title: Neutrophil elastase and matrix metalloproteinase 12 in cystic fibrosis lung disease.
abstract: Chronic lung disease remains the major cause of morbidity and mortality in patients with cystic fibrosis (CF). Recent studies in young children with CF diagnosed by newborn screening identified neutrophil elastase (NE), a major product released from neutrophils in inflamed airways, as a key risk factor for the onset and early progression of CF lung disease. However, the understanding of how NE and potentially other proteases contribute to the complex in vivo pathogenesis of CF lung disease remains limited. In this review, we summarize recent progress in this area based on studies in βENaC-overexpressing (βENaC-Tg) mice featuring CF-like lung disease and novel protease-specific Förster resonance energy transfer (FRET) sensors for localization and quantification of protease activity in the lung. These studies demonstrated that NE is implicated in several key features of CF lung disease such as neutrophilic airway inflammation, mucus hypersecretion, and structural lung damage in vivo. Furthermore, these studies identified macrophage elastase (matrix metalloproteinase 12 (MMP12)) as an additional protease contributing to early lung damage in βENaC-Tg mice. Collectively, these results suggest that NE and MMP12 released from activated neutrophils and macrophages in mucus-obstructed airways play important pathogenetic roles and may serve as potential therapeutic targets to prevent and/or delay irreversible structural lung damage in patients with CF.
authors.affiliation: Department of Translational Pulmonology, University of Heidelberg, Heidelberg, Germany.|Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany.|Molecular Medicine Partnership Unit (MMPU), University of Heidelberg and European Molecular Biology Laboratory, Heidelberg, Germany.
authors.forename: Claudius J
authors.initials: CJ
authors.lastname: Wagner
authors.affiliation: Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany.|Molecular Medicine Partnership Unit (MMPU), University of Heidelberg and European Molecular Biology Laboratory, Heidelberg, Germany.|Cell Biology and Biophysics Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Schultz
authors.affiliation: Department of Translational Pulmonology, University of Heidelberg, Heidelberg, Germany. Marcus.Mall@med.uni-heidelberg.de.|Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany. Marcus.Mall@med.uni-heidelberg.de.|Molecular Medicine Partnership Unit (MMPU), University of Heidelberg and European Molecular Biology Laboratory, Heidelberg, Germany. Marcus.Mall@med.uni-heidelberg.de.|Division of Pediatric Pulmonology and Allergy and Cystic Fibrosis Center, Department of Pediatrics, University of Heidelberg, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany. Marcus.Mall@med.uni-heidelberg.de.
authors.forename: Marcus A
authors.initials: MA
authors.lastname: Mall
keywords: Airway inflammation; Cystic fibrosis; FRET reporter; Matrix metalloproteinase 12; Neutrophil elastase