{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,22]],"date-time":"2026-02-22T09:28:31Z","timestamp":1771752511625,"version":"3.50.1"},"reference-count":74,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,1,24]],"date-time":"2023-01-24T00:00:00Z","timestamp":1674518400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"JSPS\/MEXT KAKENHI","doi-asserted-by":"publisher","award":["19H03185"],"award-info":[{"award-number":["19H03185"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Suzuken Memorial Foundation","award":["19H03185"],"award-info":[{"award-number":["19H03185"]}]},{"name":"Kwansei Gakuin University","award":["19H03185"],"award-info":[{"award-number":["19H03185"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>COPD is a lifestyle-related disease resulting from irreversible damage to respiratory tissues mostly due to chronic exposure to environmental pollutants, including cigarette smoke. Environmental pathogens and pollutants induce the acquired dysfunction of the CFTR Cl\u2212 channel, which is invoked in COPD. Despite the increased incidence of CFTR polymorphism R75Q or M470V in COPD patients, the mechanism of how the CFTR variant affects COPD pathogenesis remains unclear. Here, we investigated the impact of CFTR polymorphisms (R75Q, M470V) on the CFTR function in airway epithelial cell models. While wild-type (WT) CFTR suppressed the proinflammatory cytokine production induced by COPD-related pathogens including pyocyanin (PYO), R75Q- or M470V-CFTR failed. Mechanistically, the R75Q- or M470V-CFTR fractional PM activity (FPMA) was significantly lower than WT-CFTR in the presence of PYO. Notably, the CF drug Trikafta corrected the PM expression of R75Q- or M470V-CFTR even upon PYO exposure and consequently suppressed the excessive IL-8 production. These results suggest that R75Q or M470V polymorphism impairs the CFTR function to suppress the excessive proinflammatory response to environmental pathogens associated with COPD. Moreover, Trikafta may be useful to prevent the COPD pathogenesis associated with acquired CFTR dysfunction.<\/jats:p>","DOI":"10.3390\/ijms24032305","type":"journal-article","created":{"date-parts":[[2023,1,25]],"date-time":"2023-01-25T03:53:18Z","timestamp":1674618798000},"page":"2305","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["The COPD-Associated Polymorphism Impairs the CFTR Function to Suppress Excessive IL-8 Production upon Environmental Pathogen Exposure"],"prefix":"10.3390","volume":"24","author":[{"given":"Daichi","family":"Hinata","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, Hyogo 669-1330, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryosuke","family":"Fukuda","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, Hyogo 669-1330, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5175-2224","authenticated-orcid":false,"given":"Tsukasa","family":"Okiyoneda","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, Hyogo 669-1330, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2227","DOI":"10.1016\/S0140-6736(22)00470-6","article-title":"Chronic obstructive pulmonary disease","volume":"399","author":"Christenson","year":"2022","journal-title":"Lancet"},{"key":"ref_2","unstructured":"WHO (2016). Chronic Obstructive Pulmonary Disease (COPD), WHO."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1164\/rccm.202109-2064TR","article-title":"Cystic Fibrosis Transmembrane Conductance Regulator: Roles in Chronic Obstructive Pulmonary Disease","volume":"205","author":"Dransfield","year":"2022","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1126\/science.2475911","article-title":"Identification of the cystic fibrosis gene: Cloning and characterization of complementary DNA","volume":"245","author":"Riordan","year":"1989","journal-title":"Science"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1038\/nm1028","article-title":"Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice","volume":"10","author":"Mall","year":"2004","journal-title":"Nat. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"S215","DOI":"10.1152\/physrev.1999.79.1.S215","article-title":"Role of CFTR in airway disease","volume":"79","author":"Pilewski","year":"1999","journal-title":"Physiol. Rev."},{"key":"ref_7","first-page":"S150","article-title":"Cystic Fibrosis Transmembrane Conductance Regulator. Implications in Cystic Fibrosis and Chronic Obstructive Pulmonary Disease","volume":"13","author":"Cantin","year":"2016","journal-title":"Ann. Am. Thorac. Soc."