Neutrophil elastase cleaves epithelial cadherin in acutely injured lung epithelium.
Neutrophil elastase cleaves epithelial cadherin in acutely injured lung epithelium.
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DOI：
10.1186/s12931-016-0449-x
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发表时间：
2016-10-17
影响因子：
5.8
通讯作者：
Bentaher A
中科院分区：
文献类型：
--
作者：
Boxio R;Wartelle J;Nawrocki-Raby B;Lagrange B;Malleret L;Hirche T;Taggart C;Pacheco Y;Devouassoux G;Bentaher A
在急性肺损伤中，大量聚集的中性粒细胞(PMN)分泌异常的中性粒细胞弹性蛋白酶(NE)。活性去甲肾上腺素创造了局部的蛋白质降解环境，各种宿主分子被降解，导致组织动态平衡受损。富含中性粒细胞的病理特征之一是上皮细胞破裂，其特征是细胞与细胞之间的粘附性和完整性丧失。上皮钙粘附素(E-cad)是最重要的细胞间连接蛋白之一。E-cad具有多种功能，包括在维持组织完整性方面的作用。虽然人们对E-cad在不同生理和病理状态下的表达和作用有很大的兴趣，但对这种结构分子的蛋白降解以及由此导致的宿主肺组织损伤的潜在后果还不完全清楚。在无细胞培养和肺上皮细胞培养体系中测定NE裂解E-cad的能力。然后研究了这种分裂对上皮单分子层完整性的影响。在一个临床相关的急性肺炎实验模型中，我们利用NE缺乏的小鼠，研究了E-cad的降解是否与肺部炎症和损伤有关，以及NE是否参与了E-cad的裂解。最后，我们检查了从COPD急性加重患者的支气管肺泡灌洗液样本中是否存在E-cad和NE的降解，这是一种以中性粒细胞炎症反应为特征的临床表现。我们发现去甲肾上腺素能够在体外和培养细胞中降解E-cad。NE介导的E-cad降解伴随着上皮单层完整性的丧失。我们在体内的发现提供了证据，证明去甲肾上腺素参与了E-cad的切割，这是伴随着肺部炎症和损伤而来的。重要的是，我们观察到降解的E-cad的存在与在患病的人肺中检测到NE是一致的。活性NE具有裂解E-cad并干扰其细胞间黏附功能的能力。这些数据表明，未受抑制的去甲肾上腺素可能参与了富含中性粒细胞的肺炎性和组织破坏性疾病的发病机制。本文的在线版本(doi：10.1186/s12931-0160449-x)包含补充材料，授权用户可以使用。
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. The online version of this article (doi:10.1186/s12931-016-0449-x) contains supplementary material, which is available to authorized users.
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影响因子：
4.4
作者：
Hirche, Tim O.;Benabid, Rym;Belaaouaj, Azzaq
通讯作者：
Belaaouaj, Azzaq
影响因子：
5.5
作者：
Boxio, R;Bossenmeyer-Pourié, C;Nüsse, O
通讯作者：
Nüsse, O
影响因子：
4.8
作者：
Hirche, TO;Crouch, EC;Belaaouaj, A
通讯作者：
Belaaouaj, A
DOI：
10.1111/paa.1999.111.5.390
发表时间：
1999-09-01
期刊：
PROCEEDINGS OF THE ASSOCIATION OF AMERICAN PHYSICIANS
影响因子：
--
作者：
Ganz, T
通讯作者：
Ganz, T
DOI：
10.1083/jcb.107.4.1575
发表时间：
1988-10
期刊：
The Journal of cell biology
影响因子：
--
作者：
Gumbiner B;Stevenson B;Grimaldi A
通讯作者：
Grimaldi A