title: Neutrophil elastase cleaves epithelial cadherin in acutely injured lung epithelium.
abstract: In acutely injured lungs, massively recruited polymorphonuclear neutrophils (PMNs) secrete abnormally neutrophil elastase (NE). Active NE creates a localized proteolytic environment where various host molecules are degraded leading to impairment of tissue homeostasis. Among the hallmarks of neutrophil-rich pathologies is a disrupted epithelium characterized by the loss of cell-cell adhesion and integrity. Epithelial-cadherin (E-cad) represents one of the most important intercellular junction proteins. E-cad exhibits various functions including its role in maintenance of tissue integrity. While much interest has focused on the expression and role of E-cad in different physio- and physiopathological states, proteolytic degradation of this structural molecule and ensuing potential consequences on host lung tissue injury are not completely understood.
  
  
  
  NE capacity to cleave E-cad was determined in cell-free and lung epithelial cell culture systems. The impact of such cleavage on epithelial monolayer integrity was then investigated. Using mice deficient in NE in a clinically relevant experimental model of acute pneumonia, we examined whether degraded E-cad is associated with lung inflammation and injury and whether NE contributes to E-cad cleavage. Finally, we checked for the presence of both degraded E-cad and NE in bronchoalveolar lavage samples obtained from patients with exacerbated COPD, a clinical manifestation characterised by a neutrophilic inflammatory response.
  
  
  
  We show that NE is capable of degrading E-cad in vitro and in cultured cells. NE-mediated degradation of E-cad was accompanied with loss of epithelial monolayer integrity. Our in vivo findings provide evidence that NE contributes to E-cad cleavage that is concomitant with lung inflammation and injury. Importantly, we observed that the presence of degraded E-cad coincided with the detection of NE in diseased human lungs.
  
  
  
  Active NE has the capacity to cleave E-cad and interfere with its cell-cell adhesion function. These data suggest a mechanism by which unchecked NE participates potentially to the pathogenesis of neutrophil-rich lung inflammatory and tissue-destructive diseases.
authors.affiliation: Inflammation and Immunity of the Respiratory Epithelium Group, Faculté de Médecine Lyon Sud, EA 7426, UCBL 1, Inserm U-1111, Pierre Benite - Lyon Sud, France.
authors.forename: Rachel
authors.initials: R
authors.lastname: Boxio
authors.affiliation: Inflammation and Immunity of the Respiratory Epithelium Group, Faculté de Médecine Lyon Sud, EA 7426, UCBL 1, Inserm U-1111, Pierre Benite - Lyon Sud, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Wartelle
authors.affiliation: INSERM UMR-S 903, CHU Maison Blanche, Reims, France.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Nawrocki-Raby
authors.affiliation: Inflammation and Immunity of the Respiratory Epithelium Group, Faculté de Médecine Lyon Sud, EA 7426, UCBL 1, Inserm U-1111, Pierre Benite - Lyon Sud, France.
authors.forename: Brice
authors.initials: B
authors.lastname: Lagrange
authors.affiliation: Inflammation and Immunity of the Respiratory Epithelium Group, Faculté de Médecine Lyon Sud, EA 7426, UCBL 1, Inserm U-1111, Pierre Benite - Lyon Sud, France.
authors.forename: Laurette
authors.initials: L
authors.lastname: Malleret
authors.affiliation: Department of Pulmonary Medicine, German Clinic for Diagnostics (DKD), Wiesbaden, Germany.
authors.forename: Timothee
authors.initials: T
authors.lastname: Hirche
authors.affiliation: Centre for Infection and Immunity, Queen's University Belfast, Belfast, Northern Ireland, UK.
authors.forename: Clifford
authors.initials: C
authors.lastname: Taggart
authors.affiliation: Inflammation and Immunity of the Respiratory Epithelium Group, Faculté de Médecine Lyon Sud, EA 7426, UCBL 1, Inserm U-1111, Pierre Benite - Lyon Sud, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Pacheco
authors.affiliation: Inflammation and Immunity of the Respiratory Epithelium Group, Faculté de Médecine Lyon Sud, EA 7426, UCBL 1, Inserm U-1111, Pierre Benite - Lyon Sud, France.|CHU Croix-Rousse, Lyon, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Devouassoux
authors.affiliation: Inflammation and Immunity of the Respiratory Epithelium Group, Faculté de Médecine Lyon Sud, EA 7426, UCBL 1, Inserm U-1111, Pierre Benite - Lyon Sud, France. azzak.bentaher@inserm.fr.
authors.forename: Abderrazzaq
authors.identifier: 0000-0001-6001-5456
authors.initials: A
authors.lastname: Bentaher
mesh_terms: D055371:Acute Lung Injury / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000818:Animals; D015703:Antigens, CD; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D015820:Cadherins / Q000378:metabolism*; D002460:Cell Line; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000201:enzymology* / Q000473:pathology; D019272:Leukocyte Elastase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000201:enzymology* / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000201:enzymology*; D018410:Pneumonia, Bacterial / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D059748:Proteolysis; D029424:Pulmonary Disease, Chronic Obstructive / Q000201:enzymology*
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; C000611838:Cdh1 protein, mouse; D019272:Leukocyte Elastase
keywords: E-cadherin; Epithelium disruption; Lung inflammation and injury; Neutrophil elastase