Neutrophil elastase cleaves epithelial cadherin in acutely injured lung epithelium

被引:61
作者
Boxio, Rachel [1 ]
Wartelle, Julien [1 ]
Nawrocki-Raby, Beatrice [2 ]
Lagrange, Brice [1 ]
Malleret, Laurette [1 ]
Hirche, Timothee [3 ]
Taggart, Clifford [4 ]
Pacheco, Yves [1 ]
Devouassoux, Gilles [1 ,5 ]
Bentaher, Abderrazzaq [1 ]
机构
[1] UCBL 1, EA 7426, Fac Med Lyon Sud, Inflammat & Immun Resp Epithelium Grp,Inserm,U111, Pierre Benite, France
[2] CHU Maison Blanche, INSERM, UMR S 903, Reims, France
[3] German Clin Diagnost DKD, Dept Pulm Med, Wiesbaden, Germany
[4] Queens Univ Belfast, Ctr Infect & Immun, Belfast, Antrim, North Ireland
[5] CHU Croix Rousse, Lyon, France
来源
RESPIRATORY RESEARCH | 2016年 / 17卷
关键词
E-cadherin; Neutrophil elastase; Epithelium disruption; Lung inflammation and injury; OBSTRUCTIVE PULMONARY-DISEASE; RESPIRATORY-DISTRESS-SYNDROME; PSEUDOMONAS-AERUGINOSA; SERINE PROTEINASES; LEUKOCYTE ELASTASE; HOST-DEFENSE; NONOXIDATIVE MECHANISM; CYSTIC-FIBROSIS; CATHEPSIN-G; IN-VITRO;
D O I
10.1186/s12931-016-0449-x
中图分类号
R56 [呼吸系及胸部疾病];
学科分类号
摘要
Background: 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. Methods: 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. Results: 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. Conclusions: 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.
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页数:15
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