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Respiratory Research
Published in: Respiratory Research 1/2018

Open Access 01-12-2018 | Research

Airway surface liquid from smokers promotes bacterial growth and biofilm formation via iron-lactoferrin imbalance

Authors: Luis G. Vargas Buonfiglio, Jennifer A. Borcherding, Mark Frommelt, Gavin J. Parker, Bryce Duchman, Oriana G. Vanegas Calderón, Ruth Fernandez-Ruiz, Julio E. Noriega, Elizabeth A. Stone, Alicia K. Gerke, Joseph Zabner, Alejandro P. Comellas

Published in: Respiratory Research | Issue 1/2018

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Abstract

Background

Smoking is a leading cause of respiratory infections worldwide. Tobacco particulate matter disrupts iron homeostasis in the lungs and increases the iron content in the airways of smokers. The airway epithelia secrete lactoferrin to quench iron required for bacteria to proliferate and cause lung infections. We hypothesized that smokers would have increased bacterial growth and biofilm formation via iron lactoferrin imbalance.

Methods

We collected bronchoalveolar lavage (BAL) samples from non-smokers and smokers. We challenged these samples using a standard inoculum of Staphylococcus aureus and Pseudomonas aeruginosa and quantified bacterial growth and biofilm formation. We measured both iron and lactoferrin in the samples. We investigated the effect of supplementing non-smoker BAL with cigarette smoke extract (CSE) or ferric chloride and the effect of supplementing smoker BAL with lactoferrin on bacterial growth and biofilm formation.

Results

BAL from smokers had increased bacterial growth and biofilm formation compared to non-smokers after both S. aureus and P. aeruginosa challenge. In addition, we found that samples from smokers had a higher iron to lactoferrin ratio. Supplementing the BAL of non-smokers with cigarette smoke extract and ferric chloride increased bacterial growth. Conversely, supplementing the BAL of smokers with lactoferrin had a concentration-dependent decrease in bacterial growth and biofilm formation.

