Abstract
Cigarette smoke exposure is a risk factor for many pulmonary diseases, including Chronic Obstructive Pulmonary Disease (COPD). Cigarette smokers are more prone to respiratory infections with more severe symptoms. In those with COPD, viral infections can lead to acute exacerbations resulting in lung function decline and death. Epithelial cells in the lung are the first line of defense against inhaled insults such as tobacco smoke and are the target for many respiratory pathogens. Endocytosis is an essential cell function involved in nutrient uptake, cell signaling, and sensing of the extracellular environment, yet, the effect of cigarette smoke on epithelial cell endocytosis is not known. Here, we report for the first time that cigarette smoke alters the function of several important endocytic pathways in primary human small airway epithelial cells. Cigarette smoke exposure impairs clathrin-mediated endocytosis and fluid phase macropinocytosis while increasing caveolin mediated endocytosis. We also show that influenza virus uptake is enhanced by cigarette smoke exposure. These results support the concept that cigarette smoke-induced dysregulation of endocytosis contributes to lung infection in smokers. Targeting endocytosis pathways to restore normal epithelial cell function may be a new therapeutic approach to reduce respiratory infections in current and former smokers.
Highlights
Cigarette smoke exposure is projected to cause over 8 million deaths worldwide by 2030 [1] and is a risk factor for many diseases such as Chronic Obstructive Pulmonary Disease (COPD)
We have previously shown that cigarette smoke impairs toll-like receptor 3 (TLR3) cleavage in primary human small airway epithelial cells resulting in impaired antiviral responses [4]
Fluorescein isothiocyanate (FITC) and Alexa Fluor (AF)594 conjugated Choleratoxin B subunit (CtxB), AF488 and AF594 conjugated bovine serum albumin (BSA), AF488 conjugated to human serum transferrin (Tfn), boron-dipyrromethene (BODIPY) labeled lactosylceraminde (LacCer), and FITC conjugated 3000 MW Dextran were purchased from Molecular Probes (Eugene, OR)
Summary
Cigarette smoke exposure is projected to cause over 8 million deaths worldwide by 2030 [1] and is a risk factor for many diseases such as COPD. Robert Davis Professorship (to PJS); and the Wright Family Professorship (to RPP) This project described in this publication was supported by the University of Rochester CTSA award number UL1TR002001 from the National Center for Advancing Translational Sciences of the National Institutes of Health. Lung epithelial cells are the first line of defense against inhaled pathogens and are the target for many respiratory viruses, the dysregulation of endocytosis in these cells may affect viral susceptibility. We investigated the effect of cigarette smoke on several common endocytic pathways in human small airway epithelial cells that are exploited by viruses to gain access to the host cell. Alterations of endocytosis correlated to increased infectivity with IAV in smoke-exposed small airway epithelial cells (SAEC). Targeting endocytosis can provide a new therapeutic strategy to combat infection in the lungs of smokers
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