearance of, apoptotic cells. Statins have been shown to enhance the removal of apoptotic cells, to prevent cigarette smoke-induced emphysema in rodents, and in recent epidemiologic studies, to improve clinical outcomes in COPD patients. Accordingly, lovastatin will be examined in pilot intervention studies with COPD patients for its ability to reverse the defects in apoptotic cell clearance, enhance suppression of inflammatory mediators, proteases, and restore growth factors and ¿-catenin pathways. Since statins are also known to have direct anti-inflammatory and immunomodulatory effects that go beyond their ability to enhance apoptotic cell removal, lovastatin-treated patients will also be followed for possible reduction in the inflammatory responses. Preliminary evidence for defects in apoptotic cell uptake by circulating mononuclear phagocytes in COPD will be followed to address systemic, and perhaps fundamental, functional abnormalities, effects of statins, and also, potentially, to develop blood-based biomarkers. We suggest that these studies and intervention will show reversal of processes leading to disease progression and even, possibly evidence of enhanced lung repair. Chronic Obstructive Lung Disease (COPD) is the 4th leading cause of death and disability in the United States, and is generally associated with current or former cigarette smoking. This proposal will explore the hypothesis that in COPD, abnormal responses of the lung to damaged cells leads to defective tissue repair after injury and that this then contributes to the structural abnormalities seen in this condition. The studies will involve in vitro and animal systems as well as samples from COPD patients, smokers without COPD and normal non- smokers. We will also perform an interventional study in COPD patients with lovastatin, which is known to reverse the defective response to damaged cells in vitro and in mice exposed to cigarette smoke, and we propose, may also reverse the abnormal effects in our patients.

描述（由申请人提供）：该项目的中心论点是正常肺泡细胞稳态在慢性阻塞性肺病（COPD）中失调。肺泡细胞凋亡增加，加上识别、清除和替换这些细胞的能力缺陷，可能会导致肺泡结构丧失和肺气肿。凋亡细胞的识别是一个高度调控的过程，不仅导致凋亡细胞的清除，而且导致抗炎介质、抗蛋白酶和生长因子的产生，所有这些在慢性阻塞性肺病中都会减少。我们进一步表明，这些过程涉及 Wnt/连环蛋白途径的激活 - 推测在慢性阻塞性肺病中也发生了改变。在这里，我们将吸烟者和慢性阻塞性肺病患者与不吸烟对照者的这些假定的缺陷反应进行比较。此外，细胞复制缺陷和β-连环蛋白反应的证据也将进行类似的检查，并与凋亡细胞的反应改变和清除相关联。他汀类药物已被证明可以增强凋亡细胞的清除，预防啮齿类动物吸烟引起的肺气肿，并且在最近的流行病学研究中，可以改善慢性阻塞性肺病患者的临床结果。因此，洛伐他汀将在慢性阻塞性肺病患者的试点干预研究中进行检验，以确定其逆转凋亡细胞清除缺陷、增强对炎症介质、蛋白酶的抑制以及恢复生长因子和β-连环蛋白途径的能力。由于他汀类药物还具有直接的抗炎和免疫调节作用，超出了其增强凋亡细胞清除的能力，因此洛伐他汀治疗的患者也将被跟踪，以可能减少炎症反应。慢性阻塞性肺病（COPD）中循环单核吞噬细胞摄取凋亡细胞缺陷的初步证据将用于解决系统性的、也许是根本性的功能异常、他汀类药物的影响，并有可能开发基于血液的生物标志物。我们建议这些研究和干预措施将显示导致疾病进展的过程的逆转，甚至可能显示增强肺部修复的证据。慢性阻塞性肺病 (COPD) 是美国第四大死亡和残疾原因，通常与当前或以前吸烟有关。该提案将探讨以下假设：在慢性阻塞性肺病中，肺部对受损细胞的异常反应导致损伤后组织修复缺陷，进而导致这种情况下出现的结构异常。这些研究将涉及体外和动物系统以及来自慢性阻塞性肺病患者、非慢性阻塞性肺病吸烟者和正常非吸烟者的样本。我们还将用洛伐他汀对慢性阻塞性肺病患者进行一项介入研究，众所周知，洛伐他汀可以在体外和暴露于香烟烟雾的小鼠中逆转对受损细胞的缺陷反应，我们建议，也可能逆转我们患者的异常影响。