Secreted mucins and airway bacterial colonization in non-CF bronchiectasis
Corresponding Author
Oriol Sibila
Respiratory Department, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain
Biomedical Research Institute Sant Pau (IIB Sant Pau), Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain
Correspondence: Oriol Sibila, Respiratory Department, Hospital de la Santa Creu i Sant Pau. Sant Antoni M. Claret Street 167, Barcelona 08025, Spain. Email: [email protected]Search for more papers by this authorGuillermo Suarez-Cuartin
Respiratory Department, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain
Biomedical Research Institute Sant Pau (IIB Sant Pau), Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain
Search for more papers by this authorAna Rodrigo-Troyano
Respiratory Department, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain
Biomedical Research Institute Sant Pau (IIB Sant Pau), Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain
Search for more papers by this authorThomas C. Fardon
Tayside Respiratory Research Group, University of Dundee, Dundee, UK
Search for more papers by this authorSimon Finch
Tayside Respiratory Research Group, University of Dundee, Dundee, UK
Search for more papers by this authorEder Freddy Mateus
Biomedical Research Institute Sant Pau (IIB Sant Pau), Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain
Laboratory of Experimental Immunology, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain
Search for more papers by this authorLaia Garcia-Bellmunt
Respiratory Department, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain
Biomedical Research Institute Sant Pau (IIB Sant Pau), Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain
Search for more papers by this authorDiego Castillo
Respiratory Department, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain
Biomedical Research Institute Sant Pau (IIB Sant Pau), Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain
Search for more papers by this authorSilvia Vidal
Biomedical Research Institute Sant Pau (IIB Sant Pau), Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain
Laboratory of Experimental Immunology, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain
Search for more papers by this authorFerran Sanchez-Reus
Biomedical Research Institute Sant Pau (IIB Sant Pau), Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain
Microbiology Department, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain
Search for more papers by this authorMarcos I. Restrepo
Critical Care Department, South Texas Veterans Health Care System
Medicine Division, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
Search for more papers by this authorJames D. Chalmers
Tayside Respiratory Research Group, University of Dundee, Dundee, UK
Search for more papers by this authorCorresponding Author
Oriol Sibila
Respiratory Department, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain
Biomedical Research Institute Sant Pau (IIB Sant Pau), Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain
Correspondence: Oriol Sibila, Respiratory Department, Hospital de la Santa Creu i Sant Pau. Sant Antoni M. Claret Street 167, Barcelona 08025, Spain. Email: [email protected]Search for more papers by this authorGuillermo Suarez-Cuartin
Respiratory Department, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain
Biomedical Research Institute Sant Pau (IIB Sant Pau), Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain
Search for more papers by this authorAna Rodrigo-Troyano
Respiratory Department, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain
Biomedical Research Institute Sant Pau (IIB Sant Pau), Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain
Search for more papers by this authorThomas C. Fardon
Tayside Respiratory Research Group, University of Dundee, Dundee, UK
Search for more papers by this authorSimon Finch
Tayside Respiratory Research Group, University of Dundee, Dundee, UK
Search for more papers by this authorEder Freddy Mateus
Biomedical Research Institute Sant Pau (IIB Sant Pau), Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain
Laboratory of Experimental Immunology, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain
Search for more papers by this authorLaia Garcia-Bellmunt
Respiratory Department, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain
Biomedical Research Institute Sant Pau (IIB Sant Pau), Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain
Search for more papers by this authorDiego Castillo
Respiratory Department, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain
Biomedical Research Institute Sant Pau (IIB Sant Pau), Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain
Search for more papers by this authorSilvia Vidal
Biomedical Research Institute Sant Pau (IIB Sant Pau), Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain
Laboratory of Experimental Immunology, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain
Search for more papers by this authorFerran Sanchez-Reus
Biomedical Research Institute Sant Pau (IIB Sant Pau), Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain
Microbiology Department, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain
Search for more papers by this authorMarcos I. Restrepo
Critical Care Department, South Texas Veterans Health Care System
Medicine Division, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
Search for more papers by this authorJames D. Chalmers
Tayside Respiratory Research Group, University of Dundee, Dundee, UK
Search for more papers by this authorAbstract
Background and objective
Secreted mucins play a key role in antibacterial defence in the airway, but have not previously been characterized in non-cystic fibrosis (CF) bronchiectasis patients. We aim to investigate the relationship between secreted mucins levels and the presence of bacterial colonization due to potentially pathogenic microorganisms (PPM) in the airways of stable bronchiectasis patients.
