1 Division of Pulmonary Inflammation and.
2 Department of Infectious Diseases and Pulmonary Medicine, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
Am J Respir Crit Care Med. 2018 Jul 15;198(2):220-231. doi: 10.1164/rccm.201708-1733OC.
During pneumonia, pathogen-host interaction evokes inflammation and lung barrier dysfunction. Tie2 activation by angiopoietin-1 reduces, whereas Tie2 blockade by angiopoietin-2 increases, inflammation and permeability during sepsis. The role of angiopoietin-1/-2 in pneumonia remains unidentified.
To investigate the prognostic and pathogenic impact of angiopoietins in regulating pulmonary vascular barrier function and inflammation in bacterial pneumonia.
Serum angiopoietin levels were quantified in pneumonia patients of two independent cohorts (n = 148, n = 395). Human postmortem lung tissue, pneumolysin- or angiopoietin-2-stimulated endothelial cells, isolated perfused and ventilated mouse lungs, and mice with pneumococcal pneumonia were investigated.
In patients with pneumonia, decreased serum angiopoietin-1 and increased angiopoietin-2 levels were observed as compared with healthy subjects. Higher angiopoietin-2 serum levels were found in patients with community-acquired pneumonia who died within 28 days of diagnosis compared with survivors. Receiver operating characteristic analysis revealed improved prognostic accuracy of CURB-65 for 28-day survival, intensive care treatment, and length of hospital stay if combined with angiopoietin-2 serum levels. In vitro, pneumolysin enhanced endothelial angiopoietin-2 release, angiopoietin-2 increased endothelial permeability, and angiopoietin-1 reduced pneumolysin-evoked endothelial permeability. Ventilated and perfused lungs of mice with angiopoietin-2 knockdown showed reduced permeability on pneumolysin stimulation. Increased pulmonary angiopoietin-2 and reduced angiopoietin-1 mRNA expression were observed in Streptococcus pneumoniae-infected mice. Finally, angiopoietin-1 therapy reduced inflammation and permeability in murine pneumonia.
These data suggest a central role of angiopoietin-1/-2 in pneumonia-evoked inflammation and permeability. Increased angiopoietin-2 serum levels predicted mortality and length of hospital stay, and angiopoietin-1 may provide a therapeutic target for severe pneumonia.
在肺炎中，病原体与宿主的相互作用会引发炎症和肺屏障功能障碍。血管生成素-1 对 Tie2 的激活可减少败血症时的炎症和通透性，而血管生成素-2 对 Tie2 的阻断则会增加炎症和通透性。血管生成素-1/-2 在肺炎中的作用尚不清楚。
研究血管生成素在调节细菌性肺炎肺血管屏障功能和炎症中的预后和发病机制。
在两个独立的肺炎患者队列中（n=148，n=395）定量检测血清血管生成素水平。研究了人死后肺组织、肺炎球菌溶血素或血管生成素-2 刺激的内皮细胞、分离的灌注和通气的小鼠肺以及肺炎链球菌感染的小鼠。
与健康受试者相比，肺炎患者的血清血管生成素-1 水平降低，血管生成素-2 水平升高。与存活者相比，28 天内诊断为社区获得性肺炎且死亡的患者的血清血管生成素-2 水平更高。受试者工作特征分析显示，如果将 CURB-65 评分与血管生成素-2 血清水平相结合，可提高 28 天生存率、重症监护治疗和住院时间的预后准确性。体外，肺炎球菌溶血素增强内皮细胞血管生成素-2 的释放，血管生成素-2 增加内皮通透性，而血管生成素-1 则减少肺炎球菌溶血素引起的内皮通透性。敲低血管生成素-2 的小鼠灌注和通气肺在肺炎球菌溶血素刺激下通透性降低。在肺炎链球菌感染的小鼠中观察到肺组织中血管生成素-2 表达增加，而血管生成素-1 表达减少。最后，血管生成素-1 治疗可减轻小鼠肺炎中的炎症和通透性。
这些数据表明，血管生成素-1/-2 在肺炎引起的炎症和通透性中起核心作用。血管生成素-2 血清水平升高可预测死亡率和住院时间，而血管生成素-1 可能为严重肺炎提供治疗靶点。
