Accumulation of metals in GOLD4 COPD lungs is associated with decreased CFTR levels

Respiratory Research

Estelle Cormet-Boyaka³  Prosper N Boyaka³  Daren Knoell⁴  Junbae Jee³  Philip Diaz⁴  Robert Tarran¹  Chong Da Tan¹  Jean Tyrrell¹  David W Killilea²  Gerard Nuovo⁶  Xiaohua Xu³  Fatemat Hassan⁵ 

[1] Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina, Chapel Hill, NC, USA;Nutrition and Metabolism Center Children's Hospital Oakland Research Institute, Oakland, CA, USA;Department of Veterinary Biosciences, The Ohio State University, 1925 Coffey Road, Columbus, OH 43210, USA;Department of Internal Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, The Ohio State University, Columbus, OH, USA;Current address: Pediatric Department, Brookdale University Hospital and Medical Center, Brooklyn, NY 11212, USA;Phylogeny Inc., Columbus, OH, USA

关键词: Lung epithelial cells;    Manganese;    Cadmium;    Cigarette smoke;    CFTR;    COPD;   

Others  :  1146647
DOI  :  10.1186/1465-9921-15-69

 received in 2014-01-23, accepted in 2014-06-16,  发布年份 2014

【 摘 要 】

Background

The Cystic Fibrosis Transmembrane conductance Regulator (CFTR) is a chloride channel that primarily resides in airway epithelial cells. Decreased CFTR expression and/or function lead to impaired airway surface liquid (ASL) volume homeostasis, resulting in accumulation of mucus, reduced clearance of bacteria, and chronic infection and inflammation.

Methods

Expression of CFTR and the cigarette smoke metal content were assessed in lung samples of controls and COPD patients with established GOLD stage 4. CFTR protein and mRNA were quantified by immunohistochemistry and quantitative RT-PCR, respectively. Metals present in lung samples were quantified by ICP-AES. The effect of cigarette smoke on down-regulation of CFTR expression and function was assessed using primary human airway epithelial cells. The role of leading metal(s) found in lung samples of GOLD 4 COPD patients involved in the alteration of CFTR was confirmed by exposing human bronchial epithelial cells 16HBE14o- to metal-depleted cigarette smoke extracts.

Results

We found that CFTR expression is reduced in the lungs of GOLD 4 COPD patients, especially in bronchial epithelial cells. Assessment of metals present in lung samples revealed that cadmium and manganese were significantly higher in GOLD 4 COPD patients when compared to control smokers (GOLD 0). Primary human airway epithelial cells exposed to cigarette smoke resulted in decreased expression of CFTR protein and reduced airway surface liquid height. 16HBE14o-cells exposed to cigarette smoke also exhibited reduced levels of CFTR protein and mRNA. Removal and/or addition of metals to cigarette smoke extracts before exposure established their role in decrease of CFTR in airway epithelial cells.

Conclusions

CFTR expression is reduced in the lungs of patients with severe COPD. This effect is associated with the accumulation of cadmium and manganese suggesting a role for these metals in the pathogenesis of COPD.

