Ngamsri Kristian-Christos, Müller Anika, Bösmüller Hans, Gamper-Tsigaras Jutta, Reutershan Jörg, Konrad Franziska M
Department of Anesthesiology and Intensive Care Medicine, University Hospital of Tübingen, 72076 Tübingen, Germany.
Department of Pathology, University Hospital of Tübingen, 72076 Tübingen, Germany; and.
J Immunol. 2017 Mar 15;198(6):2403-2413. doi: 10.4049/jimmunol.1601682. Epub 2017 Feb 10.
Acute pulmonary inflammation is still a frightening complication in intensive care units and has a high mortality. Specific treatment is not available, and many details of the pathomechanism remain unclear. The recently discovered chemokine receptor CXCR7 and its ligand stromal cell-derived factor (SDF)-1 are known to be involved in inflammation. We chose to investigate the detailed role of CXCR7 in a murine model of LPS inhalation. Inflammation increased pulmonary expression of CXCR7, and the receptor was predominantly expressed on pulmonary epithelium and on polymorphonuclear neutrophil (PMNs) after transepithelial migration into the alveolar space. Specific inhibition of CXCR7 reduced transepithelial PMN migration by affecting the expression of adhesion molecules. CXCR7 antagonism reduced the most potent PMN chemoattractants CXCL1 and CXCL2/3. After inhibiting CXCR7, NF-κB phosphorylation was reduced in lungs of mice, tight junction formation increased, and protein concentration in the bronchoalveolar lavage diminished, showing the impact of CXCR7 on stabilizing microvascular permeability. In vitro studies with human cells confirmed the pivotal role of CXCR7 in pulmonary epithelium. Immunofluorescence of human lungs confirmed our in vivo data and showed an increase of the expression of CXCR7 in pulmonary epithelium. Highlighting the clinical potential of CXCR7 antagonism, nebulization of the agent before and after the inflammation showed impressive anti-inflammatory effects. Additional CXCR7 inhibition potentiated the effect of SDF-1 antagonism, most probably by downregulating SDF-1 and the second receptor of the chemokine (CXCR4) expression. In conclusion, our data identified the pivotal role of the receptor CXCR7 in pulmonary inflammation with a predominant effect on the pulmonary epithelium and PMNs.
急性肺部炎症仍是重症监护病房中令人恐惧的并发症，死亡率很高。目前尚无特效治疗方法，发病机制的许多细节仍不清楚。最近发现的趋化因子受体CXCR7及其配体基质细胞衍生因子（SDF）-1与炎症有关。我们选择在小鼠吸入脂多糖模型中研究CXCR7的具体作用。炎症会增加肺组织中CXCR7的表达，该受体主要表达于肺上皮细胞以及经上皮迁移至肺泡腔后的多形核中性粒细胞（PMN）上。特异性抑制CXCR7可通过影响黏附分子的表达来减少经上皮的PMN迁移。CXCR7拮抗作用可降低最有效的PMN趋化因子CXCL1和CXCL2/3。抑制CXCR7后，小鼠肺组织中NF-κB磷酸化水平降低，紧密连接形成增加，支气管肺泡灌洗中的蛋白浓度降低，这表明CXCR7对稳定微血管通透性有影响。用人细胞进行的体外研究证实了CXCR7在肺上皮细胞中的关键作用。人肺组织的免疫荧光证实了我们的体内数据，并显示肺上皮细胞中CXCR7的表达增加。突出CXCR7拮抗作用的临床潜力，在炎症前后雾化吸入该药物显示出令人印象深刻的抗炎效果。额外抑制CXCR7可增强SDF-1拮抗作用的效果，很可能是通过下调SDF-1以及趋化因子的第二个受体（CXCR4）的表达来实现的。总之，我们的数据确定了受体CXCR7在肺部炎症中的关键作用，对肺上皮细胞和PMN有主要影响。
