系统性炎症性疾病，如败血症和严重COVID-19，引发急性呼吸窘迫综合征，其中微血管的病理性高通透性，由无控制的炎症刺激引起肺水肿。识别诱导人肺微血管内皮细胞屏障功能障碍的炎症介质对于找到最佳的抗炎治疗方法以治疗重症急性呼吸窘迫综合征患者至关重要。我们比较了原代人肺微血管内皮细胞对由败血症和SARS-CoV2肺部感染引发的细胞因子风暴中的主要炎症介质以及从健康供体和重症败血症患者体内提取的血清的反应。内皮屏障功能通过电细胞底物阻抗感知、定量共聚焦显微镜和Western blot进行测量。人肺微血管内皮细胞屏障在IL-6与可溶性IL-6R结合以及IL-1β的作用下完全破坏，在TNF-α和IFN-γ的作用下受到中度影响，而其他细胞因子和趋化因子（如IL-6、IL-8、MCP-1和MCP-3）不受影响。同时抑制IL-1和IL-6R，而不是单独抑制，显著降低了人肺微血管内皮细胞暴露于由8种炎症介质组成的细胞因子风暴或败血症患者血清时的内皮高通透性。同时抑制IL-1和JAK-STAT信号转导节点，即IL-6和IFN-γ下游的信号转导和转录激活蛋白，还能预防败血症血清诱导的内皮屏障破坏。这些发现强烈暗示了IL-6跨膜信号和IL-1β信号在人肺微血管通透性的病理性增加中起重要作用，并揭示了能够逐渐控制肺内皮细胞屏障功能响应细胞因子风暴的联合策略。

Systemic inflammatory diseases, such as sepsis and severe COVID-19, provoke acute respiratory distress syndrome in which the pathological hyperpermeability of the microvasculature, induced by uncontrolled inflammatory stimulation, causes pulmonary edema. Identifying the inflammatory mediators that induce human lung microvascular endothelial cell barrier dysfunction is essential to find the best anti-inflammatory treatments for critically ill acute respiratory distress syndrome patients.We have compared the responses of primary human lung microvascular endothelial cells to the main inflammatory mediators involved in cytokine storms induced by sepsis and SARS-CoV2 pulmonary infection and to sera from healthy donors and severely ill patients with sepsis. Endothelial barrier function was measured by electric cell-substrate impedance sensing, quantitative confocal microscopy, and Western blot.The human lung microvascular endothelial cell barrier was completely disrupted by IL (interleukin)-6 conjugated with soluble IL-6R (IL-6 receptor) and by IL-1β, moderately affected by TNF (tumor necrosis factor)-α and IFN (interferon)-γ and unaffected by other cytokines and chemokines, such as IL-6, IL-8, MCP (monocyte chemoattractant protein)-1 and MCP-3. The inhibition of IL-1 and IL-6R simultaneously, but not separately, significantly reduced endothelial hyperpermeability on exposing human lung microvascular endothelial cells to a cytokine storm consisting of 8 inflammatory mediators or to sera from patients with sepsis. Simultaneous inhibition of IL-1 and JAK (Janus kinase)-STAT (signal transducer and activator of transcription protein), a signaling node downstream IL-6 and IFN-γ, also prevented septic serum-induced endothelial barrier disruption.These findings strongly suggest a major role for both IL-6 trans-signaling and IL-1β signaling in the pathological increase in permeability of the human lung microvasculature and reveal combinatorial strategies that enable the gradual control of pulmonary endothelial barrier function in response to a cytokine storm.