Heavy metals in cigarette smoke strongly inhibit pancreatic ductal function and promote development of chronic pancreatitis

Abstract

Smoking and cigarette smoke extract diminish pancreatic ductal fluid and HCO₃ ^– secretion as well as the expression and function of CFTR

Cd and Hg concentrations are significantly higher in the serum samples of smokers

Cd accumulates in the pancreatic tissue of smokers

Keywords

cadmium / CFTR / chronic pancreatitis / epithelial ion secretion / smoking

References

[1] BraganzaJM, LeeSH, McCloyRF, McMahon MJ. Chronic pancreatitis. Lancet. 2011;377:1184-1197.

[2] TattersallSJN, ApteMV, WilsonJS. A fire inside: current concepts in chronic pancreatitis. Intern Med J. 2008;38:592-598.

[3] KleeffJ, Whitcomb DC, ShimosegawaT, et al. Chronic pancreatitis. Nat Rev Dis Primers. 2017;3:17060.

[4] OlesenSS, Phillips AE, FaghihM, et al. Overlap and cumulative effects of pancreatic duct obstruction, abnormal pain processing and psychological distress on patient-reported outcomes in chronic pancreatitis. Gut. 2022;71:2518-2525.

[5] JagannathS, GargPK. Novel and experimental therapies in chronic pancreatitis. Dig Dis Sci. 2017;62:1751-1761.

[6] SinghVK, YadavD, GargPK. Diagnosis and management of chronic pancreatitis: a review. JAMA. 2019;322:2422-2434.

[7] WeissFU, Laemmerhirt F, LerchMM. Etiology and risk factors of acute and chronic pancreatitis. Visc Med. 2019;35:73-81.

[8] SzentesiA, FarkasN, SiposZ, et al. Alcohol consumption and smoking dose-dependently and synergistically worsen local pancreas damage. Gut. 2022;71:2601-2602.

[9] HegyiP, Párniczky A, LerchMM, et al. International Consensus Guidelines for Risk Factors in Chronic Pancreatitis. Recommendations from the working group for the international consensus guidelines for chronic pancreatitis in collaboration with the International Association of Pancreatology, the American Pancreatic Association, the Japan Pancreas Society, and European Pancreatic Club. Pancreatology. 2020;20:579-585.

[10] LugeaA, Gerloff A, SuH-Y, et al. The combination of alcohol and cigarette smoke induces endoplasmic reticulum stress and cell death in pancreatic acinar cells. Gastroenterology. 2017;153:1674-1686.

[11] CriddleDN, RaratyMGT, NeoptolemosJP, TepikinAV, Petersen OH, SuttonR. Ethanol toxicity in pancreatic acinar cells: mediation by nonoxidative fatty acid metabolites. Proc Natl Acad Sci U S A. 2004;101:10738-10743.

[12] MaléthJ, Balázs A, PallagiP, et al. Alcohol disrupts levels and function of the cystic fibrosis transmembrane conductance regulator to promote development of pancreatitis. Gastroenterology. 2015;148:427-439.e16.

[13] LeeATK, XuZ, PothulaSP, et al. Alcohol and cigarette smoke components activate human pancreatic stellate cells: implications for the progression of chronic pancreatitis. Alcohol Clin Exp Res. 2015;39:2123-2133.

[14] HegyiP, Petersen OH. The exocrine pancreas: the acinar-ductal tango in physiology and pathophysiology. Rev Physiol Biochem Pharmacol. 2013;165:1-30.

[15] HuangW, BoothDM, CaneMC, et al. Fatty acid ethyl ester synthase inhibition ameliorates ethanol-induced Ca²⁺-dependent mitochondrial dysfunction and acute pancreatitis. Gut. 2014;63:1313-1324.

[16] KusiakAA, Jakubowska MA, StopaKB, et al. Activation of pancreatic stellate cells attenuates intracellular Ca²⁺ signals due to downregulation of TRPA1 and protects against cell death induced by alcohol metabolites. Cell Death Dis. 2022;13:744.

[17] PetersenOH, Tepikin AV, GerasimenkoJV, GerasimenkoOV, SuttonR, CriddleDN. Fatty acids, alcohol and fatty acid ethyl esters: toxic Ca²⁺ signal generation and pancreatitis. Cell Calcium. 2009;45:634-642.

