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

Raju, S. Vamsee; Jackson, Patricia L.; Courville, Clifford; McNicholas, Carmel M.; Sloane, Peter A.; Sabbatini, Gina; Tidwell, Sherry; Tang, Li; Liu, Bo; Fortenberry, James A.; Jones, Caleb; Boydston, Jeremy A.; Clancy, John; Bowen, Larry E.; Accurso, Frank J.; Blalock, J. Edwin; Dransfield, Mark T.; Rowe, Steven M.

doi:10.1164/rccm.201304-0733oc

Cited by 173 publications

(230 citation statements)

References 49 publications

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“…Our preliminary data also support this notion since cigarette smoke extract dose-dependently inhibited pancreatic ductal CFTR activity and HCO 3 − secretion in guinea pigs. In fact, the latter results are in accord with those found in other organs such as the airway [64] or intestinal epithelial cells [65]. It seems that CFTR dysfunction due to smoking is primarily an acquired phenomenon and is not affected by the presence of heterozygous CFTR mutations [66].…”

Section: Smokingsupporting

confidence: 85%

“…The interpretation of these results, at least with respect to the compounds responsible for the inhibitory effect of CFTR, is difficult as cigarette smoke is estimated to contain more than 7000 chemical components. Nevertheless, several constituents of cigarette smoke have been implicated in the inhibitory effects on CFTR such as acrolein [65], cadmium and manganese [67]. Moreover, these effects were ameliorated by the use of various antioxidants like N-acetylcysteine (a known scavenger of acrolein) or alphatocopherol, suggesting that free radical-induced damage may be responsible for the inhibition of CFTR by cigarette smoke [68].…”

mentioning

confidence: 99%

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CFTR: A new horizon in the pathomechanism and treatment of pancreatitis

Hegyi

2016

Pancreatology

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Cystic fibrosis transmembrane conductance regulator (CFTR) is an ion channel that conducts chloride and bicarbonate ions across epithelial cell membranes. Mutations in the CFTR gene diminish the ion channel function and lead to impaired epithelial fluid transport in multiple organs such as the lung and the pancreas resulting in cystic fibrosis. Heterozygous carriers of CFTR mutations do not develop cystic fibrosis but exhibit increased risk for pancreatitis and associated pancreatic damage characterized by elevated mucus levels, fibrosis and cyst formation. Importantly, recent studies demonstrated that pancreatitis causing insults, such as alcohol, smoking or bile acids strongly inhibit CFTR function. Furthermore, human studies showed reduced levels of CFTR expression and function in all forms of pancreatitis. These findings indicate that impairment of CFTR is critical in the development of pancreatitis; therefore, correcting CFTR function could be the first specific therapy in pancreatitis. In this review, we summarize recent advances in the field and discuss new possibilities for the treatment of pancreatitis.Corresponding author: Prof. Dr. Peter Hegyi, Doctor of the Hungarian Academy of Sciences, First Department of Medicine, University of Szeged, Koranyi fsr. 8-10, SZEGED, H6720, Hungary, TEL: +3662545200, FAX: +3662545185, MOBILE: +36703751031, hegyi.peter@med.u-szeged.hu. Conflict of interest statement: the authors have no conflict of interest to declare HHS Public Access I. Basics of CFTR a. Biosynthesis and degradationThe cystic fibrosis transmembrane conductance regulator (CFTR) protein is a cyclic AMP (cAMP)-regulated chloride (Cl − )/bicarbonate (HCO 3 − ) channel, expressed in the apical plasma membrane (PM) of secretory epithelia in the airways, pancreas, intestine, reproductive organs and exocrine glands [1]. CFTR consists of two homologous halves, each containing a hexa-helical membrane spanning domain (MSD1 and MSD2) and a nucleotide binding domain (NBD1 and NBD2) (Figure 1). The two halves are connected by the R domain [2]. The NBDs contain conserved ATP-binding sequences: Walker A and B motifs, classifying CFTR as a member of the ATP-binding cassette (ABC) transporter family. Structural, biochemical and functional evidence suggest that the two NBD domains interact and the ATP-binding site of one NBD is complemented by the ABC signature motif of the other [2].While NBD1 folds largely co-translationally, the native fold of NBD2 as well as CFTR are attained post-translationally [3]. Assembly of MSD1, NBD1, R domain and MSD2 is necessary and sufficient to form the minimal folding unit of CFTR [4]. These and other observations support the cooperative domain folding model and ensure the dynamic conformational coupling between the cytosolic NBDs and the pore-forming MSDs in the native molecule and provide a structural explanation for the cooperative domain unfolding, caused by cystic fibrosis (CF) mutations [4].Despite interactions with several cytosolic and endoplasmic reticulum (ER) chapero...

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Section: Smokingsupporting

confidence: 85%

mentioning

confidence: 99%

CFTR: A new horizon in the pathomechanism and treatment of pancreatitis

Hegyi

2016

Pancreatology

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“…Cigarette smoke also induces an ER stress response by interfering with oxidative protein folding and protein function e.g. of cystic fibrosis transmembrane conductance regulator (CFTR), which may also contribute to COPD pathogenesis [70][71][72][73][74][75]. Of note, the proteasome itself is a direct target for environmental challenges as cigarette smoke and diesel exhaust have been shown to impair proteasome function [76,77].…”

Section: Loss Of Proteostasismentioning

confidence: 99%

Hallmarks of the ageing lung

2015

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Ageing is the main risk factor for major non-communicable chronic lung diseases, including chronic obstructive pulmonary disease, most forms of lung cancer and idiopathic pulmonary fibrosis. While the prevalence of these diseases continually increases with age, their respective incidence peaks at different times during the lifespan, suggesting specific effects of ageing on the onset and/or pathogenesis of chronic obstructive pulmonary disease, lung cancer and idiopathic pulmonary fibrosis. Recently, the nine hallmarks of ageing have been defined as cell-autonomous and non-autonomous pathways involved in ageing. Here, we review the available evidence for the involvement of each of these hallmarks in the pathogenesis of chronic obstructive pulmonary disease, lung cancer, or idiopathic pulmonary fibrosis. Importantly, we propose an additional hallmark, "dysregulation of the extracellular matrix", which we argue acts as a crucial modifier of cell-autonomous changes and functions, and as a key feature of the above-mentioned lung diseases. @ERSpublications Hallmarks of ageing are selecting factors for the pathogenesis of COPD, lung cancer and IPF

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“…Although the mechanisms responsible for altered CFTR expression in, for example, the chronic obstructive pulmonary disease lung are not restricted to miRNA-mediated effects [17], miR-101 in particular is known to be increased by cigarette smoke extracts and directly impacts on CFTR expression [8]. Finally, it is becoming increasingly evident that dysfunctional CFTR as a result of cigarette smoking can contribute to the pathophysiology of a range of extrapulmonary disease conditions, such as chronic pancreatitis, male infertility and cachexia [18]. Expanding upon the findings from airway epithelial cells reported here into non-lung cells that express CFTR may yield novel therapies for these disease conditions beyond CF.…”

mentioning

confidence: 99%