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.
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