[18] CriddleDN, MurphyJ, FistettoG, et al. Fatty acid ethyl esters cause pancreatic calcium toxicity via inositol trisphosphate receptors and loss of ATP synthesis. Gastroenterology. 2006;130:781-793.

[19] WittelUA, PandeyKK, AndrianifahananaM, et al. Chronic pancreatic inflammation induced by environmental tobacco smoke inhalation in rats. Am J Gastroenterol. 2006;101:148-159.

[20] WittelUA, SinghAP, HenleyBJ, et al. Cigarette smoke-induced differential expression of the genes involved in exocrine function of the rat pancreas. Pancreas. 2006;33:364-370.

[21] WongFH, AbuArish A, MatthesE, et al. Cigarette smoke activates CFTR through ROS-stimulated cAMP signaling in human bronchial epithelial cells. Am J Physiol Cell Physiol. 2018;314:C118-C134.

[22] SchnúrA, Premchandar A, BagdanyM, LukacsGL. Phosphorylation-dependent modulation of CFTR macromolecular signalling complex activity by cigarette smoke condensate in airway epithelia. Sci Rep. 2019;9:12706.

[23] MoranAR, Norimatsu Y, DawsonDC, MacDonaldKD. Aqueous cigarette smoke extract induces a voltage-dependent inhibition of CFTR expressed in Xenopus oocytes. Am J Physiol Lung Cell Mol Physiol. 2014;306:L284-L291.

[24] KadiyalaV, LeeLS, BanksPA, et al. Cigarette smoking impairs pancreatic duct cell bicarbonate secretion. JOP. 2013;14:31-38.

[25] BynumTE, Solomon TE, JohnsonLR, JacobsonED. Inhibition of pancreatic secretion in man by cigarette smoking. Gut. 1972;13:361-365.

[26] GibsonLE, CookeRE. A test for concentration of electrolytes in sweat in cystic fibrosis of the pancreas utilizing pilocarpine by iontophoresis. Pediatrics. 1959;23:545-549.

[27] PallagiP, Venglovecz V, RakonczayZ, et al. Trypsin reduces pancreatic ductal bicarbonate secretion by inhibiting CFTR Cl⁻ channels and luminal anion exchangers. Gastroenterology. 2011;141:2228-2239.

[28] CsekőK, Hargitai D, DraskócziL, et al. Safety of chronic hypertonic bicarbonate inhalation in a cigarette smoke-induced airway irritation guinea pig model. BMC Pulm Med. 2022;22:131.

[29] PallagiP, BallaZ, SinghAK, et al. The role of pancreatic ductal secretion in protection against acute pancreatitis in mice. Crit Care Med. 2014;42:e177-188.

[30] SiegenthalerP, de Haller R, DubachUC. Salt excretion in sweat in cystic fibrosis. JAMA. 1963;186:1178.

[31] HaussmannH-J. Use of hazard indices for a theoretical evaluation of cigarette smoke composition. Chem Res Toxicol. 2012;25:794-810.

[32] KreindlerJL, Jackson AD, KempPA, BridgesRJ, Danahay H. Inhibition of chloride secretion in human bronchial epithelial cells by cigarette smoke extract. Am J Physiol Lung Cell Mol Physiol. 2005;288:L894-L902.

[33] JentschTJ, SteinV, WeinreichF, Zdebik AA. Molecular structure and physiological function of chloride channels. Physiol Rev. 2002;82:503-568.

[34] LeeMG, OhanaE, ParkHW, Yang D, MuallemS. Molecular mechanism of pancreatic and salivary gland fluid and HCO3 secretion. Physiol Rev. 2012;92:39-74.

[35] HongJH, ParkS, ShcheynikovN, MuallemS. Mechanism and synergism in epithelial fluid and electrolyte secretion. Pflugers Arch. 2014;466:1487-1499.

[36] MadácsyT, Pallagi P, MalethJ. Cystic fibrosis of the pancreas: the role of CFTR channel in the regulation of intracellular Ca²⁺ signaling and mitochondrial function in the exocrine pancreas. Front Physiol. 2018;9:1585.

