Environmental Cadmium and COPD

肺是可吸入环境毒物的主要门户，包括重金属，如镉 (Cd)，其被认为是导致慢性阻塞性肺病（COPD）的原因。COPD是第三种 美国最大的死亡原因。气道重塑伴小气道管腔和气流丧失 阻塞先于空气腔扩大和肺气肿。气道重塑与大量 和细胞外基质蛋白的增加。波形蛋白是一种细胞内3型丝 会引发支气管周围纤维化COPD的患病率是邮政编码的两倍， 超级基金网站位于伯明翰，亚拉巴马相比，当一个控制邮政编码类似 人口统计学和吸烟率。我们假设慢性低剂量镉（Cd）暴露诱导 波形蛋白-线粒体动力学的改变导致线粒体功能障碍和异常激活 导致细支气管管腔狭窄和随后的COPD。我们将研究 这一假说的具体目的如下：（1）确定是否暴露于镉在一个队列的吸烟者 来自伯明翰社区的从不吸烟者预测气道重塑和COPD的易感性。（二） 确定镉介导波形蛋白-线粒体动力学改变的机制， 成纤维细胞活化(3)确定低剂量Cd或pSer 39 Vim是否诱导气道重塑， COPD小鼠模型中的气腔扩大与成纤维细胞侵袭、ECM沉积和 凋亡抵抗这些研究将直接解决我们理解的一个重大差距， 镉在COPD发病机制中的作用及线粒体波形蛋白丝的作用 体内平衡呼出气冷凝物中COPD的早期生物标志物可能有助于我们识别疾病 易感性重要的是，这些研究可能为COPD患者提供新的治疗策略。

The lung is a major portal for respirable environmental toxicants including heavy metals such as cadmium (Cd), which is recognized to cause chronic obstructive pulmonary disease (COPD). COPD is the third largest cause of mortality in the US. Airway remodeling with loss of the lumen of small airways and airflow obstruction precede airspace enlargement and emphysema. Airway remodeling is associated with a profusion of airway fibroblasts and an increase in extracellular matrix proteins. Vimentin is an intracellular type 3 filament that can trigger peribronchial fibrosis. The prevalence of COPD is twice as high in a zip code where a Superfund site is located in Birmingham, Alabama when compared to a control zip code with similar demographics and smoking prevalence. We postulate that chronic low dose cadmium (Cd) exposure induces alterations in vimentin-mitochondrial dynamics that results in mitochondrial dysfunction and aberrant activation of peribronchiolar fibroblasts leading to bronchiolar luminal narrowing and subsequent COPD. We will examine this hypothesis in the following specific aims: (1) Determine whether exposure to Cd in a cohort of smokers and never-smokers from a Birmingham community predicts susceptibility to airway remodeling and COPD. (2) Determine the mechanisms by which Cd mediates alterations in vimentin-mitochondrial dynamics to regulate fibroblast activation. (3) Determine whether low dose Cd, or pSer39Vim induced airway remodeling and airspace enlargement in a mouse model of COPD is associated with fibroblast invasion, ECM deposition and apoptosis resistance. These studies will directly address a significant gap in our understanding of how cadmium contributes to the pathogenesis of COPD and the role of vimentin filaments in mitochondrial homeostasis. Early biomarkers of COPD in exhaled breath condensate may help us recognize disease susceptibility. Importantly, these studies may provide novel therapeutic strategies in patients with COPD.