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1378\/chest.13-0274","article-title":"Acquired cystic fibrosis transmembrane conductance regulator dysfunction in the lower airways in COPD","volume":"144","author":"Dransfield","year":"2013","journal-title":"Chest"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"602","DOI":"10.4049\/jimmunol.1002850","article-title":"Critical modifier role of membrane-cystic fibrosis transmembrane conductance regulator-dependent ceramide signaling in lung injury and emphysema","volume":"186","author":"Bodas","year":"2011","journal-title":"J. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Zhao, R., Liang, X., Zhao, M., Liu, S., Huang, Y., Idell, S., Li, X., and Ji, H. (2014). Correlation of apical fluid-regulating channel proteins with lung function in human COPD lungs. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0109725"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"L894","DOI":"10.1152\/ajplung.00376.2004","article-title":"Inhibition of chloride secretion in human bronchial epithelial cells by cigarette smoke extract","volume":"288","author":"Kreindler","year":"2005","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.1164\/rccm.201304-0733OC","article-title":"Cigarette smoke induces systemic defects in cystic fibrosis transmembrane conductance regulator function","volume":"188","author":"Raju","year":"2013","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"13655","DOI":"10.1038\/s41598-019-49544-9","article-title":"Cigarette Smoke Exposure Induces Retrograde Trafficking of CFTR to the Endoplasmic Reticulum","volume":"9","author":"Marklew","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"7671","DOI":"10.1074\/jbc.M113.545137","article-title":"Cigarette smoke-induced Ca2+ release leads to cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction","volume":"289","author":"Rasmussen","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1093\/toxsci\/kfq101","article-title":"Cadmium regulates the expression of the CFTR chloride channel in human airway epithelial cells","volume":"116","author":"Rennolds","year":"2010","journal-title":"Toxicol. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Carrasco-Hern\u00e1ndez, L., Quintana-Gallego, E., Calero, C., Reinoso-Arija, R., Ruiz-Duque, B., and L\u00f3pez-Campos, J. (2021). Dysfunction in the Cystic Fibrosis Transmembrane Regulator in Chronic Obstructive Pulmonary Disease as a Potential Target for Personalised Medicine. Biomedicines, 9.","DOI":"10.3390\/biomedicines9101437"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"C1374","DOI":"10.1152\/ajpcell.00356.2022","article-title":"Chronic obstructive pulmonary disease and the modulation of CFTR by acute exposure to cigarette smoke","volume":"323","author":"Hanrahan","year":"2022","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1093\/jat\/bkt021","article-title":"Establishment of toxic metal reference range in tobacco from US cigarettes","volume":"37","author":"Fresquez","year":"2013","journal-title":"J. Anal. Toxicol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1434","DOI":"10.1016\/j.freeradbiomed.2004.03.010","article-title":"Cadmium inhibits the electron transfer chain and induces reactive oxygen species","volume":"36","author":"Wang","year":"2004","journal-title":"Free Radic. Biol. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1023\/A:1020229923095","article-title":"Cadmium biomonitoring and renal dysfunction among a population environmentally exposed to cadmium from smelting in China (ChinaCad)","volume":"15","author":"Jin","year":"2002","journal-title":"Biometals"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/S1470-2045(06)70548-4","article-title":"Lung cancer and exposure to environmental cadmium","volume":"7","author":"Nordberg","year":"2006","journal-title":"Lancet Oncol."},{"key":"ref_22","first-page":"477","article-title":"Cadmium in lung tissue as marker for smoking","volume":"1","author":"Anttila","year":"1988","journal-title":"Lancet"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1165\/ajrcmb.19.3.3242","article-title":"Cadmium inhibits proteoglycan and procollagen production by cultured human lung fibroblasts","volume":"19","author":"Chambers","year":"1998","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"12706","DOI":"10.1038\/s41598-019-48971-y","article-title":"Phosphorylation-dependent modulation of CFTR macromolecular signalling complex activity by cigarette smoke condensate in airway epithelia","volume":"9","author":"Premchandar","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1534","DOI":"10.1086\/593187","article-title":"The many faces of Pseudomonas aeruginosa in chronic obstructive pulmonary disease","volume":"47","author":"Murphy","year":"2008","journal-title":"Clin. Infect. Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1038\/nm.2715","article-title":"Cystic fibrosis: A mucosal immunodeficiency syndrome","volume":"18","author":"Cohen","year":"2012","journal-title":"Nat. