title: Effect of synthetic protease inhibitor gabexate mesilate on attenuation of coagulant activity and cytokine release in a rat model of islet transplantation.
abstract: BACKGROUND
  The instant blood-mediated inflammatory reaction (IBMIR), in which the activation of coagulation cascade plays a key role, is one of the serious obstacles to successful islet engraftment. Gabexate mesilate (GM) is well known to elicit anticoagulant and antiinflammatory effects. The aim of this study was to evaluate the effect of GM on syngeneic IBMIR.
  
  
  METHODS
  Syngeneic rat islet grafts (2.5 IEQ/g) were transplanted intraportally into 2 groups (control group and GM group; n = 10-11) of streptozotocin-induced diabetic rats. The GM group was injected intravenously with GM for 30 minutes before islet infusion to 1 hour after. The control group was injected with equivalent amount of saline solution. Plasma samples were collected before and 0.5, 1, 3, 6, and 24 hours after transplantation, and several proinflammatory mediators, including interleukin-6 and high-mobility group Box 1 were measured. Curative rate, intravenous glucose tolerance test, and insulin amount in the recipients' livers were also evaluated.
  
  
  RESULTS
  Little difference was observed in any proinflammatory mediators. Whereas none of the animals in the control group became normoglycemic, 2 of 6 rats transplanted with the same number of islets in the GM group became normoglycemic during the study period. The glucose tolerance response was significantly ameliorated in the GM group compared with the control group (P < 0.001). The insulin amount in the liver of the recipients was considerably higher in the GM group (5.6 ± 4.1 vs 12.6 ± 5.3 ng/IEQ; P < .05).
  
  
  CONCLUSIONS
  These data suggest that GM improves islet engraftment not through suppressing the proinflammatory cytokines but as an anticoagulant. We therefore think that GM could be a useful anticoagulant to control IBMIR induced in clinical islet transplantation, although antiinflammatory reagents are considered to be needed for the ideal regimen.
authors.affiliation: Division of Advanced Surgical Science and Technology, Tohoku University, Sendai, Miyagi, 980-8575, Japan. tsu7ka5so8mi@yahoo.co.jp
authors.forename: K
authors.initials: K
authors.lastname: Tokodai
authors.forename: M
authors.initials: M
authors.lastname: Goto
authors.forename: A
authors.initials: A
authors.lastname: Inagaki
authors.forename: T
authors.initials: T
authors.lastname: Imura
authors.forename: S
authors.initials: S
authors.lastname: Satomi
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000925:Anticoagulants; D017690:Cell Transplantation; D003029:Coagulants / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D016670:Gabexate / Q000494:pharmacology*; D007249:Inflammation; D016381:Islets of Langerhans Transplantation / Q000379:methods*; D010447:Peptide Hydrolases / Q000737:chemistry*; D011480:Protease Inhibitors / Q000494:pharmacology*; D051381:Rats; D013997:Time Factors
chemical_list: D000893:Anti-Inflammatory Agents; D000925:Anticoagulants; D003029:Coagulants; D016207:Cytokines; D011480:Protease Inhibitors; D016670:Gabexate; D010447:Peptide Hydrolases