Role of Squamous Metaplasia in Small Airways Disease in COPD

鳞状上皮化生在慢性阻塞性肺病小气道疾病中的作用

• 批准号: 7924811
• 负责人: Stephen L Nishimura
• 金额: $ 48.28万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7924811
• 关键词: Accounting; Air; Air Sacs; Alveolus; Antioxidants; Cause of Death; Cell Line; Cells; Chronic Obstructive Airway Disease; Cicatrix; Cigarette; Complex; Data; Development; Epithelial; Epithelial Cells; Event; Factor Analysis; Fibroblasts; Free Radicals; Gene Silencing; Human; Immune; Integrins; Investigation; Knowledge; Liquid substance; Lung; Mediating; Mesenchymal; Modeling; Obstruction; Oxidative Stress; Pathogenesis; Pathologic; Pathway interactions; Patients; Pattern; Phenotype; Pilot Projects; Play; Process; Proteins; Publishing; Reactive Oxygen Species; Regulation; Reporting; Role; Signal Pathway; Smoke; Smoker; Squamous Differentiation; Squamous Epithelium; Squamous Metaplasia; Stress; Surface; System; Testing; Therapeutic Agents; Tissues; Tobacco smoke; Translations; Work; airway epithelium; airway obstruction; airway remodeling; cell type; cigarette smoke-induced; cigarette smoking; cigarette smoking; cytokine; effective therapy; free radical oxygen; human disease; improved; inhibitor/antagonist; knock-down; lung development; new therapeutic target; promoter; public health relevance; research study; response; response to injury; small airways disease; spatiotemporal; therapeutic target; transcription factor

DESCRIPTION (provided by applicant): Chronic Obstructive Pulmonary Disease (COPD) is caused by loss of the walls of air sacs and by narrowing of the airways due to scarring. Currently, there are no effective therapies to treat COPD. While the loss of alveoli is unlikely to be reversible, the narrowing of the airways represents a possible therapeutic target. TGF-¿ is a potent molecule that causes scarring and there is ample evidence that it plays a role in airway wall narrowing. However, TGF-¿ must be made active before it can function. Our preliminary data suggest that in COPD, TGF-¿ activation is caused by two other molecules, called integrins, located on the surface of airway cell types. Furthermore, our pilot studies suggest that integrin-mediated TGF-¿ activation in airway cell types correlates with worsening airway obstruction. This data suggests that integrins might be novel therapeutic targets in COPD. Major toxic components of tobacco smoke are oxygen free radicals. Free radicals likely play a role in amplifying integrin expression and integrin-mediated TGF-¿ activation since our preliminary data suggest that reactive oxygen species (ROS) initiate a self-amplifying loop of integrin-mediated activation of TGF-¿. Ultimately, increased TGF-¿ activation leads to replacement of the ciliated airway lining cells with squamous epithelium (called squamous metaplasia), which resemble epidermal cells. Furthermore, our recently published studies suggest that the squamous epithelium that has replaced the normal ciliated epithelium of the airway begins to elaborate the other proteins that stimulate scarring of the airways. Squamous metaplasia is associated with airway obstruction in COPD but has traditionally been viewed as an adaptive response to environmental stress rather than a part of the pathogenic process. Our studies are the first, to our knowledge, that suggest that squamous metaplasia may actively contribute to the pathogenesis of airway thickening. Here, in this proposal, we test the hypothesis that integrins contribute to squamous metaplasia, which increases integrin-dependent activation of TGF-¿ by the cells of the airway wall, which leads to airway wall thickening. We will use freshly derived primary human airway cell types for these investigations to maximize the application of our findings to human disease. The successful completion of this project will be a crucial translation step in establishing the role and mechanism of squamous metaplasia in small airways disease in COPD. PUBLIC HEALTH RELEVANCE: The experiments proposed, utilizing primary human cell systems are the first to explore the role and mechanism of squamous metaplasia in the pathogenesis of airway wall thickening in COPD. Successful completion of this proposal will provide a much needed advance in the field as it will explore the mechanisms of cigarette-smoke induced squamous metaplasia and the elaboration of fibrogenic cytokines by the squamous metaplasia cells. These will be key experiments that will identify av¿6 and squamous metaplasia as therapeutic agents in COPD.

描述（由申请人提供）：慢性阻塞性肺疾病（COPD）是由气囊壁的损失和由于疤痕导致的气道狭窄引起的。目前，还没有有效的治疗方法来治疗COPD。虽然肺泡的丧失不太可能是可逆的，但气道的狭窄是一个可能的治疗靶点。TGF-β是一种引起瘢痕形成的有效分子，有充分的证据表明它在气道壁狭窄中起作用。然而，TGF-β必须在发挥作用之前被激活。我们的初步数据表明，在COPD中，TGF-β激活是由位于气道细胞类型表面的另外两种分子引起的，称为整合素。此外，我们的初步研究表明，气道细胞类型中整合素介导的TGF-β活化与气道阻塞恶化相关。这些数据表明，整合素可能是COPD的新的治疗靶点。烟草烟雾的主要有毒成分是氧自由基。自由基可能在放大整合素表达和整合素介导的TGF-β激活中发挥作用，因为我们的初步数据表明活性氧（ROS）启动了整合素介导的TGF-β激活的自放大循环。最终，增加的TGF-β活化导致纤毛气道衬里细胞被鳞状上皮细胞（称为鳞状化生）替代，鳞状上皮细胞类似于表皮细胞。此外，我们最近发表的研究表明，鳞状上皮细胞已经取代了正常的纤毛上皮细胞的气道开始阐述其他蛋白质刺激气道疤痕。鳞状上皮化生与COPD的气道阻塞有关，但传统上被视为对环境压力的适应性反应，而不是致病过程的一部分。据我们所知，我们的研究是第一个表明鳞状上皮化生可能积极促进气道增厚的发病机制。在这里，在这个建议中，我们测试的假设，整合素有助于鳞状上皮化生，增加整合素依赖性激活TGF-β的细胞的气道壁，这导致气道壁增厚。我们将使用新鲜衍生的原代人类气道细胞类型进行这些研究，以最大限度地将我们的发现应用于人类疾病。该项目的成功完成将是建立鳞状上皮化生在COPD小气道疾病中的作用和机制的关键翻译步骤。公共卫生相关性：利用原代人类细胞系统提出的实验首次探索了鳞状上皮化生在COPD气道壁增厚发病机制中的作用和机制。该提案的成功完成将在该领域提供急需的进展，因为它将探索香烟烟雾诱导的鳞状化生的机制和鳞状化生细胞产生纤维化细胞因子的机制。这些将是关键的实验，将确定α v β 6和鳞状上皮化生作为COPD的治疗药物。