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Abstract：
Endothelial dysfunction is a critical feature of acute respiratory distress syndrome (ARDS) associated with higher disease severity and worse outcomes. Preclinical in vivo models of sepsis and ARDS have failed to yield useful therapies in humans, perhaps due to interspecies differences in inflammatory responses and heterogeneity of human host responses. Use of microphysiological systems (MPS) to investigate lung endothelial function may shed light on underlying mechanisms and targeted treatments for ARDS. We assessed the response to plasma from critically ill sepsis patients in our lung endothelial MPS through measurement of endothelial permeability, expression of adhesion molecules, and inflammatory cytokine secretion. Sepsis plasma induced areas of endothelial cell (EC) contraction, loss of cellular coverage, and luminal defects. EC barrier function was significantly worse following incubation with sepsis plasma compared to healthy plasma. EC ICAM-1 expression, IL-6 and soluble ICAM-1 secretion increased significantly more after incubation with sepsis plasma compared with healthy plasma. Plasma from sepsis patients who developed ARDS further increased IL-6 and sICAM-1 compared to plasma from sepsis patients without ARDS and healthy plasma. Our results demonstrate the proof of concept that lung endothelial MPS can enable interrogation of specific mechanisms of endothelial dysfunction that promote ARDS in sepsis patients.
摘要：
内皮功能障碍是急性呼吸窘迫综合征（ARDS）的重要特征，与更高的疾病严重程度和更差的预后有关。败血症和ARDS的临床前体内模型未能在人类中产生有用的治疗方法，可能是由于炎症反应的种间差异和人类宿主反应的异质性。使用微生理系统（MPS）研究肺内皮功能可能会阐明ARDS的潜在机制和靶向治疗。我们通过测量内皮通透性来评估我们的肺内皮MPS对重症脓毒症患者血浆的反应，粘附分子的表达，和炎性细胞因子分泌。脓毒症血浆诱导区域内皮细胞（EC）收缩，蜂窝覆盖的损失，和管腔缺陷。与健康血浆相比，与败血症血浆孵育后的EC屏障功能明显更差。ECICAM-1表达，与健康血浆相比，与败血症血浆孵育后，IL-6和可溶性ICAM-1分泌显着增加更多。与来自没有ARDS的脓毒症患者和健康血浆的血浆相比,来自发生ARDS的脓毒症患者的血浆进一步增加IL-6和sICAM-1。我们的结果证明了肺内皮MPS可以询问促进脓毒症患者ARDS的内皮功能障碍的特定机制的概念。
