Vasculotide reduces pulmonary hyperpermeability in experimental pneumococcal pneumonia.
Vasculotide reduces pulmonary hyperpermeability in experimental pneumococcal pneumonia.
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DOI：
10.1186/s13054-017-1851-6
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发表时间：
2017-11-13
期刊：
影响因子：
--
通讯作者：
Witzenrath M
中科院分区：
文献类型：
--
作者：
Gutbier B;Jiang X;Dietert K;Ehrler C;Lienau J;Van Slyke P;Kim H;Hoang VC;Maynes JT;Dumont DJ;Gruber AD;Weissmann N;Mitchell TJ;Suttorp N;Witzenrath M
社区获得性肺炎(CAP)是世界范围内发病率和死亡率的重要原因。尽管进行了有效的抗菌治疗，CAP仍可诱导肺内皮细胞高通透性，由于夸大了宿主与病原体的相互作用，导致危及生命的肺衰竭。急性肺损伤的治疗主要是支持性的，因为炎症诱导的屏障破坏的关键因素仍然不确定。血管生成素-1(Ang-1)介导的Tie2活化减少，Ang-1拮抗剂Ang-2增加脓毒症的炎症反应和内皮通透性。血管紧张素(VT)是一种聚乙二醇簇的Tie2结合肽，模拟Ang-1的作用。我们研究的目的是通过实验测试VT是否能够减轻肺炎引起的肺损伤。色氨酸荧光光谱分析和磷酸化Tie-2酶联免疫吸附试验分析Tie2的VT结合和磷酸化。采用免疫荧光染色和细胞-底物阻抗传感技术对人和小鼠肺内皮细胞进行检测。用肺炎球菌外毒素溶气素(PLY)刺激VT处理、隔离、灌流和通风的小鼠肺，对肺高通透性进行量化。此外，对感染肺炎链球菌的小鼠进行了VT治疗。VT呈剂量依赖性结合和磷酸化Tie2。VT预处理可保护肺内皮细胞单层免受PLY诱导的破坏。在小鼠离体肺中，VT可降低PLY诱导的肺通透性。同样，肺炎链球菌感染小鼠的VT治疗显著降低了肺炎引起的高通透性。然而，未观察到VT对肺或全身炎症反应的影响。VT可促进不同肺炎球菌肺炎模型肺内皮细胞的稳定性，降低肺通透性。因此，VT可能为降低肺炎球菌肺炎所致肺损伤的通透性提供新的治疗前景。本文的在线版本(doi：10.1186/s13054-0171851-6)包含补充材料，授权用户可以使用。
Community-acquired pneumonia (CAP) is a significant cause of morbidity and mortality worldwide. Despite effective antimicrobial therapy, CAP can induce pulmonary endothelial hyperpermeability resulting in life-threatening lung failure due to an exaggerated host-pathogen interaction. Treatment of acute lung injury is mainly supportive because key elements of inflammation-induced barrier disruption remain undetermined. Angiopoietin-1 (Ang-1)-mediated Tie2 activation reduces, and the Ang-1 antagonist Ang-2 increases, inflammation and endothelial permeability in sepsis. Vasculotide (VT) is a polyethylene glycol-clustered Tie2-binding peptide that mimics the actions of Ang-1. The aim of our study was to experimentally test whether VT is capable of diminishing pneumonia-induced lung injury. VT binding and phosphorylation of Tie2 were analyzed using tryptophan fluorescence spectroscopy and phospho-Tie-2 enzyme-linked immunosorbent assay. Human and murine lung endothelial cells were investigated by immunofluorescence staining and electric cell-substrate impedance sensing. Pulmonary hyperpermeability was quantified in VT-pretreated, isolated, perfused, and ventilated mouse lungs stimulated with the pneumococcal exotoxin pneumolysin (PLY). Furthermore, Streptococcus pneumoniae-infected mice were therapeutically treated with VT. VT showed dose-dependent binding and phosphorylation of Tie2. Pretreatment with VT protected lung endothelial cell monolayers from PLY-induced disruption. In isolated mouse lungs, VT decreased PLY-induced pulmonary permeability. Likewise, therapeutic treatment with VT of S. pneumoniae-infected mice significantly reduced pneumonia-induced hyperpermeability. However, effects by VT on the pulmonary or systemic inflammatory response were not observed. VT promoted pulmonary endothelial stability and reduced lung permeability in different models of pneumococcal pneumonia. Thus, VT may provide a novel therapeutic perspective for reduction of permeability in pneumococcal pneumonia-induced lung injury. The online version of this article (doi:10.1186/s13054-017-1851-6) contains supplementary material, which is available to authorized users.
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DOI：
10.1016/s0140-6736(03)15021-0
发表时间：
2003-12-13
期刊：
Lancet (London, England)
影响因子：
--
作者：
File TM
通讯作者：
File TM
影响因子：
3.6
作者：
Müller-Redetzky HC;Suttorp N;Witzenrath M
通讯作者：
Witzenrath M
影响因子：
15.8
作者：
Parikh SM;Mammoto T;Schultz A;Yuan HT;Christiani D;Karumanchi SA;Sukhatme VP
通讯作者：
Sukhatme VP
影响因子：
15.1
作者：
Kuempers, Philipp;Gueler, Faikah;Shushakova, Nelli
通讯作者：
Shushakova, Nelli
影响因子：
10
作者：
Ewig, S.;Birkner, N.;Hoeffken, G.
通讯作者：
Hoeffken, G.