Isoflurane Ameliorates Acute Lung Injury by Preserving Epithelial Tight Junction Integrity.
Isoflurane Ameliorates Acute Lung Injury by Preserving Epithelial Tight Junction Integrity.
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DOI：
10.1097/aln.0000000000000742
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发表时间：
2015-08
期刊：
影响因子：
8.8
通讯作者：
Baron RM
中科院分区：
文献类型：
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作者：
Englert JA;Macias AA;Amador-Munoz D;Pinilla Vera M;Isabelle C;Guan J;Magaoay B;Suarez Velandia M;Coronata A;Lee A;Fredenburgh LE;Culley DJ;Crosby G;Baron RM
异氟醚可能在肺损伤的临床前模型中具有保护作用，但其在肺损伤患者中的使用仍存在争议，其保护作用的机制仍不清楚。我们假设这种保护是在肺泡紧密连接水平介导的，并研究了反映人类急性呼吸窘迫综合征的两次肺损伤模型中的可能性。野生型小鼠在接触雾化内毒素 (n=8) 或盐水对照 (n=9) 一小时后接受异氟烷治疗，然后在机械通气（MV，潮气量 15 mL/kg，2 小时）之前恢复 24 小时，产生呼吸机诱发的肺损伤。暴露于脂多糖一小时后，用异氟烷类似地处理小鼠肺上皮细胞。第二天对细胞进行循环拉伸，以反映体内使用的 MV 方案。在暴露于吸入内毒素后和 MV 之前接受异氟醚治疗的小鼠表现出明显较少的生理性肺功能障碍。这些作用似乎是由血管渗漏减少介导的，但不是炎症指数改变所介导的。用脂多糖和循环拉伸处理的小鼠肺上皮细胞以及用脂多糖和 MV 处理后从小鼠中采集的肺，其关键紧密连接蛋白（即封闭带 1）的水平降低，而异氟烷治疗可以恢复这一水平。异氟烷可通过调节关键紧密连接蛋白的表达来维持肺泡毛细血管屏障的完整性，从而挽救内毒素暴露和 MV 二次打击模型引起的肺损伤。
Isoflurane may be protective in pre-clinical models of lung injury but its use in patients with lung injury remains controversial and the mechanism of its protective effects remains unclear. We hypothesized that this protection is mediated at the level of alveolar tight junctions and investigated the possibility in a two-hit model of lung injury that mirrors human acute respiratory distress syndrome. Wild-type mice were treated with isoflurane one hour after exposure to nebulized endotoxin (n=8) or saline control (n=9) then allowed to recover for 24 hrs prior to mechanical ventilation (MV, tidal volume 15 mL/kg, 2 hrs) producing ventilator-induced lung injury. Mouse lung epithelial cells were similarly treated with isoflurane one hour after exposure to lipopolysaccharide. Cells were cyclically stretched the following day to mirror the MV protocol used in vivo. Mice treated with isoflurane following exposure to inhaled endotoxin and prior to MV exhibited significantly less physiologic lung dysfunction. These effects appeared to be mediated by decreased vascular leak, but not altered inflammatory indices. Mouse lung epithelial cells treated with lipopolysaccharide and cyclic stretch and lungs harvested from mice following treatment with lipopolysaccharide and MV had decreased levels of a key tight junction protein (i.e. zona occludens 1) that was rescued by isoflurane treatment. Isoflurane rescued lung injury induced by a two-hit model of endotoxin exposure followed by MV by maintaining the integrity of the alveolar-capillary barrier possibly by modulating the expression of a key tight junction protein.