Altered protease and antiprotease balance during a COPD exacerbation contributes to mucus obstruction

Respiratory Research

Markus O. Henke⁴  Bruce K. Rubin²  Lutz Nahrlich¹  Andreas Guenther⁵  Claus Vogelmeier³  Gaurav Sarode⁴  Poornima Mahavadi¹  Christian Müller³  Sebastian Licht³  Jenni Preuss³  Shashi Chillappagari¹ 

[1] Member of the German Centre for Lung Research (DZL), Giessen, Germany;Department of Pediatrics, Virginia Commonwealth University School of Medicine, 1001 East Marshall Street, Richmond 23298, VA, USA;Department of Pulmonary Medicine, Philipps-University Marburg, Baldingerstrasse 1, Marburg 35043, Germany;Member of the Comprehensive Pneumology Center (CPC), Helmholtz Zentrum, Munich, Germany;Lung Clinic Waldhof-Elgershausen, Greifenstein, Germany

关键词: Hypersecretion;    Cigarette smoke;    Neutrophil elastase;    Alpha-1-protease inhibitor;    Proteases;    Mucin;    COPD;   

Others  :  1227516
DOI  :  10.1186/s12931-015-0247-x

 received in 2015-04-14, accepted in 2015-07-01,  发布年份 2015

【 摘 要 】

Background

Proteases have been shown to degrade airway mucin proteins and to damage the epithelium impairing mucociliary clearance. There are increased proteases in the COPD airway but changes in protease-antiprotease balance and mucin degradation have not been investigated during the course of a COPD exacerbation. We hypothesized that increased protease levels would lead to mucin degradation in acute COPD exacerbations.

Methods

We measured neutrophil elastase (NE) and alpha 1 protease inhibitor (A1-PI) levels using immunoblotting, and conducted protease inhibitor studies, zymograms, elastin substrate assays and cigarette smoke condensate experiments to evaluate the stability of the gel-forming mucins, MUC5AC and MUC5B, before and 5–6 weeks after an acute pulmonary exacerbation of COPD (n = 9 subjects).

Results

Unexpectedly, mucin concentration and mucin stability were highest at the start of the exacerbation and restored to baseline after 6 weeks. Consistent with these data, immunoblots and zymograms confirmed decreased NE concentration and activity and increased A1-PI at the start of the exacerbation. After recovery there was an increase in NE activity and a decrease in A1-PI levels. In vitro, protease inhibitor studies demonstrated that serine proteases played a key role in mucin degradation. Mucin stability was further enhanced upon treating with cigarette smoke condensate (CSC).

Conclusion

There appears to be rapid consumption of secreted proteases due to an increase in antiproteases, at the start of a COPD exacerbation. This leads to increased mucin gel stability which may be important in trapping and clearing infectious and inflammatory mediators, but this may also contribute acutely to mucus retention.

【 授权许可】

   
2015 Chillappagari et al.

【 图 表 】

Fig. 1.

Fig. 2.

Fig. 3.

Fig. 4.

Fig. 5.

