title: 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.
authors.affiliation: Wayne State University, Marian and Michael Ilitch Department of Surgery, Detroit, MI 48201, USA. Electronic address: mdiebel@med.wayne.edu.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Diebel
authors.affiliation: Wayne State University, Marian and Michael Ilitch Department of Surgery, Detroit, MI 48201, USA. Electronic address: ldiebel@med.wayne.edu.
authors.forename: Lawrence N
authors.initials: LN
authors.lastname: Diebel
authors.affiliation: Wayne State University, Marian and Michael Ilitch Department of Surgery, Detroit, MI 48201, USA. Electronic address: dliberat@med.wayne.edu.
authors.forename: David M
authors.initials: DM
authors.lastname: Liberati
mesh_terms: D000072198:ADAM17 Protein / Q000187:drug effects / Q000378:metabolism; D000933:Antifibrinolytic Agents / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000187:drug effects / Q000378:metabolism; D007422:Intestines / Q000166:cytology; D008168:Lung / Q000166:cytology; D020780:Matrix Metalloproteinase 9 / Q000187:drug effects / Q000378:metabolism; D012771:Shock, Hemorrhagic / Q000150:complications; D053667:Syndecans / Q000378:metabolism; D014148:Tranexamic Acid / Q000494:pharmacology*; D014357:Trypsin / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000933:Antifibrinolytic Agents; D053667:Syndecans; D018799:Intercellular Adhesion Molecule-1; D014148:Tranexamic Acid; D014357:Trypsin; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human
keywords: Caco-2 cells; HT29-MTX cells; Sheddases; Tranexamic acid