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1186\/1465-9921-14-82","article-title":"Pyocyanin-induced mucin production is associated with redox modification of FOXA2","volume":"14","author":"Hao","year":"2013","journal-title":"Respir. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2515","DOI":"10.1128\/iai.56.9.2515-2517.1988","article-title":"Measurement of Pseudomonas aeruginosa phenazine pigments in sputum and assessment of their contribution to sputum sol toxicity for respiratory epithelium","volume":"56","author":"Wilson","year":"1988","journal-title":"Infect. Immun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1016\/j.tiv.2011.05.004","article-title":"Pyocyanin-induced toxicity in A549 respiratory cells is causally linked to oxidative stress","volume":"25","author":"Gloyne","year":"2011","journal-title":"Toxicol. In Vitro"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1111\/j.1462-5822.2006.00696.x","article-title":"Pseudomonas aeruginosa pyocyanin inactivates lung epithelial vacuolar ATPase-dependent cystic fibrosis transmembrane conductance regulator expression and localization","volume":"8","author":"Kong","year":"2006","journal-title":"Cell Microbiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1653","DOI":"10.1016\/j.freeradbiomed.2008.09.011","article-title":"Oxidative stress caused by pyocyanin impairs CFTR Cl\u2014Transport in human bronchial epithelial cells","volume":"45","author":"Schwarzer","year":"2008","journal-title":"Free. Radic. Biol. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1016\/j.jinf.2013.09.003","article-title":"Infectious etiology of acute exacerbations in severe COPD patients","volume":"67","author":"Domenech","year":"2013","journal-title":"J. Infect."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1183\/09031936.00003309","article-title":"Pseudomonas aeruginosa in patients hospitalised for COPD exacerbation: A prospective study","volume":"34","author":"Almagro","year":"2009","journal-title":"Eur. Respir. J."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1159\/000490190","article-title":"Pseudomonas aeruginosa in Chronic Obstructive Pulmonary Disease Patients with Frequent Hospitalized Exacerbations: A Prospective Multicentre Study","volume":"96","author":"Melo","year":"2018","journal-title":"Respiration"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1007\/s004390100467","article-title":"CFTR gene mutations\u2014Including three novel nucleotide substitutions\u2014And haplotype background in patients with asthma, disseminated bronchiectasis and chronic obstructive pulmonary disease","volume":"108","author":"Tzetis","year":"2001","journal-title":"Hum. Genet."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1053\/j.gastro.2010.10.045","article-title":"Combined bicarbonate conductance-impairing variants in CFTR and SPINK1 variants are associated with chronic pancreatitis in patients without cystic fibrosis","volume":"140","author":"Schneider","year":"2011","journal-title":"Gastroenterology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1172\/JCI639","article-title":"Polyvariant mutant cystic fibrosis transmembrane conductance regulator genes. The polymorphic (Tg)m locus explains the partial penetrance of the T5 polymorphism as a disease mutation","volume":"101","author":"Cuppens","year":"1998","journal-title":"J. Clin. Investig."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"4188","DOI":"10.1091\/mbc.e12-06-0424","article-title":"Proinflammatory cytokine secretion is suppressed by TMEM16A or CFTR channel activity in human cystic fibrosis bronchial epithelia","volume":"23","author":"Veit","year":"2012","journal-title":"Mol. Biol. Cell"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1089\/gte.2007.0069","article-title":"The CFTR M470V gene variant as a potential modifier of COPD severity: Study of Serbian population","volume":"12","author":"Stankovic","year":"2008","journal-title":"Genet. Test"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.jcf.2004.05.049","article-title":"High frequency of the R75Q CFTR variation in patients with chronic obstructive pulmonary disease","volume":"3","author":"Divac","year":"2004","journal-title":"J. Cyst. Fibros."