【 授权许可】

   
2014 Hassan et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

【 参考文献 】

• [1]Chung KF, Adcock IM: Multifaceted mechanisms in COPD: inflammation, immunity, and tissue repair and destruction. Eur Respir J 2008, 31:1334-1356.
• [2]Sandford AJ, Weir TD, Pare PD: Genetic risk factors for chronic obstructive pulmonary disease. Eur Respir J 1997, 10:1380-1391.
• [3]Roth M: Pathogenesis of COPD: Part III. Inflammation in COPD. Int J Tuberc Lung Dis 2008, 12:375-380.
• [4]Boucher RC: New concepts of the pathogenesis of cystic fibrosis lung disease. Eur Respir J 2004, 23:146-158.
• [5]Cantin AM, Hanrahan JW, Bilodeau G, Ellis L, Dupuis A, Liao J, Zielenski J, Durie P: Cystic fibrosis transmembrane conductance regulator function is suppressed in cigarette smokers. Am J Respir Crit Care Med 2006, 173:1139-1144.
• [6]Welsh MJ: Cigarette smoke inhibition of ion transport in canine tracheal epithelium. J Clin Invest 1983, 71:1614-1623.
• [7]Bodas M, Min T, Vij N: Critical role of CFTR-dependent lipid rafts in cigarette smoke-induced lung epithelial injury. Am J Physiol Lung Cell Mol Physiol 2011, 300:L811-L820.
• [8]Clunes LA, Davies CM, Coakley RD, Aleksandrov AA, Henderson AG, Zeman KL, Worthington EN, Gentzsch M, Kreda SM, Cholon D, Bennett WD, Riordan JR, Boucher RC, Tarran R: Cigarette smoke exposure induces CFTR internalization and insolubility, leading to airway surface liquid dehydration. Faseb J 2012, 26:533-545.
• [9]Rennolds J, Butler S, Maloney K, Boyaka PN, Davis IC, Knoell DL, Parinandi NL, Cormet-Boyaka E: Cadmium regulates the expression of the CFTR chloride channel in human airway epithelial cells. Toxicol Sci 2010, 116:349-358.
• [10]Bomberger JM, Coutermarsh BA, Barnaby RL, Stanton BA: Arsenic promotes ubiquitinylation and lysosomal degradation of cystic fibrosis transmembrane conductance regulator (CFTR) chloride channels in human airway epithelial cells. J Biol Chem 2012, 287:17130-17139.
• [11]Caruso RV, O'Connor RJ, Stephens WE, Cummings KM, Fong GT: Toxic metal concentrations in cigarettes obtained from U.S. smokers in 2009: results from the International Tobacco Control (ITC) United States survey cohort. Int J Environ Res Public Health 2014, 11:202-217.
• [12]Matsui H, Grubb BR, Tarran R, Randell SH, Gatzy JT, Davis CW, Boucher RC: Evidence for periciliary liquid layer depletion, not abnormal ion composition, in the pathogenesis of cystic fibrosis airways disease. Cell 1998, 95:1005-1015.
• [13]Ghio AJ, Hilborn ED, Stonehuerner JG, Dailey LA, Carter JD, Richards JH, Crissman KM, Foronjy RF, Uyeminami DL, Pinkerton KE: Particulate matter in cigarette smoke alters iron homeostasis to produce a biological effect. Am J Respir Crit Care Med 2008, 178:1130-1138.
• [14]Tarran R, Sabater JR, Clarke TC, Tan CD, Davies CM, Liu J, Yeung A, Garland AL, Stutts MJ, Abraham WM, Phillips G, Baker WR, Wright CD, Wilbert S: Nonantibiotic macrolides prevent human neutrophil elastase-induced mucus stasis and airway surface liquid volume depletion. Am J Physiol Lung Cell Mol Physiol 2013, 304:L746-L756.
• [15]Rollins BM, Burn M, Coakley RD, Chambers LA, Hirsh AJ, Clunes MT, Lethem MI, Donaldson SH, Tarran R: A2B adenosine receptors regulate the mucus clearance component of the lung's innate defense system. Am J Respir Cell Mol Biol 2008, 39:190-197.
• [16]Cormet-Boyaka E, Di A, Chang SY, Naren AP, Tousson A, Nelson DJ, Kirk KL: CFTR chloride channels are regulated by a SNAP-23/syntaxin 1A complex. Proc Natl Acad Sci U S A 2002, 99:12477-12482.
• [17]Rennolds J, Malireddy S, Hassan F, Tridandapani S, Parinandi N, Boyaka PN, Cormet-Boyaka E: Curcumin regulates airway epithelial cell cytokine responses to the pollutant cadmium. Biochem Biophys Res Commun 2012, 417:256-261.
• [18]Killilea AN, Downing KH, Killilea DW: Zinc deficiency reduces paclitaxel efficacy in LNCaP prostate cancer cells. Cancer Lett 2007, 258:70-79.
• [19]Boucher RC: Evidence for airway surface dehydration as the initiating event in CF airway disease. J Intern Med 2007, 261:5-16.
