Apoptosis and defective repair in COPD

COPD 中的细胞凋亡和修复缺陷

• 批准号: 7547055
• 负责人: PETER M HENSON
• 金额: $ 69.21万
• 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 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7547055
• 关键词: Address; Alveolar; Alveolar Cell; Alveolar wall; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Apoptotic; Biological Markers; Blood; Cause of Death; Cells; Chronic Obstructive Airway Disease; Cigarette smoke-induced emphysema; Clinical; Collectins; Coupled; Defect; Development; Digestion; Disease; Disease Progression; Endothelium; Epidemiologic Studies; Epithelial; Epithelial Cells; Epithelium; Epoprostenol; Excision; Generations; Germ Cells; Growth; Growth Factor; Homeostasis; Impairment; In Vitro; Inflammation; Inflammation Mediators; Inflammatory Response; Injury; Interleukin-10; Intervention; Intervention Studies; Lead; Lovastatin; Lung; Lung Inflammation; Maintenance; Mononuclear; Mus; Natural regeneration; Necrosis; Outcome; Pathway interactions; Patients; Peptide Hydrolases; Phagocytes; Physiological; Process; Production; Pulmonary Emphysema; Pulmonary Surfactant-Associated Protein D; Rodent; Sampling; Signal Transduction; Smoker; Smoking; Sputum; Structure; System; Time; Tissues; United States; Vascular Endothelial Growth Factors; Work; Wound Healing; airway inflammation; base; cell injury; cigarette smoking; cigarette smoking; disability; human subject; immunogenic; improved; macrophage; monocyte; non-smoker; non-smoking; prevent; repaired; response; rho; 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COPD患者正常肺泡细胞稳态失调。肺泡细胞凋亡增加，再加上识别、清除和替换这些细胞的能力缺陷，可能导致肺泡结构丧失和肺气肿。对凋亡细胞的识别是一个高度调控的过程，不仅导致它们被清除，还导致抗炎介质、抗蛋白酶和生长因子的产生，所有这些在COPD中都减少。我们进一步认为，这些过程涉及Wnt/catenin通路的激活——也可能在COPD中发生改变。在这里，我们将比较吸烟者和COPD患者与非吸烟对照组的这些假定的缺陷反应。此外，缺陷细胞复制和¿-catenin反应的证据也将被类似地检查，并与对凋亡细胞的改变反应和清除相关。在最近的流行病学研究中，他汀类药物已被证明可以增强凋亡细胞的清除，防止香烟引起的啮齿动物肺气肿，并改善慢性阻塞性肺病患者的临床结果。因此，洛伐他汀将在COPD患者的试点干预研究中检验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¿-catenin通路的能力。由于已知他汀类药物还具有直接的抗炎和免疫调节作用，这些作用超出了其增强凋亡细胞清除的能力，因此也将对洛伐他汀治疗的患者进行随访，以可能减少炎症反应。慢性阻塞性肺病患者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他汀类药物的全体性（可能是根本的）功能异常，以及潜在的基于血液的生物标志物的开发。我们认为这些研究和干预将显示导致疾病进展的过程逆转，甚至可能是增强肺修复的证据。慢性阻塞性肺疾病（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。本研究将探讨COPD中肺对受损细胞的异常反应导致损伤后组织修复缺陷的假说，并由此导致COPD中结构异常。这些研究将涉及体外和动物系统，以及来自COPD患者、非COPD吸烟者和正常非吸烟者的样本。我们还将在COPD患者中进行洛伐他汀的介入研究，已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，并且我们认为，也可能逆转我们患者的异常作用。