title: Altered protease and antiprotease balance during a COPD exacerbation contributes to mucus obstruction.
abstract: 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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pediatrics, Justus Liebig University Giessen, Feulgenstrasse 12, Giessen, 35392, Germany.|Department of Internal Medicine, Justus-Liebig-University Giessen, Klinikstrasse-36, Giessen, 35392, Germany.|Department of Pulmonary Medicine, Philipps-University Marburg, Baldingerstrasse 1, Marburg, 35043, Germany.|Member of the German Centre for Lung Research (DZL), Giessen, Germany.
authors.forename: Shashi
authors.initials: S
authors.lastname: Chillappagari
authors.affiliation: Department of Pulmonary Medicine, Philipps-University Marburg, Baldingerstrasse 1, Marburg, 35043, Germany.
authors.forename: Jenni
authors.initials: J
authors.lastname: Preuss
authors.affiliation: Department of Pulmonary Medicine, Philipps-University Marburg, Baldingerstrasse 1, Marburg, 35043, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Licht
authors.affiliation: Department of Pulmonary Medicine, Philipps-University Marburg, Baldingerstrasse 1, Marburg, 35043, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Müller
authors.affiliation: Department of Internal Medicine, Justus-Liebig-University Giessen, Klinikstrasse-36, Giessen, 35392, Germany.|Member of the German Centre for Lung Research (DZL), Giessen, Germany.
authors.forename: Poornima
authors.initials: P
authors.lastname: Mahavadi
authors.affiliation: Asklepios Fachkliniken München-Gauting, Robert-Koch-Allee 2, Gauting, 82131, Germany.|Member of the Comprehensive Pneumology Center (CPC), Helmholtz Zentrum, Munich, Germany.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Sarode
authors.affiliation: Department of Pulmonary Medicine, Philipps-University Marburg, Baldingerstrasse 1, Marburg, 35043, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Vogelmeier
authors.affiliation: Department of Internal Medicine, Justus-Liebig-University Giessen, Klinikstrasse-36, Giessen, 35392, Germany.|Member of the German Centre for Lung Research (DZL), Giessen, Germany.|Member of the European IPF Registry/Biobank, Giessen, Germany.|Lung Clinic Waldhof-Elgershausen, Greifenstein, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Guenther
authors.affiliation: Department of Pediatrics, Justus Liebig University Giessen, Feulgenstrasse 12, Giessen, 35392, Germany.|Member of the German Centre for Lung Research (DZL), Giessen, Germany.
authors.forename: Lutz
authors.initials: L
authors.lastname: Nahrlich
authors.affiliation: Department of Pediatrics, Virginia Commonwealth University School of Medicine, 1001 East Marshall Street, Richmond, 23298, VA, USA.
authors.forename: Bruce K
authors.initials: BK
authors.lastname: Rubin
authors.affiliation: Department of Pulmonary Medicine, Philipps-University Marburg, Baldingerstrasse 1, Marburg, 35043, Germany. m.henke@asklepios.com.|Asklepios Fachkliniken München-Gauting, Robert-Koch-Allee 2, Gauting, 82131, Germany. m.henke@asklepios.com.|Member of the Comprehensive Pneumology Center (CPC), Helmholtz Zentrum, Munich, Germany. m.henke@asklepios.com.
authors.forename: Markus O
authors.initials: MO
authors.lastname: Henke
mesh_terms: D000368:Aged; D005260:Female; D006801:Humans; D019272:Leukocyte Elastase / Q000032:analysis / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D055271:Mucin 5AC / Q000032:analysis / Q000378:metabolism; D009079:Mucociliary Clearance / Q000502:physiology; D009093:Mucus / Q000737:chemistry / Q000378:metabolism*; D011480:Protease Inhibitors / Q000032:analysis / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000175:diagnosis / Q000378:metabolism*; D013183:Sputum / Q000737:chemistry / Q000378:metabolism; D000515:alpha 1-Antitrypsin / Q000032:analysis / Q000378:metabolism*
chemical_list: D055271:Mucin 5AC; D011480:Protease Inhibitors; D000515:alpha 1-Antitrypsin; D019272:Leukocyte Elastase