Methods
Clinically stable bronchiectasis patients were studied prospectively at two centres. Patients with other pulmonary conditions were excluded. Spontaneous sputum was subject to bacterial culture, and secreted mucins (MUC2, MUC5AC and MUC5B) were measured in sputum supernatants by ELISA.
Results
A total of 50 patients were included. PPM were identified from sputum samples in 30 (60%), with Pseudomonas aeruginosa (n = 10) and Haemophilus influenzae (n = 10) as the most common PPM. There were no baseline differences among airway colonized and non-colonized patients. Patients with airways colonized by PPM presented higher levels of airway MUC2. No differences in MUC5AC levels were found among groups, whereas MUC5B levels were undetectable. Patients with P. aeruginosa colonization expressed the highest levels of MUC2. High levels of MUC2 and MUC5AC are also correlated with disease severity using the Bronchiectasis Severity Index.
Conclusions
Airway MUC2 levels were higher in bronchiectasis patients colonized with PPM compared with those without airway colonization, especially in patients with P. aeruginosa. These findings suggest that airway-secreted mucins levels may play a role in the pathogenesis of airway infection in non-CF bronchiectasis.
References
- 1McShane PJ, Naureckas ET, Tino G, Strek ME. Non-cystic fibrosis bronchiectasis. Am. J. Respir. Crit. Care Med. 2013; 188: 647–656.
- 2Fuschillo S, De Felice A, Balzano G. Mucosal inflammation in idiopatic bronchiectasis; cellular and molecular mechanisms. Eur. Respir. J. 2008; 31: 396–406.
- 3Chalmers JD, Hill AT. Mechanisms of immune dysfunction and bacterial persistence in non-cystic fibrosis bronchiectasis. Mol. Immunol. 2013; 55: 27–34.
- 4Angrill J, Agusti C, de Celis R, Raño A, Gonzalez J, Sole T, Xaubet A, Rodriguez-Roisin R, Torres A. Bacterial colonization in patients with bronchiectasis. Microbiological pattern and risk factors. Thorax 2002; 57: 15–19.
- 5Cole PJ. A new look at the pathogenesis, management of persistent bronchial sepsis: a ‘vicious circle’ hypothesis and its logical therapeutic connotations. In: RJ Davies (ed) Strategies for the Management of Chronic Bacterial Sepsis. Medicine Publishing Foundation, Oxford, 1984; 1–20.
- 6Kaliner M, Marom Z, Patow C, Shelhamer J. Human respiratory mucus. J. Allergy Clin. Immunol. 1984; 73: 318–323.
- 7Rose MC, Voynow JA. Respiratory tract mucin genes and mucin glycoproteins in health and disease. Physiol. Rev. 2006; 86: 245–278.
- 8Thornton DJ, Carlstedt I, Howard M, Devine PL, Price MR, Sheehan JK. Respiratory mucins: identification of core proteins and glycoforms. Biochem. J. 1996; 316: 967–975.
- 9Rose MC, Nickola TJ, Voynow JA. Airway mucus obstruction: mucin glycoproteins, MUC gene regulation and globet cell hyperplasia. Am. J. Respir. Cell Mol. Biol. 2001; 24: 533–537.
10.1165/ajrcmb.25.5.f218 Google Scholar
- 10Voynow JA, Rubin BK. Mucins, mucus and sputum. Chest 2009; 135: 505–512.
- 11Kirham S, Seehan JK, Knight D, Richardson PS, Thornton DJ. Heterogeneity of airway mucus: variations in the amounts and glycoforms of the major oligomeric mucins MUC5AC and MUC5B. Biochem. J. 2002; 361: 537–546.
- 12Rose MC, Brown CF, Jacoby JZ, Lynn WS, Kaufman B. Biochemical properties of tracheobronchial mucins from cystic fibrosis and non-cystic fibrosis individuals. Pediatr. Res. 1987; 22: 545–551.
- 13Henke MO, Renner A, Huber RM, Seeds MC, Rubin BK. MUC5AC and MUC5B mucins are decreased in cystic fibrosis airway secretions. Am J Respir Cell Moll Biol. 2004; 31: 86–89.
- 14Henke MO, John G, Germann M, Lindemann H, Rubin BK. MUC5AC and MUC5B mucins increase in cystic fibrosis airway secretions during pulmonary exacerbations. Am. J. Respir. Crit. Care Med. 2007; 175: 816–821.
- 15Roy MG, Livraghi-Butrico A, Fletcher AA, McElwee MM, Evans SE, Boerner RM, Alexander SN, Bellinghausen LK, Song AS, Petrova YM et al. MUC5B is required for airway defense. Nature 2014; 505: 412–416.