【 参考文献 】

• [1]Abboud RT, Vimalanathan S. Pathogenesis of COPD. Part I. The role of protease-antiprotease imbalance in emphysema. Int J Tuberc Lung Dis. 2008; 12:361-7.
• [2]Anthonisen NR, Manfreda J, Warren CP, Hershfield ES, Harding GK, Nelson NA. Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann Intern Med. 1987; 106:196-204.
• [3]Carp H, Miller F, Hoidal JR, Janoff A. Potential mechanism of emphysema: alpha 1-proteinase inhibitor recovered from lungs of cigarette smokers contains oxidized methionine and has decreased elastase inhibitory capacity. Proc Natl Acad Sci U S A. 1982; 79:2041-5.
• [4]Crooks SW, Bayley DL, Hill SL, Stockley RA. Bronchial inflammation in acute bacterial exacerbations of chronic bronchitis: the role of leukotriene B4. Eur Respir J. 2000; 15:274-80.
• [5]Doring G. The role of neutrophil elastase in chronic inflammation. Am J Respir Crit Care Med. 1994; 150:S114-7.
• [6]Dubois AV, Gauthier A, Brea D, Varaigne F, Diot P, Gauthier F et al.. Influence of DNA on the activities and inhibition of neutrophil serine proteases in cystic fibrosis sputum. Am J Respir Cell Mol Biol. 2012; 47:80-6.
• [7]Ganrot PO, Laurell CB, Eriksson S. Obstructive lung disease and trypsin inhibitors in alpha-1-antitrypsin deficiency. Scand J Clin Lab Invest. 1967; 19:205-8.
• [8]Gompertz S, O’Brien C, Bayley DL, Hill SL, Stockley RA. Changes in bronchial inflammation during acute exacerbations of chronic bronchitis. Eur Respir J. 2001; 17:1112-9.
• [9]Henke MO, John G, Rheineck C, Chillappagari S, Naehrlich L, Rubin BK. Serine proteases degrade airway mucins in cystic fibrosis. Infect Immun. 2011; 79:3438-44.
• [10]Henke MO, Renner A, Huber RM, Seeds MC, Rubin BK. MUC5AC and MUC5B mucins Are decreased in cystic fibrosis airway secretions. Am J Respir Cell Mol Biol. 2004; 31:86-91.
• [11]Hogg JC. Pathophysiology of airflow limitation in chronic obstructive pulmonary disease. Lancet. 2004; 364:709-21.
• [12]Hogg JC, Chu FS, Tan WC, Sin DD, Patel SA, Pare PD et al.. Survival after lung volume reduction in chronic obstructive pulmonary disease: insights from small airway pathology. Am J Respir Crit Care Med. 2007; 176:454-9.
• [13]Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, Buzatu L et al.. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med. 2004; 350:2645-53.
• [14]Keatings VM, Barnes PJ. Granulocyte activation markers in induced sputum: comparison between chronic obstructive pulmonary disease, asthma, and normal subjects. Am J Respir Crit Care Med. 1997; 155:449-53.
• [15]Koczulla AR, Noeske S, Herr C, Koepke J, Jorres RA, Nell C et al.. Alpha-1 antitrypsin is elevated in exhaled breath condensate and serum in exacerbated COPD patients. Respir Med. 2012; 106:120-6.
• [16]Moraes TJ, Zurawska JH, Downey GP. Neutrophil granule contents in the pathogenesis of lung injury. Curr Opin Hematol. 2006; 13:21-7.
• [17]Papayannopoulos V, Staab D, Zychlinsky A. Neutrophil elastase enhances sputum solubilization in cystic fibrosis patients receiving DNase therapy. PLoS One. 2011; 6:e28526.
• [18]Picot R, Das I, Reid L. Pus, deoxyribonucleic acid, and sputum viscosity. Thorax. 1978; 33:235-42.
• [19]Prescott E, Lange P, Vestbo J. Chronic mucus hypersecretion in COPD and death from pulmonary infection. Eur Respir J. 1995; 8:1333-8.
• [20]Ramos FL, Krahnke JS, Kim V. Clinical issues of mucus accumulation in COPD. Int J Chron Obstruct Pulmon Dis. 2014; 9:139-50.
• [21]Reid L. The pathology of emphysema. Postgrad Med. 1966; 39:367-73.
• [22]Rogers DF. Physiology of airway mucus secretion and pathophysiology of hypersecretion. Respir Care. 2007; 52:1134-46.
• [23]Rose 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; 22:545-51.
• [24]Rose MC, Voynow JA. Respiratory tract mucin genes and mucin glycoproteins in health and disease. Physiol Rev. 2006; 86:245-78.
• [25]Rubin BK, Finegan B, Ramirez O, King M. General anesthesia does not alter the viscoelastic or transport properties of human respiratory mucus. Chest. 1990; 98:101-4.
• [26]Rubin BK, Ramirez O, Zayas JG, Finegan B, King M. Collection and analysis of respiratory mucus from subjects without lung disease. Am Rev Respir Dis. 1990; 141:1040-3.
• [27]Sethi S, Wrona C, Eschberger K, Lobbins P, Cai X, Murphy TF. Inflammatory profile of new bacterial strain exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2008; 177:491-7.
• [28]Stockley RA. Neutrophils and protease/antiprotease imbalance. Am J Respir Crit Care Med. 1999; 160:S49-52.
• [29]Stockley RA, Burnett D. Alpha,-antitrypsin and leukocyte elastase in infected and noninfected sputum. Am Rev Respir Dis. 1979; 120:1081-6.
• [30]Vestbo J, Hurd SS, Agusti AG, Jones PW, Vogelmeier C, Anzueto A et al.. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med. 2013; 187:347-65.
• [31]Vestbo J, Hurd SS, Agusti AG, Jones PW, Vogelmeier C, Anzueto A et al.. Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease, GOLD executive summary. Am J Respir Crit Care Med. 2013; 187:347-65.
• [32]White AJ, Gompertz S, Bayley DL, Hill SL, O’Brien C, Unsal I et al.. Resolution of bronchial inflammation is related to bacterial eradication following treatment of exacerbations of chronic bronchitis. Thorax. 2003; 58:680-5.