Conclusion

Cigarette smoking produces factors which increase bacterial growth and biofilm formation in the BAL. We propose that smoking disrupts the iron-to-lactoferrin in the airways. This finding offers a new avenue for potential therapeutic interventions to prevent respiratory infections in smokers.
Appendix
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Literature
1.
Nuorti JP, Butler JC, Farley MM, Harrison LH, McGeer A, Kolczak MS, Breiman RF. Cigarette smoking and invasive pneumococcal disease. Active bacterial Core surveillance team. N Engl J Med. 2000;342:681–9.CrossRefPubMed
2.
Blake GH, Abell TD, Stanley WG. Cigarette smoking and upper respiratory infection among recruits in basic combat training. Ann Intern Med. 1988;109:198–202.CrossRefPubMed
3.
Pastor P, Medley F, Murphy TV. Invasive pneumococcal disease in Dallas County, Texas: results from population-based surveillance in 1995. Clin Infect Dis. 1998;26:590–5.CrossRefPubMed
4.
Bogaert D, van Belkum A, Sluijter M, Luijendijk A, de Groot R, Rümke HC, Verbrugh HA, Hermans PWM. Colonisation by Streptococcus pneumoniae and Staphylococcus aureus in healthy children. Lancet. 2004;363:1871–2.CrossRefPubMed
5.
Brook I, Gober AE. Recovery of potential pathogens and interfering bacteria in the nasopharynx of smokers and nonsmokers. Chest. 2005;127:2072–5.CrossRefPubMed
6.
7.
8.
Jukosky J, Gosselin BJ, Foley L, Dechen T, Fiering S, Crane-Godreau MA. In vivo cigarette smoke exposure decreases CCL20, SLPI, and BD-1 secretion by human primary nasal epithelial cells. Front Psychiatry. 2015;6:185.PubMed
9.
Qian YJ, Wang X, Gao YF, Duan N, Huang XF, Sun FF, Han XD, Wang WM. Cigarette smoke modulates NOD1 signal pathway and human beta Defensins expression in human oral mucosa. Cell Physiol Biochem. 2015;36:457–73.CrossRefPubMed
10.
Crane-Godreau MA, Maccani MA, Eszterhas SK, Warner SL, Jukosky JA, Fiering S. Exposure to cigarette smoke disrupts CCL20-mediated antimicrobial activity in respiratory epithelial cells. Open Immunol J. 2009;2:86–93.PubMedPubMedCentral
11.
Vargas Buonfiglio LG, Cano M, Pezzulo AA, Vanegas Calderon OG, Zabner J, Gerke AK, Comellas AP. Effect of vitamin D3 on the antimicrobial activity of human airway surface liquid: preliminary results of a randomised placebo-controlled double-blind trial. BMJ Open Respir Res. 2017;4
12.
McEachern EK, Hwang JH, Sladewski KM, Nicatia S, Dewitz C, Mathew DP, Nizet V, Crotty Alexander LE. Analysis of the effects of cigarette smoke on staphylococcal virulence phenotypes. Infect Immun. 2015;83:2443–52.CrossRefPubMedPubMedCentral
13.
Singh PK, Parsek MR, Greenberg EP, Welsh MJ. A component of innate immunity prevents bacterial biofilm development. Nature. 2002;417:552–5.CrossRefPubMed
14.
Maisetta G, Di Luca M, Esin S, Florio W, Brancatisano FL, Bottai D, Campa M, Batoni G. Evaluation of the inhibitory effects of human serum components on bactericidal activity of human beta defensin 3. Peptides. 2008;29:1–6.CrossRefPubMed
15.
Krishnakumari V, Packiyanathan KK, Nagaraj R. Human-beta-defensins-1-3 and analogs do not require proton motive force for antibacterial activity against Escherichia coli. FEMS Microbiol Lett. 2013;348:52–7.CrossRefPubMed
16.
Travis SM, Conway BA, Zabner J, Smith JJ, Anderson NN, Singh PK, Greenberg EP, Welsh MJ. Activity of abundant antimicrobials of the human airway. Am J Respir Cell Mol Biol. 1999;20:872–9.CrossRefPubMed
17.
Pezzulo AA, Tang XX, Hoegger MJ, Alaiwa MH, Ramachandran S, Moninger TO, Karp PH, Wohlford-Lenane CL, Haagsman HP, van Eijk M, et al. Reduced airway surface pH impairs bacterial killing in the porcine cystic fibrosis lung. Nature. 2012;487:109–13.CrossRefPubMedPubMedCentral
18.