- 16Vendrell M, de Gracia J, Olveira C, Martínez MA, Giron R, Maiz L, Cantón R, Coll R, Escribano A, Sole A. Diagnosis and treatment of bronchiectasis. Spanish Society of Pneumology and Thoracic Surgery. Arch. Bronconeumol. 2008; 44: 629–640.
- 17Pasteur MC, Bilton D, Hill AT. British Thoracic Society guideline for non-CF bronchiectasis. Thorax 2010; 65(Suppl. 1): i1–58.
- 18Chalmers JD, Goeminne P, Aliberti S, McDonnell MJ, Lonni S, Davidson J, Poppelwell L, Salih W, Pesci A, Dupont LJ et al. The Bronchiectasis Severity Index: an international derivation and validation study. Am. J. Respir. Crit. Care Med. 2014; 189: 576–585.
- 19Chalmers JD, Smith PM, McHugh BJ, Coherty C, Govan JR, Hill AT. Short-and long-term antibiotic treatment reduces airway and systemic inflammation in non-cystic fibrosis bronchiectasis. Am. J. Respir. Crit. Care Med. 2012; 186: 657–665.
- 20Ballows A, Hauser WJ, Hermann KL, Isenberg HD, Shadomy HJ. Manual of clinical microbiology, 5th edn. American Society of Microbiology, Washington, DC, 1991.
- 21Thornton DJ, Rousseau K, McGuckin MA. Structure and function of the polymeric mucins in airways mucus. Annu. Rev. Physiol. 2008; 70: 459–486.
- 22Busine MP, Devisme L, Copin MC, Durand-Reville M, Gosselin B, Aubert PJ, Porchet N. Developmental mucin gene expression in the human respiratory tract. Am. J. Respir. Cell Mol. Biol. 1999; 20: 209–218.
- 23Vinall LE, Fowler JC, Jones AL, Kirkbride HJ, de Bolos C, Laine A, Porchet N, Gum JR, Kim YS, Moss FM et al. Polymorphisms of human mucin genes in chest disease: possible significance of MUC2. Am. J. Respir. Cell Mol. Biol. 2000; 23: 678–686.
- 24Kirkham S, Kolsum U, Rousseau K, Singh D, Vestbo J, Thornton DJ. MUC5B is the major mucin in the gel phase of sputum in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2008; 178: 1033–1039.
- 25Cole PJ. Inflammation: a two-edged sword—the model of bronchiectasis. Eur. J. Respir. Dis. Suppl. 1986; 147: 6–15.
- 26Watt AP, Brown V, Courtney J, Kelly M, Garske L, Elborn JS, Ennis M. Neutrophil apoptosis, proinflammatory mediators and cell counts in bronchiectasis. Thorax 2004; 59: 232–236.
- 27Loebinger MR, Wells AU, Hansell DM, Chinyanganya N, Devaraj A, Meister M, Wilson R. Mortality in bronchiectasis: a long-term study assessing the factors influencing survival. Eur. Respir. J. 2009; 34: 843–849.
- 28Kawakubo M, Ito Y, Okimura Y, Kobayashi M, Sakura K, Kasama S, Fukuda MN, Fukuda M, Katsuyama T, Nakayama J. Natural antibiotic function of a human gastric mucin against Helicobacter pylori infection. Science 2004; 305: 1003–1006.
- 29Fischer BM, Rochelle LG, Voynow JA, Akley NJ, Adler KB. Tumor necrosis factor-alfa stimulates mucin secretion and cyclic GMP production by guinea pig tracheal epithelial cells in vitro. Am. J. Respir. Cell Mol. Biol. 1999; 20: 413–422.
- 30Park JA, He F, Martin LD, Li Y, Chorley BN, Adler KB. Human neutrophil elastase induces hypersecretion of mucin from well-differentiated human bronchial epithelial cells in vitro via a protein kinase C-mediated mechanism. Am. J. Pathol. 2005; 167: 651–661.
- 31Klinger JD, Tandler B, Liedtke CM, Boat TF. Proteinases of Pseudomonas aeruginosa evoke mucin release by tracheal epithelium. J. Clin. Invest. 1984; 74: 1669–1678.
- 32Fujisawa T, Chang MM, Velichko S, Thai P, Hung LY, Huang F, Phuong N, Chen Y, Wu R. NF-kB mediates IL-1B adn IL-17A-induced MUC5B expression in airway epithelial cells. Am. J. Respir. Cell Mol. Biol. 2011; 45: 246–252.
- 33Murray MP1, Govan JR, Doherty CJ, Simpson AJ, Wilkinson TS, Chalmers JD, Greening AP, Haslett C, Hill AT. A randomized controlled trial of nebulized gentamicin in non-cystic fibrosis bronchiectasis. Am. J. Respir. Crit. Care Med. 2011; 183: 491–499.