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Background
Chronic obstructive pulmonary disease (COPD) is a chronic lung disease commonly associated with inhalation of cigarette smoke (CS). While the pathology of COPD is generally considered to be destructive in nature, epithelial remodeling and sub-epithelial fibrosis of the small airways is now recognized as a key histopathological feature of the disease [1, 2]. While CS directly activates and damages the epithelium, viral infections, which occur frequently in smokers with and without COPD also influences epithelial phenotype and function [3]. Moreover, viral-induced exacerbations contribute significantly to disease progression, accelerated decline of lung function and disease morbidity and mortality [3]. Unfortunately, the mechanisms that drive changes to the epithelium in COPD following exposure to CSE and respiratory viruses remains largely unexplored.
What is known, suggests that damage to the epithelium triggers a temporal cascade of inflammatory and cell signaling events that under normal circumstances leads to inflammation, resolution of inflammation and repair. However, under conditions of chronic inflammation, the epithelium fails to repair effectively with structural and functional changes including goblet cell hyperplasia, squamous cell metaplasia, induction of pro-inflammatory chemokines [4], matrix metalloproteinases [5] and epithelial cell apoptosis and proliferation [6]. The mechanisms by which these changes occur are unclear, although endoplasmic reticulum (ER) stress and oxidative damage have been proposed as initiators of epithelial cell apoptosis in COPD [7-11].
One aberrant epithelial response that has been associated with abnormal repair and fibrosis is epithelial to mesenchymal transition (EMT). This phenomenon, commonly observed in cancer and a component of normal organ development, occurs when epithelial cells transform into highly motile mesenchymal cells. EMT has been shown to contribute to airway disease and fibrosis in several organs, including the lung [12, 13]. However, the underlying mechanisms and the functional consequences of EMT in the airways from COPD patients remain unclear [14].
In this study we investigated the epithelial phenotype in COPD and responses to CS extract (CSE) on normal and COPD bronchial epithelial cell function in vitro. We assessed the impact of CSE on apoptosis, proliferation and chemokine production. We show that in the short term, cigarette smoke does not modulate EMT, but rather induces epithelial cell proliferation, apoptosis and CXCL8/IL8 production. Exposing mice to CSE combined with poly I:C challenge revealed that CSE induces apoptosis and...