Role of Metalloproteinases in Mucin Overproduction in COPD

描述（由申请人提供）：问题。慢性阻塞性肺疾病（COPD）是第四大死因，显然是由吸烟和其他环境刺激物引起的。COPD的一个特征涉及气道上皮的表型转变，其特征在于纤毛细胞和Clara细胞减少和粘液产生细胞增加。重要的是，香烟烟雾中的刺激物，特别是丙烯醛，可以引发这些事件。虽然基质金属蛋白酶（MMPs）在COPD中的可能作用已被充分认识，但MMPs激活如何协调上皮细胞功能的持续变化的机制尚不确定。因此，本提案的总体目标是确定激活MMPs/上皮生长因子受体（EGFR）信号传导的分子机制，从而导致持续的粘液过度生产。假设：丙烯醛/香烟烟雾最初激活MMPs，增加粘蛋白转录。此外，慢性暴露进一步刺激MMPs的转录，并抑制金属蛋白酶组织抑制剂的转录。结合起来，这些即时和延迟的反应导致持续的粘液产生。目标。确定控制以下因素的分子机制：1）气道上皮细胞中MMP 14活化/表达增加，2）气道上皮细胞中MMP 9活化/表达增加，3）小鼠粘蛋白产生中MMP 14/MMP 9/EGFR信号传导。意义该提案旨在建立吸入刺激物激活调节粘蛋白基因表达的信号通路的机制。在这个项目完成后，我们期望更好地了解丙烯醛或香烟烟雾如何1）激活MMP 14，2）修改控制持续MMP 9转录的细胞信号传导，3）调节小鼠气道中急性和持续的粘蛋白产生，以及4）产生一种可以通过前蛋白转化酶/ EGFR抑制来预防的持续粘蛋白产生机制。项目叙述。这项研究是重要的和创新的，因为它将确定丙烯醛和香烟烟雾可以激活基质金属蛋白酶（MMPs）和启动控制持续粘蛋白生产的事件的机制。在该项目完成后，我们预计：1）更好地理解丙烯醛激活人气道上皮细胞中MMP 14的机制，2）了解丙烯醛在体外改变控制持续MMP 9产生/激活和粘蛋白产生的细胞信号传导的机制，3）鉴定在香烟烟雾和丙烯醛暴露的动物模型的气道中急性和持续粘蛋白产生中调节的事件，和4）确定蛋白转化酶/EGFR抑制剂是否可以预防导致持续性粘蛋白产生的事件。本研究的预期人类健康影响是对针对MMP 14/MMP 9/EGFR信号传导的治疗可用于治疗COPD中粘液过度产生的可能性的循证科学验证或反驳。

DESCRIPTION (provided by applicant): Problem. Chronic obstructive pulmonary disease (COPD), the fourth leading cause of death, is clearly caused by cigarette smoking and other environmental irritants. One feature of COPD involves a phenotypic shift in the airway epithelium characterized by decreased ciliated and Clara cells and increased mucus producing cells. Importantly, irritants in cigarette smoke, particularly acrolein, can trigger these events. Although the possible roles of matrix metalloproteinases (MMPs) in COPD are well recognized, the mechanisms of how MMP-activation orchestrates a persistent change in epithelial cell function are uncertain. Thus, the overall objective of this proposal is to determine the molecular mechanisms activating MMPs/epithelial growth factor receptor (EGFR) signaling that in turn lead to persistent mucus overproduction. Hypothesis: Acrolein/cigarette smoke initially activates MMPs that increase mucin transcription. In addition, chronic exposure further stimulates transcription of MMPs, and represses transcription of tissue inhibitors of metalloproteinase. Combined, these immediate and delayed responses lead to persistent mucus production. Aims. To determine the molecular mechanisms controlling: 1) increased MMP14 activation/ expression in airway epithelial cells, 2) increased MMP9 activation/expression in airway epithelial cells, and 3) MMP14/MMP9/ EGFR-signaling in mucin production in mice. Significance. This proposal seeks to establish the mechanisms by which inhaled irritants activate signaling pathways that regulate mucin gene expression. At the completion of this project, we expect to obtain a better understanding of how acrolein or cigarette smoke 1) activates MMP14, 2) modifies cell signaling that controls persistent MMP9 transcription, 3) modulates acute and persistent mucin production in the airways of mice, and 4) generates a mechanism to persistent mucin production that can be prevented by proprotein convertase/ EGFR inhibition. PROJECT NARRATIVE. This research is significant and innovative because it will determine the mechanisms by which acrolein and cigarette smoke can activate matrix metalloproteinases (MMPs) and initiate events controlling persistent mucin production. At the completion of this project, we expect: 1) to obtain a better understanding of the mechanisms by which acrolein activates MMP14 in human airway epithelial cells, 2) to gain knowledge into the mechanism by which acrolein modifies cell signaling that controls persistent MMP9 production/activation and mucin production in vitro, 3) to identify the events modulated in acute and persistent mucin production in the airways of an animal model of cigarette smoke and acrolein exposure, and 4) to determine whether protein convertase/EGFR inhibitors can prevent the events that leads to persistent mucin production. The anticipated human health impact of this study is an evidence-based scientific verification or refutation of the likelihood that therapeutics directed at MMP14/MMP9/EGFR signaling can be considered for the treatment of mucus overproduction in COPD.