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"LaRusch, J., Jung, J., and General, I. (2014). Mechanisms of CFTR Functional Variants That Impair Regulated Bicarbonate Permeation and Increase Risk for Pancreatitis but Not for Cystic Fibrosis. PLoS Genet., 10.","DOI":"10.1371\/journal.pgen.1004376"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1007\/s00441-005-0062-7","article-title":"Towards an in vitro model of cystic fibrosis small airway epithelium: Characterisation of the human bronchial epithelial cell line CFBE41o-","volume":"323","author":"Ehrhardt","year":"2006","journal-title":"Cell Tissue Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1016\/j.devcel.2018.02.001","article-title":"Chaperone-Independent Peripheral Quality Control of CFTR by RFFL E3 Ligase","volume":"44","author":"Okiyoneda","year":"2018","journal-title":"Dev. Cell"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1113\/jphysiol.2005.096669","article-title":"Failure of cAMP agonists to activate rescued deltaF508 CFTR in CFBE41o- airway epithelial monolayers","volume":"569","author":"Bebok","year":"2005","journal-title":"J. Physiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1001\/archinte.165.8.891","article-title":"Microbiologic determinants of exacerbation in chronic obstructive pulmonary disease","volume":"165","author":"Rosell","year":"2005","journal-title":"Arch Intern. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1378\/chest.116.1.40","article-title":"Relationship between bacterial flora in sputum and functional impairment in patients with acute exacerbations of COPD. Study Group of Bacterial Infection in COPD","volume":"116","author":"Miravitlles","year":"1999","journal-title":"Chest"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1542","DOI":"10.1378\/chest.113.6.1542","article-title":"Infective exacerbations of chronic bronchitis: Relation between bacteriologic etiology and lung function","volume":"113","author":"Eller","year":"1998","journal-title":"Chest"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1164\/rccm.200709-1413OC","article-title":"Pseudomonas aeruginosa in chronic obstructive pulmonary disease","volume":"177","author":"Murphy","year":"2008","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1096\/fj.11-192377","article-title":"Cigarette smoke exposure induces CFTR internalization and insolubility, leading to airway surface liquid dehydration","volume":"26","author":"Clunes","year":"2012","journal-title":"FASEB J."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1038\/s41467-017-00444-4","article-title":"Chaperones rescue the energetic landscape of mutant CFTR at single molecule and in cell","volume":"8","author":"Bagdany","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1113\/jphysiol.2002.022400","article-title":"Oxidant stress stimulates anion secretion from the human airway epithelial cell line Calu-3: Implications for cystic fibrosis lung disease","volume":"543","author":"Cowley","year":"2002","journal-title":"J. Physiol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2001","DOI":"10.1007\/s40265-019-01233-7","article-title":"Elexacaftor\/Ivacaftor\/Tezacaftor: First Approval","volume":"79","author":"Hoy","year":"2019","journal-title":"Drugs"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"e139983","DOI":"10.1172\/jci.insight.139983","article-title":"Allosteric folding correction of F508del and rare CFTR mutants by elexacaftor-tezacaftor-ivacaftor (Trikafta) combination","volume":"5","author":"Veit","year":"2020","journal-title":"JCI Insight"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1184","DOI":"10.2353\/ajpath.2008.070310","article-title":"Cystic fibrosis transmembrane conductance regulator controls lung proteasomal degradation and nuclear factor-kappaB activity in conditions of oxidative stress","volume":"172","author":"Boncoeur","year":"2008","journal-title":"Am. J. Pathol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"C262","DOI":"10.1152\/ajpcell.00070.2005","article-title":"Oxidant stress suppresses CFTR expression","volume":"290","author":"Cantin","year":"2006","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"22299","DOI":"10.1074\/jbc.M109.098566","article-title":"Loss of cystic fibrosis transmembrane conductance regulator function enhances activation of p38 and ERK MAPKs, increasing interleukin-6 synthesis in airway epithelial cells exposed to Pseudomonas aeruginosa","volume":"285","author":"Roussel","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1038\/nature11130","article-title":"Reduced airway surface pH impairs bacterial killing in the porcine cystic fibrosis lung","volume":"487","author":"Pezzulo","year":"2012","journal-title":"Nature"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"C741","DOI":"10.1152\/ajpcell.00379.2005","article-title":"Hyperacidity of secreted fluid from submucosal glands in early cystic fibrosis","volume":"290","author":"Song","year":"2006","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1006\/bbrc.1998.9697","article-title":"Glutathione downregulates the phosphorylation of I kappa B: Autoloop regulation of the NF-kappa B-mediated expression of NF-kappa B subunits by TNF-alpha in mouse vascular endothelial cells","volume":"253","author":"Cho","year":"1998","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_60","first-page":"837","article-title":"Intracellular glutathione redox status modulates MCP-1 expression in pulmonary granulomatous vasculitis","volume":"79","author":"Desai","year":"1999","journal-title":"Lab Invest."