title: A small molecule neutrophil elastase inhibitor, KRP-109, inhibits cystic fibrosis mucin degradation.
abstract: Neutrophil elastase (NE) rapidly degrades gel-forming airway mucins in cystic fibrosis (CF) sputum. We hypothesized that KRP-109, a small molecule NE inhibitor, would inhibit CF mucin degradation in vitro.
  
  
  
  Sputa were collected from CF patients (n=5) chronically or intermittently infected with Pseudomonas aeruginosa (P.a.). Mucin degradation was analyzed using western blot. Protease inhibitor studies were performed using alpha1-proteinase inhibitor (A1-PI Prolastin®) and KRP-109. Elastase activity assays were performed using spectrophotometry.
  
  
  
  There were significant differences in the amount of active NE in different CF sputum samples. KRP-109 decreased the NE driven mucin degradation in vitro. Pseudomonas elastases appeared to blunt elastase inhibition by A1-PI or KRP-109.
  
  
  
  Inhibitors of neutrophil and Pseudomonas-derived elastases might rescue mucus clearance and reverse airway obstruction in CF.
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; 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: Christian
authors.initials: C
authors.lastname: Müller
authors.affiliation: Department of Internal Medicine, Justus-Liebig-University Giessen, Klinikstrasse-36, Giessen 35392, Germany; German Centre for Lung Research (DZL), Giessen, Germany.
authors.forename: Poornima
authors.initials: P
authors.lastname: Mahavadi
authors.affiliation: Department of Internal Medicine, Justus-Liebig-University Giessen, Klinikstrasse-36, Giessen 35392, Germany; German Centre for Lung Research (DZL), Giessen, Germany; European IPF Registry/Biobank, 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; German Centre for Lung Research (DZL), Giessen, Germany.
authors.forename: Lutz
authors.initials: L
authors.lastname: Nährlich
authors.affiliation: ActivX Biosciences, Inc., 11025 North Torrey Pines Road, Suite 120, La Jolla, CA 92037, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Rosenblum
authors.affiliation: Department of Pediatrics, Virginia Commonwealth University School of Medicine, 1001 East Marshall Street, Richmond, VA 23298, 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; Asklepios Fachkliniken München-Gauting, Gauting, Germany; Comprehensive Pneumology Center (CPC), Helmholtz Zentrum, Munich, Germany. Electronic address: m.henke@asklepios.com.
authors.forename: Markus O
authors.initials: MO
authors.lastname: Henke
mesh_terms: D000402:Airway Obstruction / Q000378:metabolism / Q000503:physiopathology; D048588:Benzoxazines / Q000378:metabolism*; D003550:Cystic Fibrosis / Q000150:complications / Q000378:metabolism; D006801:Humans; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors / Q000378:metabolism; D009077:Mucins / Q000032:analysis / Q000378:metabolism; D009079:Mucociliary Clearance; D011552:Pseudomonas Infections / Q000175:diagnosis / Q000209:etiology; D011550:Pseudomonas aeruginosa / Q000302:isolation & purification / Q000502:physiology; D011759:Pyrrolidines / Q000378:metabolism*; D012141:Respiratory Tract Infections / Q000175:diagnosis / Q000209:etiology; D013053:Spectrophotometry / Q000379:methods; D013183:Sputum / Q000378:metabolism / Q000382:microbiology
chemical_list: D048588:Benzoxazines; C570830:KRP-109; D009077:Mucins; D011759:Pyrrolidines; D019272:Leukocyte Elastase
keywords: Cystic fibrosis; Mucin; Protease and anti-protease balance; Small molecule inhibitors