Department of Anesthesiology, Qianfoshan Hospital, Shandong University, Jinan, Shandong, China (mainland).
Med Sci Monit. 2018 Dec 27;24:9413-9423. doi: 10.12659/MSM.911268.
BACKGROUND Increased endothelial permeability is involved in ventilator-induced lung injury (VILI). Stim1/Orai1 mediates store-operated Ca2+ activation, which modulates endothelial permeability. However, the underlying mechanisms of the Stim1/Orai1 pathway in VILI are poorly understood. MATERIAL AND METHODS Wistar rats were exposed to low tidal volume (7 mL/kg) or high tidal volume (40mL/kg) ventilation. Human Lung Microvascular Endothelial Cells (HULEC) were subjected to 8% or 18% cyclic stretching (CS). BTP2 pretreatment was performed. Lung wet/dry weight ratio, histological changes of lung injury, and bronchoalveolar lavage fluid (BALF) protein were measured. Endothelial permeability and intracellular calcium concentration were evaluated in HULECs. Protein expression was determined by Western blotting. RESULTS High tidal volume mechanical ventilation-induced lung injury (such as severe congestion and hemorrhage) and BTP2 pretreatment protected lungs from injury. The expression of Stim1, Orai1, and PKCα, lung wet/dry weight ratio, and BALF protein level significantly increased in the high tidal volume group compared to the control group and low tidal volume group. Importantly, BTP2 pretreatment alleviated the above-mentioned effects. Compared with exposure to 8% CS, the protein levels of Stim1, Orai1, and PKCα in HULECs significantly increased after exposure to 18% CS for 4 h, whereas BTP2 pretreatment significantly inhibited the increase (P<0.05). BTP2 pretreatment also suppressed increase of endothelial permeability and the intracellular calcium induced by 18% CS (P<0.05). CONCLUSIONS When exposed to high tidal volume or large-magnitude CS, Stim1 and Orai1 expression are upregulated, which further activates calcium-sensitive PKCα and results in calcium overload, endothelial hyperpermeability, and, finally, lung injury.
血管内皮通透性增加与呼吸机相关性肺损伤（VILI）有关。Stim1/Orai1 介导的储存操纵的 Ca2+ 激活，调节血管内皮通透性。然而，Stim1/Orai1 通路在 VILI 中的潜在机制仍知之甚少。
Wistar 大鼠接受小潮气量（7 mL/kg）或大潮气量（40mL/kg）通气。人肺微血管内皮细胞（HULEC）接受 8%或 18%的周期性拉伸（CS）。进行 BTP2 预处理。测量肺湿/干重比、肺损伤的组织学变化和支气管肺泡灌洗液（BALF）蛋白。评估 HULEC 的内皮通透性和细胞内钙浓度。通过 Western 印迹测定蛋白表达。
大潮气量机械通气引起的肺损伤（如严重充血和出血）和 BTP2 预处理可保护肺免受损伤。与对照组和小潮气量组相比，大潮气量组的 Stim1、Orai1 和 PKCα 的表达、肺湿/干重比和 BALF 蛋白水平显著增加。重要的是，BTP2 预处理减轻了上述作用。与暴露于 8% CS 相比，HULECs 在暴露于 18% CS 4 小时后，Stim1、Orai1 和 PKCα 的蛋白水平显著增加，而 BTP2 预处理明显抑制了这种增加（P<0.05）。BTP2 预处理还抑制了 18% CS 诱导的内皮通透性增加和细胞内钙（P<0.05）。
当暴露于大潮气量或大振幅 CS 时，Stim1 和 Orai1 的表达上调，进而激活钙敏感的 PKCα，导致钙超载、内皮通透性增加，最终导致肺损伤。
