Cystic fibrosis transmembrane conductance regulator modulation by the tobacco smoke toxin acrolein

Abstract

Objectives Evidence indicates that decreased mucociliary clearance (MCC) is a major contributing feature to chronic rhinosinusitis. Tobacco-smoke exposure is thought to inhibit transepithelial Cl− secretion – a major determinant of airway surface liquid hydration and MCC. The objective of the current study was to evaluate the effects of acrolein exposure (a prominent tobacco smoke toxin) on vectorial Cl− transport through the major apical anion channel CFTR in sinonasal epithelium. Study Design In vitro investigation. Methods Primary murine nasal septal (MNSE, wild type and transgenic CFTR−/−) cultures were exposed to acrolein in Ussing chambers and effects on Cl− secretion investigated using pharmacologic manipulation. Cellular cAMP signaling and cytotoxicity were also investigated. Results Acrolein stimulated Cl− secretion (ΔISC – change in short-circuit current in µA/cm2) at concentrations similar to smoker’s airways (100 μM, 15.8 +/− 2.2 vs. 2.4 +/− 0.8(control); p<0.0001), suppressed forskolin-stimulated Cl− transport at 300 μM (13.3 +/− 1.2 vs. 19.9 +/− 1.0; p < 0.01}, and completely abolished all transport at 500 μM (−1.1+/− 1.6). Stimulated Cl− secretion was solely reliant upon the presence of CFTR (confirmed in transgenic CFTR−/− MNSE), but independent of cAMP signaling. Inhibition at higher concentrations was not secondary to cellular cytotoxicity. Conclusions The present study demonstrates that acrolein has complex, but pronounced interaction with the major apical Cl− transport mechanism that utilizes CFTR. Further investigations are required to determine acrolein’s impact as a tobacco smoke constituent on mucociliary transport.

Cigarette Smoke Induces Systemic Defects in Cystic Fibrosis Transmembrane Conductance Regulator Function

“…Aside from direct inhalation via cigarette smoke, acrolein can also be produced through endogenous pathways associated with inflammation (26). Our findings are also supported by studies demonstrating the acute effects of acrolein on CFTR function, albeit at concentrations unlikely to be observed in systemic circulation for sustained periods (37). Acrolein protein modification occurs in the epithelia of patients with COPD and could partially explain persistent decrements in CFTR activity observed due to smoking, because acrolein-protein adducts persist despite prolonged smoking cessation and would be unlikely to be detected in former smokers with COPD (38).…”

Correlation of T2R38 taste phenotype and in vitro biofilm formation from nonpolypoid chronic rhinosinusitis patients

“…Tobacco smoke impacts sinonasal epithelial function, 54–57 and several epidemiologic studies have demonstrated that smokers have an increased prevalence of CRS. 58,59 A previous study reported increased biofilm mass in cultures from smokers when the cultures were repetitively exposed to exogenous tobacco smoke, compared to cultures taken from nonsmokers.…”

Vocal Fold Ion Transport and Mucin Expression Following Acrolein Exposure

“…In the current study we investigated whether acrolein affects epithelial ion transport and mucin synthesis. In the distal airway, acrolein rapidly alters epithelial ion transport and mucin synthesis in a manner that may indicate reduced airway defenses (Borchers et al 1998; Welsh 1983; Alexander et al 2012). A 60 minute acrolein challenge significantly inhibited cAMP-dependent ion transport.…”

“…Acrolein is a byproduct of mobile exhaust, industrial processes, and tobacco smoke (Bein and Leikauf 2011). In the nasal passages, trachea, and lungs, acrolein has a profound and rapid effect on epithelial ion transport and mucin synthesis (Alexander et al 2012; Welsh 1983; Borchers et al 1998; Borchers et al 1999). In excised canine tracheal epithelium and in cultures of sinonasal epithelial cells, exposure to acrolein significantly reduced ion transport within 30 minutes of initial exposure (Welsh 1983; Alexander et al 2012).…”

“…In the nasal passages, trachea, and lungs, acrolein has a profound and rapid effect on epithelial ion transport and mucin synthesis (Alexander et al 2012; Welsh 1983; Borchers et al 1998; Borchers et al 1999). In excised canine tracheal epithelium and in cultures of sinonasal epithelial cells, exposure to acrolein significantly reduced ion transport within 30 minutes of initial exposure (Welsh 1983; Alexander et al 2012). In cultured lung epithelial cells, both 60 and 240 minute acrolein exposures promotes increased synthesis of the secreted mucin, MUC5AC (Burcham et al 2010; Borchers et al 1999).…”