Apoptosis and defective repair in COPD

描述(申请人提供)：本项目的中心论题是慢性阻塞性肺疾病患者的正常肺泡细胞动态平衡失调。肺泡细胞的凋亡增加，加上识别、清除和替换这些细胞的能力缺陷，被认为是导致肺泡结构丧失和肺气肿的原因。对凋亡细胞的识别是一个高度调控的过程，不仅导致它们的去除，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中都会减少。我们进一步认为，这些过程涉及Wnt/Catenin通路的激活--推测在COPD中也会改变。在这里，我们将把吸烟者和COPD患者的这些假定的缺陷反应与不吸烟的对照组进行比较。此外，细胞复制缺陷和连环蛋白反应的证据将被类似地检查，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，他汀类药物被证明可以促进凋亡细胞的清除，预防吸烟引起的啮齿动物肺气肿，并改善COPD患者的临床结果。因此，洛伐他汀将在COPD患者的试验性干预研究中接受检验，以了解其逆转细胞凋亡清除缺陷的能力，增强对炎症介质、蛋白酶的抑制，并恢复生长因子和连环蛋白途径。由于已知他汀类药物还具有直接的抗炎和免疫调节作用，超出了它们促进凋亡细胞清除的能力，洛伐他汀治疗的患者也将被跟踪观察，以可能减少炎症反应。COPD患者外周血单核吞噬细胞的凋亡细胞摄取缺陷的初步证据将被用来解决他汀类药物的全身性，也许是根本性的功能异常，也可能是开发基于血液的生物标记物。我们认为，这些研究和干预将显示逆转导致疾病进展的过程，甚至可能是增强肺修复的证据。慢性阻塞性肺病(COPD)是美国第四大致死和致残原因，通常与现在或以前吸烟有关。这项建议将探索这样一种假设，即在COPD中，肺对受损细胞的异常反应会导致损伤后组织修复的缺陷，从而导致这种情况下的结构异常。这些研究将涉及体外和动物系统，以及来自COPD患者、非COPD吸烟者和正常不吸烟者的样本。我们还将在使用洛伐他汀的COPD患者中进行一项干预性研究，众所周知，洛伐他汀可以逆转体外和暴露于香烟烟雾中的小鼠对受损细胞的缺陷反应，我们认为，也可能逆转我们患者的异常影响。

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.