Le Catherine T K, Laidlaw Grace, Morehouse Christopher A, Naiman Brian, Brohawn Philip, Mustelin Tomas, Connor Jane R, McDonald Donald M
Department of Anatomy, Cardiovascular Research Institute, University of California San Francisco, San Francisco, California; University of California San Francisco Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California.
MedImmune LLC, Gaithersburg, Maryland.
Am J Pathol. 2015 Nov;185(11):2949-68. doi: 10.1016/j.ajpath.2015.07.010. Epub 2015 Sep 5.
Remodeling of blood vessels and lymphatics are prominent features of sustained inflammation. Angiopoietin-2 (Ang2)/Tie2 receptor signaling and tumor necrosis factor-α (TNF)/TNF receptor signaling are known to contribute to these changes in airway inflammation after Mycoplasma pulmonis infection in mice. We determined whether Ang2 and TNF are both essential for the remodeling on blood vessels and lymphatics, and thereby influence the actions of one another. Their respective contributions to the initial stage of vascular remodeling and sprouting lymphangiogenesis were examined by comparing the effects of function-blocking antibodies to Ang2 or TNF, given individually or together during the first week after infection. As indices of efficacy, vascular enlargement, endothelial leakiness, venular marker expression, pericyte changes, and lymphatic vessel sprouting were assessed. Inhibition of Ang2 or TNF alone reduced the remodeling of blood vessels and lymphatics, but inhibition of both together completely prevented these changes. Genome-wide analysis of changes in gene expression revealed synergistic actions of the antibody combination over a broad range of genes and signaling pathways involved in inflammatory responses. These findings demonstrate that Ang2 and TNF are essential and synergistic drivers of remodeling of blood vessels and lymphatics during the initial stage of inflammation after infection. Inhibition of Ang2 and TNF together results in widespread suppression of the inflammatory response.
血管和淋巴管重塑是持续性炎症的显著特征。已知血管生成素-2（Ang2）/Tie2受体信号传导以及肿瘤坏死因子-α（TNF）/TNF受体信号传导在小鼠肺部支原体感染后的气道炎症这些变化中起作用。我们确定Ang2和TNF对于血管和淋巴管重塑是否均必不可少，从而相互影响彼此的作用。通过比较在感染后第一周单独或联合给予针对Ang2或TNF的功能阻断抗体的效果，研究了它们对血管重塑和新生淋巴管生成初始阶段的各自贡献。作为疗效指标，评估了血管扩张、内皮渗漏、小静脉标志物表达、周细胞变化和淋巴管新生。单独抑制Ang2或TNF可减少血管和淋巴管的重塑，但同时抑制两者则完全阻止了这些变化。对基因表达变化进行全基因组分析揭示了抗体组合在广泛参与炎症反应的基因和信号通路中的协同作用。这些发现表明，Ang2和TNF是感染后炎症初始阶段血管和淋巴管重塑的必需且协同驱动因素。同时抑制Ang2和TNF会导致炎症反应的广泛抑制。
