Tranexamic acid and the gut barrier: Protection by inhibition of trypsin uptake and activation of downstream intestinal proteases

Abstract Objective Intraluminal pancreatic trypsin and other digestive enzymes injure the gut barrier following trauma-hemorrhagic shock (T/HS). Intestinal proteases (sheddases) exert important effects on normal gut function but may cause barrier disruption due to exaggerated production following T/HS. We hypothesized that the protective mechanism of TXA on the gut barrier following T/HS includes inhibition of these "downstream" proteases. This was studied in vitro. Methods Trypsin, matrix metalloproteinase (MMP-9) and ADAM-17 activity were measured in intestinal epithelial cells (IEC) exposed to HR + trypsin. TXA was added to IEC subsets. Pulmonary microvascular endothelial cells (HMVEC) were exposed to IEC supernatants and syndecan release and ICAM-1 expression determined. Results Trypsin activity and the activity of the “downstream” sheddases ADAM-17, MMP was increased in IEC lysates following exposure to HR + trypsin. Syndecan and ICAM-1 were increased in HMVEC exposed to IEC supernatants. TXA administration ‘early’ abrogated these effects. Conclusions TXA administration early after shock protects the gut barrier by inhibiting trypsin uptake and activity and the subsequent downstream protease cascade. To be effective, TXA should be administered early in all “at risk” patients.