Role of Squamous Metaplasia in Small Airways Disease in COPD

描述(申请人提供)：慢性阻塞性肺疾病(COPD)是由于气囊壁的丧失和由于疤痕造成的呼吸道狭窄引起的。目前，还没有有效的治疗COPD的方法。虽然肺泡的丧失不太可能是可逆的，但呼吸道的狭窄代表了一个可能的治疗靶点。转化生长因子β是一种引起瘢痕形成的有效分子，有大量证据表明它在气道壁狭窄中发挥作用。然而，在发挥作用之前，转化生长因子-β必须处于激活状态。我们的初步数据表明，在COPD中，转化生长因子β的激活是由另外两个分子引起的，称为整合素，位于不同类型的呼吸道细胞表面。此外，我们的初步研究表明，整合素介导的转化生长因子-β在呼吸道细胞类型中的激活与气道阻塞的恶化有关。这一数据表明，整合素可能是COPD的新治疗靶点。烟草烟雾的主要有毒成分是氧自由基。自由基可能在增强整合素的表达和整合素介导的转化生长因子-β的激活中起作用，因为我们的初步数据表明，活性氧物种(ROS)启动了整合素介导的转化生长因子-β活化的自我放大循环。最终，转化生长因子-β的活性增加会导致纤毛形成的呼吸道衬里细胞被类似于表皮细胞的鳞状上皮(称为鳞状化生)所取代。此外，我们最近发表的研究表明，取代了正常纤毛上皮的鳞状上皮开始精心设计其他刺激呼吸道瘢痕形成的蛋白质。鳞状化生与COPD的呼吸道阻塞有关，但传统上被视为对环境应激的适应性反应，而不是致病过程的一部分。据我们所知，我们的研究首次表明鳞状化生可能积极参与了气道增厚的发病机制。在这个方案中，我们测试了整合素促进鳞状化生的假设，鳞状化生增加了气道壁细胞对整合素依赖的转化生长因子-β的激活，从而导致气道壁增厚。我们将使用新鲜衍生的原代人类呼吸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确定鳞状化生在COPD小气道疾病中的作用和机制的关键一步。公共卫生相关性：该实验利用原代人体细胞系统首次探索鳞状化生在COPD气道壁增厚发病机制中的作用和机制。这项提案的成功完成将在该领域取得亟需的进展，因为它将探索香烟烟雾诱导的鳞状化生的机制，以及鳞状化生细胞产生纤维化细胞因子的机制。这些将是确定av？6和鳞状化生为慢性阻塞性肺疾病治疗因素的关键实验。

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.