• [20]Stanton CR, Thibodeau R, Lankowski A, Shaw JR, Hamilton JW, Stanton BA: Arsenic inhibits CFTR-mediated chloride secretion by killifish (Fundulus heteroclitus) opercular membrane. Cell Physiol Biochem 2006, 17:269-278.
• [21]Maitra R, Hamilton JW: Arsenite regulates Cystic Fibrosis Transmembrane Conductance Regulator and P-glycoprotein: evidence of pathway independence. Cell Physiol Biochem 2005, 16:109-118.
• [22]Bernhard D, Rossmann A, Wick G: Metals in cigarette smoke. IUBMB Life 2005, 57:805-809.
• [23]Mizumura K, Cloonan SM, Haspel JA, Choi AM: The emerging importance of autophagy in pulmonary diseases. Chest 2012, 142:1289-1299.
• [24]Chung KF, Marwick JA: Molecular mechanisms of oxidative stress in airways and lungs with reference to asthma and chronic obstructive pulmonary disease. Ann N Y Acad Sci 2010, 1203:85-91.
• [25]Barnes PJ: New anti-inflammatory targets for chronic obstructive pulmonary disease. Nat Rev Drug Discov 2013, 12:543-559.
• [26]Sloane PA, Shastry S, Wilhelm A, Courville C, Tang LP, Backer K, Levin E, Raju SV, Li Y, Mazur M, Byan-Parker S, Grizzle W, Sorscher EJ, Dransfield MT, Rowe SM: A pharmacologic approach to acquired cystic fibrosis transmembrane conductance regulator dysfunction in smoking related lung disease. PLoS One 2012, 7:e39809.
• [27]Dransfield MT, Wilhelm AM, Flanagan B, Courville C, Tidwell SL, Raju SV, Gaggar A, Steele C, Tang LP, Liu B, Rowe SM: Acquired cystic fibrosis transmembrane conductance regulator dysfunction in the lower airways in COPD. Chest 2013, 144:498-506.
• [28]Croxton TL, Weinmann GG, Senior RM, Hoidal JR: Future research directions in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2002, 165:838-844.
• [29]Marcorelles P, Montier T, Gillet D, Lagarde N, Ferec C: Evolution of CFTR protein distribution in lung tissue from normal and CF human fetuses. Pediatr Pulmonol 2007, 42:1032-1040.
• [30]Fang X, Song Y, Hirsch J, Galietta LJ, Pedemonte N, Zemans RL, Dolganov G, Verkman AS, Matthay MA: Contribution of CFTR to apical-basolateral fluid transport in cultured human alveolar epithelial type II cells. Am J Physiol Lung Cell Mol Physiol 2006, 290:L242-L249.
• [31]Smith CJ, Livingston SD, Doolittle DJ: An international literature survey of “IARC Group I carcinogens” reported in mainstream cigarette smoke. Food Chem Toxicol 1997, 35:1107-1130.
• [32]Paakko P, Anttila S, Kokkonen P, Kalliomaki PL: Cadmium in lung tissue as marker for smoking. Lancet 1988, 1:477.
• [33]Chambers RC, Laurent GJ, Westergren-Thorsson G: Cadmium inhibits proteoglycan and procollagen production by cultured human lung fibroblasts. Am J Respir Cell Mol Biol 1998, 19:498-506.
• [34]Abu-Hayyeh S, Sian M, Jones KG, Manuel A, Powell JT: Cadmium accumulation in aortas of smokers. Arterioscler Thromb Vasc Biol 2001, 21:863-867.
• [35]Roels H, Lauwerys R, Buchet JP, Genet P, Sarhan MJ, Hanotiau I, de Fays M, Bernard A, Stanescu D: Epidemiological survey among workers exposed to manganese: effects on lung, central nervous system, and some biological indices. Am J Ind Med 1987, 11:307-327.
• [36]Mahoney JP, Small WJ: Studies on manganese. 3. The biological half-life of radiomanganese in man and factors which affect this half-life. J Clin Invest 1968, 47:643-653.
• [37]Mannino DM, Holguin F, Greves HM, Savage-Brown A, Stock AL, Jones RL: Urinary cadmium levels predict lower lung function in current and former smokers: data from the Third National Health and Nutrition Examination Survey. Thorax 2004, 59:194-198.
• [38]Davison AG, Fayers PM, Taylor AJ, Venables KM, Darbyshire J, Pickering CA, Chettle DR, Franklin D, Guthrie CJ, Scott MC: Cadmium fume inhalation and emphysema. Lancet 1988, 1:663-667.
• [39]Kirschvink N, Martin N, Fievez L, Smith N, Marlin D, Gustin P: Airway inflammation in cadmium-exposed rats is associated with pulmonary oxidative stress and emphysema. Free Radic Res 2006, 40:241-250.
• [40]Kirschvink N, Vincke G, Fievez L, Onclinx C, Wirth D, Belleflamme M, Louis R, Cataldo D, Peck MJ, Gustin P: Repeated cadmium nebulizations induce pulmonary MMP-2 and MMP-9 production and emphysema in rats. Toxicology 2005, 211:36-48.