Abou Alaiwa MH, Reznikov LR, Gansemer ND, Sheets KA, Horswill AR, Stoltz DA, Zabner J, Welsh MJ. pH modulates the activity and synergism of the airway surface liquid antimicrobials beta-defensin-3 and LL-37. Proc Natl Acad Sci U S A. 2014;111:18703–8.CrossRefPubMedPubMedCentral
19.
Musharraf SG, Shoaib M, Siddiqui AJ, Najam-Ul-Haq M, Ahmed A. Quantitative analysis of some important metals and metalloids in tobacco products by inductively coupled plasma-mass spectrometry (ICP-MS). Chem Cent J. 2012;6:56.PubMedPubMedCentral
20.
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;178:1130–8.CrossRefPubMed
21.
Borcherding J, Baltrusaitis J, Chen H, Stebounova L, Wu CM, Rubasinghege G, Mudunkotuwa IA, Caraballo JC, Zabner J, Grassian VH, Comellas AP. Iron oxide nanoparticles induce growth, induce biofilm formation, and inhibit antimicrobial peptide function. Environ Sci Nano. 2014;1:123–32.CrossRefPubMedPubMedCentral
22.
Borcherding JA, Chen H, Caraballo JC, Baltrusaitis J, Pezzulo AA, Zabner J, Grassian VH, Comellas AP. Coal fly ash impairs airway antimicrobial peptides and increases bacterial growth. PLoS One. 2013;8:e57673.CrossRefPubMedPubMedCentral
23.
Tunney MM, Einarsson GG, Wei L, Drain M, Klem ER, Cardwell C, Ennis M, Boucher RC, Wolfgang MC, Elborn JS. Lung microbiota and bacterial abundance in patients with bronchiectasis when clinically stable and during exacerbation. Am J Respir Crit Care Med. 2013;187:1118–26.CrossRefPubMedPubMedCentral
24.
Hansbro PM, Starkey MR, Mattes J, Horvat JC. Pulmonary immunity during respiratory infections in early life and the development of severe asthma. Ann Am Thorac Soc. 2014;11(Suppl 5):S297–302.CrossRefPubMed
25.
Hayden LP, Hobbs BD, Cohen RT, Wise RA, Checkley W, Crapo JD, Hersh CP. Childhood pneumonia increases risk for chronic obstructive pulmonary disease: the COPDGene study. Respir Res. 2015;16:115.CrossRefPubMedPubMedCentral
26.
Durmaz R, Tekerekoglu MS, Kalcioglu T, Ozturan O. Nasal carriage of methicillin-resistant Staphylococcus aureus among smokers and cigarette factory workers. New Microbiol. 2001;24:143–7.PubMed
27.
Wertheim HF, Vos MC, Ott A, van Belkum A, Voss A, Kluytmans JA, van Keulen PH, Vandenbroucke-Grauls CM, Meester MH, Verbrugh HA. Risk and outcome of nosocomial Staphylococcus aureus bacteraemia in nasal carriers versus non-carriers. Lancet. 2004;364:703–5.CrossRefPubMed
28.
Murphy TF, Brauer AL, Eschberger K, Lobbins P, Grove L, Cai X, Sethi S. Pseudomonas aeruginosa in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2008;177:853–60.CrossRefPubMed
29.
Miravitlles M, Espinosa C, Fernandez-Laso E, Martos JA, Maldonado JA, Gallego M. Relationship between bacterial flora in sputum and functional impairment in patients with acute exacerbations of COPD. Study Group of Bacterial Infection in COPD. Chest. 1999;116:40–6.CrossRefPubMed
30.
Lin SH, Kuo PH, Hsueh PR, Yang PC, Kuo SH. Sputum bacteriology in hospitalized patients with acute exacerbation of chronic obstructive pulmonary disease in Taiwan with an emphasis on Klebsiella pneumoniae and Pseudomonas aeruginosa. Respirology. 2007;12:81–7.CrossRefPubMed
31.
Yager D, Cloutier T, Feldman H, Bastacky J, Drazen JM, Kamm RD. Airway surface liquid thickness as a function of lung volume in small airways of the Guinea pig. J Appl Physiol (1985). 1994;77:2333–40.CrossRef
32.
Bartlett JA, Albertolle ME, Wohlford-Lenane C, Pezzulo AA, Zabner J, Niles RK, Fisher SJ, PB MC Jr, Williams KE. Protein composition of bronchoalveolar lavage fluid and airway surface liquid from newborn pigs. Am J Physiol Lung Cell Mol Physiol. 2013;305:L256–66.CrossRefPubMedPubMedCentral
33.
Gerke AK, Pezzulo AA, Tang F, Cavanaugh JE, Bair TB, Phillips E, Powers LS, Monick MM. Effects of vitamin D supplementation on alveolar macrophage gene expression: preliminary results of a randomized, controlled trial. Multidiscip Respir Med. 2014;9:18.CrossRefPubMedPubMedCentral
