Protective effect of CFTR modulators on endothelial barrier failure in COVID-19 induced ARDS (C09*)

CFTR 调节剂对 COVID-19 诱导的 ARDS 内皮屏障衰竭的保护作用 (C09*)

• 批准号: 405489606
• 金额: --
• 依托单位: Medizinische Klinik mit Schwerpunkt Infektiologie und Pneumologie (einschl. Arbeitsbereich ambulante Pneumologie) (CVK)
• 依托单位国家: 德国
• 项目类别: CRC/Transregios
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/405489606?language=en
• 关键词: Protective; effect; CFTR; modulators; endothelial

Severe SARS-CoV-2 induced pneumonia causes injury of and increased leak across the lung endothelial barrier. We recently identified the Cl- channel cystic fibrosis transmembrane conductance regulator (CFTR) as critical regulator of endothelial barrier function. Specifically, we found that Streptococcus pneumoniae infection causes loss of CFTR protein and function that drives endothelial barrier failure but can be prevented by CFTR modulators. In pilot data, we demonstrate a similar loss of endothelial barrier function in severe COVID-19 that is again attenuated by CFTR modulators. As CFTR dysfunction in pulmonary artery smooth muscle cells, platelets, and neutrophils inhibits hypoxic pulmonary vasoconstriction, and causes platelet and neutrophil activation, loss of functional CFTR in COVID-19 may present a master switch that drives key features of the disease, and can be therapeutically targeted by CFTR modulators. Here, we will put this hypothesis to the test.

严重的SARS-CoV-2诱导的肺炎导致肺内皮屏障的损伤和增加的渗漏。我们最近确定了氯离子通道囊性纤维化跨膜传导调节因子（CFTR）作为内皮屏障功能的关键调节因子。具体地说，我们发现肺炎链球菌感染导致CFTR蛋白和功能丧失，导致内皮屏障衰竭，但可以通过CFTR调节剂预防。在初步数据中，我们证明了严重COVID-19中内皮屏障功能的类似丧失，这再次被CFTR调节剂减弱。由于肺动脉平滑肌细胞、血小板和中性粒细胞中的CFTR功能障碍抑制缺氧性肺血管收缩，并导致血小板和中性粒细胞活化，因此COVID-19中功能性CFTR的丧失可能是驱动疾病关键特征的主开关，并且可以通过CFTR调节剂进行治疗靶向。在这里，我们将对这一假设进行检验。