title: Protease inhibitor nafamostat mesilate attenuates complement activation and improves function of xenografts in a discordant lung perfusion model.
abstract: BACKGROUND
  Anti-complement activity of nafamostat mesilate (FUT-175) is strong including its variety of pharmacological effects. The effect of FUT-175 for xenografts in an ex vivo guinea pig-to-rat lung perfusion model was evaluated.
  
  
  METHODS
  Heparinized Lewis rat blood was used to perfuse the lungs in three groups (n = 6 each). Group I used Lewis rat left lung for donor, Group X used guinea pig left lung for donor, and Group XF used guinea pig left lung for donor, which was perfused with Lewis rat blood with 0.2 mg/ml of FUT-175. Complement activity causing 50% hemolysis (CH50) in the perfusion blood and pulmonary function either before or during perfusion were serially measured. Pathological assessments of the lungs were also carried out after perfusion.
  
  
  RESULTS
  The duration of satisfactory pulmonary function was significantly increased in Group XF. Complement activity causing 50% hemolysis in Group XF decreased more significantly compared to Group X. FUT-175 suppressed both the increase in pulmonary arterial pressure and airway resistance, and the decrease in dynamic lung compliance. In Group X, pathology showed intra-alveolar hemorrhage, perivascular edema, and medial thickening with endothelial swelling of the pulmonary arteries. In Group XF, less changes were observed compared to Group X. Group X showed deposition of IgM, IgG, and C3 at the endothelium of arteries, which was fewer in Group XF, and even fewer in Group I.
  
  
  CONCLUSIONS
  This study suggests that FUT-175 inhibited complement activation and improved lung xenograft function. FUT-175 ameliorates hyperacute rejection in a guinea pig-to-rat ex vivo xenogeneic lung perfusion model.
authors.affiliation: Department of Translational Medical Science, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan. tomtgw@nagasaki-u.ac.jp
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Tagawa
mesh_terms: D000818:Animals; D001550:Benzamidines; D003167:Complement Activation / Q000187:drug effects*; D051056:Complement Inactivating Agents / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology*; D006168:Guinea Pigs; D008168:Lung / Q000098:blood supply* / Q000187:drug effects* / Q000502:physiology; D008170:Lung Compliance / Q000187:drug effects; D008297:Male; D010477:Perfusion; D011480:Protease Inhibitors / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D014183:Transplantation, Heterologous / Q000502:physiology*
chemical_list: D001550:Benzamidines; D051056:Complement Inactivating Agents; D006146:Guanidines; D011480:Protease Inhibitors; C032855:nafamostat