34.
O'Toole GA. Microtiter dish biofilm formation assay. J Vis Exp. 2011;2437
35.
Brekman A, Walters MS, Tilley AE, Crystal RG. FOXJ1 prevents cilia growth inhibition by cigarette smoke in human airway epithelium in vitro. Am J Respir Cell Mol Biol. 2014;51:688–700.CrossRefPubMedPubMedCentral
36.
Thompson AB, Bohling T, Payvandi F, Rennard SI. Lower respiratory tract lactoferrin and lysozyme arise primarily in the airways and are elevated in association with chronic bronchitis. J Lab Clin Med. 1990;115:148–58.PubMed
37.
Jenabian N, Pouramir M, Motallebnejad M, Bamdadian J, Rahimi-Rad M. Evaluation of the effect of passive smoking on Lactoferrin and AST on 12 - 15 years old children and adolescents. Iran J Pediatr. 2015;25:e2996.CrossRefPubMedPubMedCentral
38.
Reid DW, Anderson GJ, Lamont IL. Role of lung iron in determining the bacterial and host struggle in cystic fibrosis. Am J Physiol Lung Cell Mol Physiol. 2009;297:L795–802.CrossRefPubMed
39.
40.
Nelson ME, O'Brien-Ladner AR, Wesselius LJ. Regional variation in iron and iron-binding proteins within the lungs of smokers. Am J Respir Crit Care Med. 1996;153:1353–8.CrossRefPubMed
41.
McGowan SE, Henley SA. Iron and ferritin contents and distribution in human alveolar macrophages. J Lab Clin Med. 1988;111:611–7.PubMed
42.
Corhay JL, Weber G, Bury T, Mariz S, Roelandts I, Radermecker MF. Iron content in human alveolar macrophages. Eur Respir J. 1992;5:804–9.PubMed
43.
Thompson AB, Bohling T, Heires A, Linder J, Rennard SI. Lower respiratory tract iron burden is increased in association with cigarette smoking. J Lab Clin Med. 1991;117:493–9.PubMed
44.
Ghio AJ, Soukup JM, Dailey LA. Air pollution particles and iron homeostasis. Biochim Biophys Acta. 1860;2016:2816–25.
45.
46.
47.
Moreno JJ, Foroozesh M, Church DF, Pryor WA. Release of iron from ferritin by aqueous extracts of cigarette smoke. Chem Res Toxicol. 1992;5:116–23.CrossRefPubMed
48.
Hunter RC, Asfour F, Dingemans J, Osuna BL, Samad T, Malfroot A, Cornelis P, Newman DK. Ferrous iron is a significant component of bioavailable iron in cystic fibrosis airways. MBio. 2013;4:1–7.CrossRef
49.
50.
Gangaidzo IT, Moyo VM, Mvundura E, Aggrey G, Murphree NL, Khumalo H, Saungweme T, Kasvosve I, Gomo ZA, Rouault T, et al. Association of pulmonary tuberculosis with increased dietary iron. J Infect Dis. 2001;184:936–9.CrossRefPubMed
51.
Gordeuk VR, McLaren CE, MacPhail AP, Deichsel G, Bothwell TH. Associations of iron overload in Africa with hepatocellular carcinoma and tuberculosis: Strachan's 1929 thesis revisited. Blood. 1996;87:3470–6.PubMed
52.
Hassan F, Xu X, Nuovo G, Killilea DW, Tyrrell J, Da Tan C, Tarran R, Diaz P, Jee J, Knoell D, et al. Accumulation of metals in GOLD4 COPD lungs is associated with decreased CFTR levels. Respir Res. 2014;15:69.CrossRefPubMedPubMedCentral
53.
Leem AY, Kim SK, Chang J, Kang YA, Kim YS, Park MS, Kim SY, Kim EY, Chung KS, Jung JY. Relationship between blood levels of heavy metals and lung function based on the Korean National Health and nutrition examination survey IV–V. Int J Chron Obstruct Pulmon Dis. 2015;10:1559–70.PubMedPubMedCentral
54.
Rab A, Rowe SM, Raju SV, Bebok Z, Matalon S, Collawn JF. Cigarette smoke and CFTR: implications in the pathogenesis of COPD. Am J Physiol Lung Cell Mol Physiol. 2013;305:L530–41.CrossRefPubMedPubMedCentral
55.
Pace E, Ferraro M, Minervini MI, Vitulo P, Pipitone L, Chiappara G, Siena L, Montalbano AM, Johnson M, Gjomarkaj M. Beta defensin-2 is reduced in central but not in distal airways of smoker COPD patients. PLoS One. 2012;7:e33601.CrossRefPubMedPubMedCentral
56.
Nemery B. Metal toxicity and the respiratory tract. Eur Respir J. 1990;3:202–19.PubMed
