Disarray of Injury/Regeneration Homeostasis in Smoking-Induced COPD

慢性阻塞性肺疾病（COPD）是肺部残疾和死亡的主要原因，主要由吸烟引起。最初的病理改变发生在小气道和中央小叶肺泡，伴有慢性炎症，并伴有蛋白酶、氧化剂、凋亡和其他可损伤气道和肺泡的炎症介质的局部表达。Weill - Cornell COPD SCCOR的基本主题是，当肺的再生过程不再能够维持正常的肺结构和功能时，COPD的临床表型就会发生变化。吸烟引起的气道/肺泡持续性损伤下的功能和吸烟引起的炎症宿主反应。有了这个主题，拟议的SCCOR有6个核心支持的5个项目。4个临床项目（项目1、2、4、5），均关注COPD患者肺特定成分的基因表达。一个项目是临床前（项目3），重点是肺再生。核心A、B提供支持人类受试者研究的服务，核心C、D提供生物材料分析服务，核心E侧重于培养临床研究技能的教育，核心F提供行政支持。所有的项目都使用新颖的策略来评估潜在的主题。项目1基于临床观察HIV-1+吸烟者早期肺气肿发生率高且吸烟史有限，提出通过研究肺泡巨噬细胞中的基因表达来了解哪些介质在介导肺破坏中最重要。项目2利用对果蝇和发育中的小鼠胚胎的研究发现Notch通路是分化的“看门人”，以帮助揭示COPD气道上皮中观察到的异常分化模式。项目3应用小鼠肺切除术后肺快速再生模型，解读CXCR4+VEGFR1 +血管生成前体在肺血运重建中的作用。项目4在稳态和创伤诱导气道上皮再生后的一段时间内研究用于纤毛发生的基因，以评估基因表达紊乱在COPD纤毛功能异常中的作用。项目5采用一种新开发的策略，对人小气道上皮进行重复采样，以确定与COPD发病机制相关的多类基因的异常表达，并利用这种异常的“小气道分子特征”来评估戒烟、气溶胶皮质类固醇治疗或白三烯途径抑制剂治疗对COPD相关分子通路的影响。

Chronic obstructive lung disease (COPD), a leading cause of pulmonary disability and death, is caused mainly by cigarette smoking. The initial pathologic changes are in the small airways and central lobular alveoli, with chronic inflammation and concomitant local expression of protease, oxidant, apoptotic and other inflammatory mediators capable of injuring the airways and alveoli. The theme underlying the Weill Cornell COPD SCCOR is that the clinical phenotype of COPD evolves when the regenerative process of the lung are no longer capable of maintaining normal lung structure and.function under the persistent injury to airways/alveoli caused by smoking and the inflammatory host response to smoking. With this theme, the proposed SCCOR has 5 projects supported by 6 cores. Four projects are clinical (Projects 1, 2, 4, 5), all focused on gene expression of specific components of the lung in patients with COPD. One project is pre-clinical (Project 3), focused on lung regeneration. Cores A, B provide services to support the study of human subjects, Cores C, D provide services for analysis of biologic materials, Core E is focused on education for developing clinical research skills, and Core F provides administrative support. All of the projects use novel strategies to assess the underlying theme. Project 1, based on the clinical observation that smokers that are HIV-1+ have a high incidence of emphysema at an early age and limited smoking history, proposes to study gene expression in alveolar macrophages to help understand which mediators are the most important in mediating lung destruction. Project 2 exploits the knowledge from studies of Drosophila and the developing murine embryo that the Notch pathway is a "gatekeeper" for differentiation to help unravel the abnormal pattern of differentiation observed in the airway epithelium in COPD. Project 3 applies to the murine model of rapid postpneumonectomy lung regeneration to decipher the role of CXCR4+VEGFR1 + hemangiogenic precursor to lung revascularization. Project 4 studies genes used for ciliogenesis in the steady state and over time after wounding-induced airway epithelial regeneration to assess the role of deranged gene expression in abnormal cilia function in COPD. Project 5 utilizes a newly developed strategy to repetitively sample the human small airway epithelium to define abnormal expression of multiple categories of genes implicated in the pathogenesis of COPD, and uses this abnormal "small airway molecular signature" to assess the impact of smoking cessation, aerosol corticosteroid therapy, or leukotriene pathway inhibitor therapy on molecular pathways relevant to COPD.