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1482","DOI":"10.1378\/chest.117.5.1482","article-title":"The role of nuclear factor-kappa B in pulmonary diseases","volume":"117","author":"Christman","year":"2000","journal-title":"Chest"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1034\/j.1398-9995.2000.00455.x","article-title":"Regulation by intracellular glutathione of TNF-alpha-induced p38 MAP kinase activation and RANTES production by human pulmonary vascular endothelial cells","volume":"55","author":"Hashimoto","year":"2000","journal-title":"Allergy"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1034\/j.1399-3003.1999.14a17.x","article-title":"Thiol regulation of the production of TNF-alpha, IL-6 and IL-8 by human alveolar macrophages","volume":"14","author":"Gosset","year":"1999","journal-title":"Eur. Respir. J."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.jcmgh.2019.09.003","article-title":"Regulation of CFTR Bicarbonate Channel Activity by WNK1: Implications for Pancreatitis and CFTR-Related Disorders","volume":"9","author":"Kim","year":"2020","journal-title":"Cell Mol. Gastroenterol. Hepatol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"C118","DOI":"10.1152\/ajpcell.00099.2017","article-title":"Cigarette smoke activates CFTR through ROS-stimulated cAMP signaling in human bronchial epithelial cells","volume":"314","author":"Wong","year":"2018","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"27536","DOI":"10.1074\/jbc.274.39.27536","article-title":"Redox reagents and divalent cations alter the kinetics of cystic fibrosis transmembrane conductance regulator channel gating","volume":"274","author":"Harrington","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1278","DOI":"10.1016\/S0006-3495(02)75484-2","article-title":"Cysteine residues in the nucleotide binding domains regulate the conductance state of CFTR channels","volume":"82","author":"Harrington","year":"2002","journal-title":"Biophys. J."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.coph.2017.09.013","article-title":"The therapeutic potential of CFTR modulators for COPD and other airway diseases","volume":"34","author":"Solomon","year":"2017","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1165\/rcmb.2013-0228OC","article-title":"Cystic fibrosis transmembrane conductance regulator activation by roflumilast contributes to therapeutic benefit in chronic bronchitis","volume":"50","author":"Lambert","year":"2014","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Sloane, P., Shastry, S., Wilhelm, A., Courville, C., Tang, L., Backer, K., Levin, E., Raju, S., Li, Y., and Mazur, M. (2012). A pharmacologic approach to acquired cystic fibrosis transmembrane conductance regulator dysfunction in smoking related lung disease. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0039809"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1165\/rcmb.2016-0226OC","article-title":"The Cystic Fibrosis Transmembrane Conductance Regulator Potentiator Ivacaftor Augments Mucociliary Clearance Abrogating Cystic Fibrosis Transmembrane Conductance Regulator Inhibition by Cigarette Smoke","volume":"56","author":"Raju","year":"2017","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1126\/science.1191542","article-title":"Peripheral protein quality control removes unfolded CFTR from the plasma membrane","volume":"329","author":"Okiyoneda","year":"2010","journal-title":"Science"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1126\/science.ade2216","article-title":"Molecular structures reveal synergistic rescue of \u0394508 CFTR by Trikafta modulators","volume":"378","author":"Fiedorczuk","year":"2022","journal-title":"Science"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1083\/jcb.200808124","article-title":"N-glycans are direct determinants of CFTR folding and stability in secretory and endocytic membrane traffic","volume":"184","author":"Glozman","year":"2009","journal-title":"J. Cell Biol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/3\/2305\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:14:44Z","timestamp":1760120084000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/3\/2305"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,24]]},"references-count":74,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["ijms24032305"],"URL":"https:\/\/doi.org\/10.3390\/ijms24032305","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,24]]}}}