Intraluminal tranexamic acid inhibits intestinal sheddases and mitigates gut and lung injury and inflammation in a rodent model of hemorrhagic shock.
Intraluminal tranexamic acid inhibits intestinal sheddases and mitigates gut and lung injury and inflammation in a rodent model of hemorrhagic shock.
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DOI：
10.1097/ta.0000000000001056
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发表时间：
2016-08
期刊：
影响因子：
--
通讯作者：
Kozar RA
中科院分区：
文献类型：
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作者：
Peng Z;Ban K;LeBlanc A;Kozar RA
静脉注射氨甲环酸（TXA）是失血性休克（HS）后有效的辅助药物，因为它具有抗纤溶的特性。TXA也是一种丝氨酸蛋白酶抑制剂，最近的实验室数据表明，进入小肠的腔内TXA可以抑制消化蛋白酶并保护肠道。ADAM-17和TNFα是肠syndecan-1的有效脱落酶，当脱落时，使底层肠上皮暴露于消化蛋白酶和随后的全身损伤。因此，我们假设，作为丝氨酸蛋白酶抑制剂的腔内TXA可以减少肠脱落酶和syndecan-1的脱落，减轻肠道和远处器官（肺）的损伤。小鼠接受90分钟的失血性休克，平均动脉压为35±5 mm Hg，随后给予腔内TXA或载药。3小时后，取小肠、肺、血液进行分析。与单独失血性休克相比，腔内TXA显著减少了肠道和肺部的组织病理学损伤和炎症。出血性休克使肠道、肺和全身的ADAM-17和TNFα显著升高，而TXA使其降低。此外，肠和肺的syndecan-1免疫染色得以保留，TXA后全身脱落减少。与假药组相比，TXA降低了TXA-sham动物的ADAM-17和TNFα，但没有降低syndecan-1。本研究结果表明，实验性失血性休克后，肠和肺腔内TXA的有益作用部分是由于ADAM-17和TNFα抑制了syndecan-1的脱落。需要进一步的研究来确定口服TXA是否能提供类似的肠道保护，从而对有器官损伤风险的可存活出血患者有潜在的益处。这对可能无法获得及时医疗护理的病人或士兵尤其重要。NA
Intravenous tranexamic acid (TXA) is an effective adjunct after hemorrhagic shock (HS) due to its antifibrinolytic properties. TXA is also a serine protease inhibitor and recent laboratory data demonstrated that intraluminal TXA into the small bowel inhibited digestive proteases and protected the gut. .ADAM-17 and TNFα are effective sheddases of intestinal syndecan-1 which when shed, exposes the underlying intestinal epithelium to digestive proteases and subsequent systemic insult. We therefore hypothesized that intraluminal TXA as a serine protease inhibitor would reduce intestinal sheddases and syndecan-1 shedding, mitigating gut and distant organ (lung) damage. Mice underwent 90 minutes of hemorrhagic shock to a mean arterial pressure of 35±5 mm Hg following by the intraluminal administration of TXA or vehicle. After 3 hours, small intestine, lung, and blood were collected for analysis. Intraluminal TXA significantly reduced gut and lung histopathologic injury and inflammation compared to hemorrhagic shock alone. Gut, lung, and systemic ADAM-17 and TNFα were significantly increased by hemorrhagic shock but lessened by TXA. Additionally, gut and lung syndecan-1 immunostaining were preserved and systemic shedding lessened after TXA. TXA reduced ADAM-17 and TNFα, but not syndecan-1, in TXA-sham animals compared to sham vehicles. Results of the present study demonstrate a beneficial effect of intraluminal TXA in the gut and lung after experimental hemorrhagic shock in part due to inhibition of the syndecan-1 shedding by ADAM-17 and TNFα. Further studies are needed to determine if orally administered TXA could provide similar intestinal protection and thus be of potential benefit to patients with survivable hemorrhage at risk for organ injury. This is particularly relevant in patients or soldiers who may not have access to timely medical care. NA