Intraluminal tranexamic acid inhibits intestinal sheddases and mitigates gut and lung injury and inflammation in a rodent model of hemorrhagic shock.

Background: 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 TNF[alpha] 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. Methods: 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. Results: Intraluminal TXA significantly reduced gut and lung histopathologic injury and inflammation compared to hemorrhagic shock alone. Gut, lung, and systemic ADAM-17 and TNF[alpha] 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 TNF[alpha], but not syndecan-1, in TXA-sham animals compared to sham vehicles. Conclusions: 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 TNF[alpha]. 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. (C) 2016 Lippincott Williams & Wilkins, Inc.

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