Mark E Diebel1, Lawrence N Diebel2, David M Liberati3. 1. Wayne State University, Marian and Michael Ilitch Department of Surgery, Detroit, MI 48201, USA. Electronic address: mdiebel@med.wayne.edu. 2. Wayne State University, Marian and Michael Ilitch Department of Surgery, Detroit, MI 48201, USA. Electronic address: ldiebel@med.wayne.edu. 3. Wayne State University, Marian and Michael Ilitch Department of Surgery, Detroit, MI 48201, USA. Electronic address: dliberat@med.wayne.edu.
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.
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.