LAUSR

Background Cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel expressed on the mucosal surface of epithelial cells lining several tissues including airways. Inherited defects in the CFTR gene cause cystic fibrosis (CF), an autosomal recessive disease causing a progressive decline in lung function ultimately resulting in reduced life span. CF patients exhibit impaired mucociliary clearance (MCC), a principle defense of airways against inhaled irritants and pathogens. The MCC apparatus consists of airway surface liquid (ASL), which has a mucus layer that traps pathogens to be removed by the coordinated beating of surface cilia [1]. Physiologic levels of ASL and PCL determine the effectiveness of MCC, a process tightly regulated through CFTR activity [2, 3]. As a result of reduced CFTR-mediated ion transport, CF airways fail to maintain optimal surface hydration and clear inhaled pathogens. Decreased MCC efficiency causes accumulation of thick mucus, opportunistic infections, and chronic inflammation. Beyond inherited defects, several different environmental insults can also negatively affect CFTR function even in those with normal genetics. For example, exposure to cigarette smoke is known to cause decreased CFTR activity in mice [4], rats [5], ferrets [6], dogs [7], and humans [8, 9]. Reports also suggest excessive alcohol intake [10] and exposure to cadmium [11] and arsenic [12, 13] result in diminished CFTR activity supporting the concept of ‘acquired CFTR dysfunction’. Secondhand smoke (SHS) exposure is an important health concern for many never smokers [14]. In spite of regulations limiting smoking in many public places, there are 1.8 billion non-smokers around the world that are frequently exposed to SHS resulting in more than 600,000 deaths per year [15, 16]. Exposure to SHS is a risk factor for respiratory infections and pulmonary diseases including lung cancer, asthma, and chronic obstructive pulmonary disease (COPD), the third leading cause of death in the U. S [17–20]. However, there is currently a limited understanding of how SHS exposure alters lung physiology to cause these diseases. Savitski et al. reported that SHS exposure, like mainstream smoking, results in decreased CFTR anion transport in human bronchial epithelial cells [21], suggesting CFTR abnormality may explain delayed mucociliary clearance and increased disease burden in never smokers [22, 23]. However, the observation of SHS-induced defects in CFTR is yet to be verified in a suitable animal model. Moreover, the functional consequences of such CFTR dysfunction on mucus physiology remain unexplored. To address these important follow-up questions, we have monitored CFTR-mediated ion transport in A/J mice exposed to SHS. We have previously found that A/ J mice exhibit susceptibility to smoking induced changes in CFTR function in a dose-dependent manner [4]. Based on these data, we have used A/J mice as an in vivo model to test the hypothesis that SHS reduces CFTR function and disrupts physiologically optimal airway surface hydration and mucociliary transport.