[37] TrappS, Aghdassi AA, GlaubitzJ, et al. Pancreatitis severity in mice with impaired CFTR function but pancreatic sufficiency is mediated via ductal and inflammatory cells—not acinar cells. J Cell Mol Med. 2021;25:4658-4670.

[38] CantinAM, Hanrahan JW, BilodeauG, et al. Cystic fibrosis transmembrane conductance regulator function is suppressed in cigarette smokers. Am J Respir Crit Care Med. 2006;173:1139-1144.

[39] KoSBH, MizunoN, YatabeY, et al. Corticosteroids correct aberrant CFTR localization in the duct and regenerate acinar cells in autoimmune pancreatitis. Gastroenterology. 2010;138:1988-1996.

[40] ZengM, Szymczak M, AhujaM, et al. Restoration of CFTR activity in ducts rescues acinar cell function and reduces inflammation in pancreatic and salivary glands of mice. Gastroenterology. 2017;153:1148-1159.

[41] Sahin-TóthM. Channelopathy of the pancreas causes chronic pancreatitis. Gastroenterology. 2020;158:1538-1540.

[42] RaynerRE, MakenaP, PrasadGL, Cormet-Boyaka E. Cigarette and ENDS preparations differentially regulate ion channels and mucociliary clearance in primary normal human bronchial 3D cultures. Am J Physiol Lung Cell Mol Physiol. 2019;317:L295-L302.

[43] BalázsA, BallaZ, KuiB, et al. Ductal mucus obstruction and reduced fluid secretion are early defects in chronic pancreatitis. Front Physiol. 2018;9:632.

[44] ClunesLA, DaviesCM, CoakleyRD, et al. Cigarette smoke exposure induces CFTR internalization and insolubility, leading to airway surface liquid dehydration. FASEB J. 2012;26:533-545.

[45] VengloveczV, Rakonczay Z, OzsváriB, et al. Effects of bile acids on pancreatic ductal bicarbonate secretion in guinea pig. Gut. 2008;57:1102-1112.

[46] CohenNA, ZhangS, SharpDB, et al. Cigarette smoke condensate inhibits transepithelial chloride transport and ciliary beat frequency. Laryngoscope. 2009;119:2269-2274.

[47] VirginFW, AzbellC, SchusterD, et al. Exposure to cigarette smoke condensate reduces calcium activated chloride channel transport in primary sinonasal epithelial cultures. Laryngoscope. 2010;120:1465-1469.

[48] BashirN, Manoharan V, MiltonprabuS. Grape seed proanthocyanidins protects against cadmium induced oxidative pancreatitis in rats by attenuating oxidative stress, inflammation and apoptosis via Nrf-2/HO-1 signaling. J Nutr Biochem. 2016;32:128-141.

[49] HongH, XuY, XuJ, et al. Cadmium exposure impairs pancreatic β-cell function and exaggerates diabetes by disrupting lipid metabolism. Environ Int. 2021;149:106406.

[50] HuangC-C, KuoC-Y, YangC-Y, et al. Cadmium exposure induces pancreatic β-cell death via a Ca²⁺-triggered JNK/CHOP-related apoptotic signaling pathway. Toxicology. 2019;425:152252.

[51] ChangK-C, HsuC-C, LiuS-H, et al. Cadmium induces apoptosis in pancreatic β-cells through a mitochondria-dependent pathway: the role of oxidative stress-mediated c-Jun N-terminal kinase activation. PLoS One. 2013;8:e54374.

[52] RennoldsJ, ButlerS, MaloneyK, et al. Cadmium regulates the expression of the CFTR chloride channel in human airway epithelial cells. Toxicol Sci. 2010;116:349-358.

[53] HassanF, XuX, NuovoG, et al. Accumulation of metals in GOLD4 COPD lungs is associated with decreased CFTR levels. Respir Res. 2014;15:69.

[54] RasmussenLW, Stanford D, LaFontaineJ, AllenAD, RajuSV. Nicotine aerosols diminish airway CFTR function and mucociliary clearance. Am J Physiol Lung Cell Mol Physiol. 2023;324:L557-L570.

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2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.