57.
Ertel A, Eng R, Smith SM. THe differential effect of cigarette smoke on the growth of bacteria found in humans. Chest. 1991;100:628–30.CrossRefPubMed
58.
Byrd TF, Horwitz MA. Lactoferrin inhibits or promotes legionella pneumophila intracellular multiplication in nonactivated and interferon gamma-activated human monocytes depending upon its degree of iron saturation. Iron-lactoferrin and nonphysiologic iron chelates reverse monocyte activation against legionella pneumophila. J Clin Invest. 1991;88:1103–12.CrossRefPubMedPubMedCentral
59.
Konings AF, Martin LW, Sharples KJ, Roddam LF, Latham R, Reid DW, Lamont IL. Pseudomonas aeruginosa uses multiple pathways to acquire iron during chronic infection in cystic fibrosis lungs. Infect Immun. 2013;81:2697–704.CrossRefPubMedPubMedCentral
60.
Minandri F, Imperi F, Frangipani E, Bonchi C, Visaggio D, Facchini M, Pasquali P, Bragonzi A, Visca P. Role of Iron uptake systems in Pseudomonas aeruginosa virulence and airway infection. Infect Immun. 2016;84:2324–35.CrossRefPubMedPubMedCentral
61.
Cornelis P, Dingemans J. Pseudomonas aeruginosa adapts its iron uptake strategies in function of the type of infections. Front Cell Infect Microbiol. 2013;3:75.CrossRefPubMedPubMedCentral
62.
Reid DW, Carroll V, O'May C, Champion A, Kirov SM. Increased airway iron as a potential factor in the persistence of Pseudomonas aeruginosa infection in cystic fibrosis. Eur Respir J. 2007;30:286–92.CrossRefPubMed
63.
Philippot Q, Deslee G, Adair-Kirk TL, Woods JC, Byers D, Conradi S, Dury S, Perotin JM, Lebargy F, Cassan C, et al. Increased iron sequestration in alveolar macrophages in chronic obstructive pulmonary disease. PLoS One. 2014;9:e96285.CrossRefPubMedPubMedCentral
64.
Ellison RT 3rd, Giehl TJ, LaForce FM. Damage of the outer membrane of enteric gram-negative bacteria by lactoferrin and transferrin. Infect Immun. 1988;56:2774–81.PubMedPubMedCentral
65.
66.
Appelmelk BJ, An YQ, Geerts M, Thijs BG, de Boer HA, MacLaren DM, de Graaff J, Nuijens JH. Lactoferrin is a lipid A-binding protein. Infect Immun. 1994;62:2628–32.PubMedPubMedCentral
67.
Woodruff PG, Barr RG, Bleecker E, Christenson SA, Couper D, Curtis JL, Gouskova NA, Hansel NN, Hoffman EA, Kanner RE, et al. Clinical significance of symptoms in smokers with preserved pulmonary function. N Engl J Med. 2016;374:1811–21.CrossRefPubMedPubMedCentral
68.
Bowler RP, Kim V, Regan E, Williams AAA, Santorico SA, Make BJ, Lynch DA, Hokanson JE, Washko GR, Bercz P, et al. Prediction of acute respiratory disease in current and former smokers with and without COPD. Chest. 2014;146:941–50.CrossRefPubMedPubMedCentral
69.
Cloonan SM, Glass K, Laucho-Contreras ME, Bhashyam AR, Cervo M, Pabon MA, Konrad C, Polverino F, Siempos II, Perez E, et al. Mitochondrial iron chelation ameliorates cigarette smoke-induced bronchitis and emphysema in mice. Nat Med. 2016;22:163–74.CrossRefPubMedPubMedCentral
70.
DeMeo DL, Mariani T, Bhattacharya S, Srisuma S, Lange C, Litonjua A, Bueno R, Pillai SG, Lomas DA, Sparrow D, et al. Integration of genomic and genetic approaches implicates IREB2 as a COPD susceptibility gene. Am J Hum Genet. 2009;85:493–502.CrossRefPubMedPubMedCentral
Metadata
Title
Airway surface liquid from smokers promotes bacterial growth and biofilm formation via iron-lactoferrin imbalance
Authors
Luis G. Vargas Buonfiglio
Jennifer A. Borcherding
Mark Frommelt
Gavin J. Parker
Bryce Duchman
Oriana G. Vanegas Calderón
Ruth Fernandez-Ruiz
Julio E. Noriega
Elizabeth A. Stone
Alicia K. Gerke
Joseph Zabner
Alejandro P. Comellas
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Respiratory Research / Issue 1/2018
Electronic ISSN: 1465-993X
DOI
https://doi.org/10.1186/s12931-018-0743-x

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