Department of Pediatrics, Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, Rochester, New York, 14642, USA.
Research Centre for Infectious Diseases, Department of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia, Australia.
Sci Rep. 2019 Feb 14;9(1):2096. doi: 10.1038/s41598-018-38312-w.
The role of Endoplasmic Reticulum Chaperone and Signaling Regulator BiP/GRP78 in acute inflammatory injury, particularly in the context of lung endothelium, is poorly defined. In his study, we monitored the effect of SubAB, a holoenzyme that cleaves and specifically inactivates BiP/GRP78 and its inactive mutant SubAB on lung inflammatory injury in an aerosolized LPS inhalation mouse model of acute lung injury (ALI). Analysis of lung homogenates and bronchoalveolar lavage (BAL) fluid showed that LPS-induced lung inflammation and injury were significantly inhibited in SubAB- but not in SubAB-treated mice. SubAB-treated mice were also protected from LPS-induced decrease in lung compliance. Gene transfer of dominant negative mutant of BiP in the lung endothelium protected against LPS-induced lung inflammatory responses. Consistent with this, stimulation of endothelial cells (EC) with thrombin caused an increase in BiP/GRP78 levels and inhibition of ER stress with 4-phenylbutyric acid (4-PBA) prevented this response as well as increase in VCAM-1, ICAM-1, IL-6, and IL-8 levels. Importantly, thrombin-induced Ca signaling and EC permeability were also prevented upon BiP/GRP78 inactivation. The above EC responses are mediated by intracellular BiP/GRP78 and not by cell surface BiP/GRP78. Together, these data identify intracellular BiP/GRP78 as a novel regulator of endothelial dysfunction associated with ALI.
内质网伴侣和信号调节因子 BiP/GRP78 在急性炎症损伤中的作用，特别是在肺内皮细胞中，还没有得到很好的定义。在他的研究中，我们监测了 SubAB 的作用，SubAB 是一种全酶，可切割并特异性失活 BiP/GRP78 及其无活性突变体 SubAB，在脂多糖雾化吸入急性肺损伤（ALI）小鼠模型中观察其对肺炎症损伤的影响。对肺匀浆和支气管肺泡灌洗液（BAL）的分析表明，SubAB 处理可显著抑制 LPS 诱导的肺炎症和损伤，但 SubAB 处理的小鼠则没有这种作用。SubAB 处理的小鼠也能防止 LPS 诱导的肺顺应性下降。肺内皮细胞中 BiP 显性负突变体的基因转移可防止 LPS 诱导的肺炎症反应。与此一致的是，凝血酶刺激内皮细胞（EC）会导致 BiP/GRP78 水平增加，而用 4-苯丁酸（4-PBA）抑制内质网应激可以阻止这种反应以及 VCAM-1、ICAM-1、IL-6 和 IL-8 水平的增加。重要的是，BiP/GRP78 失活还可以防止凝血酶诱导的 Ca 信号和 EC 通透性增加。上述 EC 反应是由细胞内 BiP/GRP78 介导的，而不是由细胞表面 BiP/GRP78 介导的。总之，这些数据表明细胞内 BiP/GRP78 是与 ALI 相关的内皮功能障碍的新型调节因子。
