Role of Squamous Metaplasia in Small Airways Disease in COPD

描述（由申请人提供）：慢性阻塞性肺疾病（COPD）是由气囊壁丧失和气道狭窄引起的。目前，还没有治疗慢性阻塞性肺病的有效方法。虽然肺泡的丧失不太可能是可逆的，但气道狭窄代表了一个可能的治疗目标。TGF-¿是一种导致瘢痕形成的强效分子，有充分证据表明它在气道壁狭窄中起作用。然而，TGF-¿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-¿活化是由位于气道细胞类型表面的另外两种称为整合素的分子引起的。此外，我们的前期研究表明，气道细胞类型中整合素介导的TGF-¿激活与气道阻塞恶化相关。这一数据提示整合素可能是COPD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-¿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-¿激活的自我放大循环。最终，增加的TGF-¿激活导致纤毛气道内衬细胞被类似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，鳞状上皮取代了气道正常的纤毛上皮，开始产生其他刺激气道瘢痕形成的蛋白质。在慢性阻塞性肺病中，鳞状皮化生与气道阻塞有关，但传统上被认为是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，我们的研究首次表明，鳞状化生可能积极促进气道增厚的发病机制。在本文中，我们验证了整合素促进鳞状皮化生的假设，这增加了气道壁细胞对整合素依赖性TGF-¿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。本课题的成功完成将是确立COPD小气道病变中鳞状化生的作用和机制的关键转译一步。公共卫生相关性：利用原代人细胞系统提出的实验首次探讨了肺鳞状化生在COPD气道壁增厚发病机制中的作用和机制。本研究的成功完成将为该领域提供一个急需的进展，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对纤维原性细胞因子的阐述。这些将是关键的实验，将确定av - 6和鳞状化生作为慢性阻塞性肺病的治疗药物。

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.