Human Neutrophil Elastase Degrades SPLUNC1 and Impairs Airway Epithelial Defense against Bacteria
Human Neutrophil Elastase Degrades SPLUNC1 and Impairs Airway Epithelial Defense against Bacteria
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DOI：
10.1371/journal.pone.0064689
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发表时间：
2013-05-31
期刊：
影响因子：
3.7
通讯作者：
Chu, Hong Wei
中科院分区：
文献类型：
--
作者：
Jiang, Di;Wenzel, Sally E.;Chu, Hong Wei
背景：慢性阻塞性肺疾病急性加重（AECOPD）是COPD患者死亡的重要原因，并给医疗保健带来巨大负担。 AECOPD 的主要原因之一是气道细菌（例如不可分型流感嗜血杆菌 [NTHi]）感染。然而，AECOPD 期间细菌感染的机制仍知之甚少。由于包括人中性粒细胞弹性蛋白酶 (HNE) 释放增加在内的中性粒细胞炎症是 AECOPD 的显着特征，因此我们假设 HNE 通过降解气道上皮宿主防御蛋白（例如短腭、肺和鼻上皮克隆 1 (SPLUNC1)）来损害气道上皮对 NTHi 的防御。方法/主要结果：将重组人 SPLUNC1 蛋白与 HNE 一起孵育，以通过以下方法确认 SPLUNC1 降解： HNE。为了确定 HNE 介导的宿主针对 NTHi 防御的损害是否是 SPLUNC1 依赖性的，将 SPLUNC1 蛋白添加到 HNE 处理的原代正常人气道上皮细胞中。通过用 NTHi 鼻内感染 SPLUNC1 敲除小鼠和野生型小鼠，研究了 SPLUNC1 在 NTHi 防御中的体内功能。我们发现：（1）HNE直接增加人气道上皮细胞中的NTHi负荷； (2) HNE降解人SPLUNC1蛋白； (3)重组SPLUNC1蛋白降低HNE处理的人气道上皮细胞中NTHi水平； (4) SPLUNC1敲除小鼠肺部NTHi水平较野生型小鼠升高； (5) COPD 患者肺部的 SPLUNC1 减少。结论：我们的研究结果表明，中性粒细胞弹性蛋白酶降解 SPLUNC1 可能会增加气道对细菌感染的易感性。 SPLUNC1 疗法可能会减轻 AECOPD 期间的细菌感染。
Background: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are a significant cause of mortality of COPD patients, and pose a huge burden on healthcare. One of the major causes of AECOPD is airway bacterial (e. g. nontypeable Haemophilus influenzae [NTHi]) infection. However, the mechanisms underlying bacterial infections during AECOPD remain poorly understood. As neutrophilic inflammation including increased release of human neutrophil elastase (HNE) is a salient feature of AECOPD, we hypothesized that HNE impairs airway epithelial defense against NTHi by degrading airway epithelial host defense proteins such as short palate, lung, and nasal epithelium clone 1 (SPLUNC1).Methodology/Main Results: Recombinant human SPLUNC1 protein was incubated with HNE to confirm SPLUNC1 degradation by HNE. To determine if HNE-mediated impairment of host defense against NTHi was SPLUNC1-dependent, SPLUNC1 protein was added to HNE-treated primary normal human airway epithelial cells. The in vivo function of SPLUNC1 in NTHi defense was investigated by infecting SPLUNC1 knockout and wild-type mice intranasally with NTHi. We found that: (1) HNE directly increased NTHi load in human airway epithelial cells; (2) HNE degraded human SPLUNC1 protein; (3) Recombinant SPLUNC1 protein reduced NTHi levels in HNE-treated human airway epithelial cells; (4) NTHi levels in lungs of SPLUNC1 knockout mice were increased compared to wild-type mice; and (5) SPLUNC1 was reduced in lungs of COPD patients.Conclusions: Our findings suggest that SPLUNC1 degradation by neutrophil elastase may increase airway susceptibility to bacterial infections. SPLUNC1 therapy likely attenuates bacterial infections during AECOPD.