Protective effect of FUT-175 on pulmonary function of xenografts in a guinea pig-to-rat lung perfusion model

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  • RYU Chusei
    Division of Surgical Oncology, Department of Translational Medical Science, Nagasaki University Graduate School of Biomedical Sciences
  • TAGAWA Tsutomu
    Division of Surgical Oncology, Department of Translational Medical Science, Nagasaki University Graduate School of Biomedical Sciences
  • NAGAYASU Takeshi
    Division of Surgical Oncology, Department of Translational Medical Science, Nagasaki University Graduate School of Biomedical Sciences

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Background: FUT-175 (nafamostat mesilate) has a variety of pharmacological effects; in addition to its stable potent serine protease inhibitory activity, it exerts far stronger anti-complement activity than other protease inhibitors. Here, we evaluated the protective effect of FUT-175 on pulmonary function of xenografts in an ex vivo guinea pig-to-rat lung perfusion model, using a device for analyzing pulmonary function in small animals. Methods: Animals were divided into three groups (n = 6 each), Isograft (Group I), Xenograft (Group X), and Xenograft with FUT-175 (Group XF). In the latter, 10 mg of FUT-175 was added to the extracorporeal circuit before perfusion with xenogeneic blood was started. The following parameters were serially measured in these three groups: complement activity causing 50% hemolysis (CH50 units) in the perfusion blood either before or during perfusion, pulmonary arterial pressure, dynamic pulmonary compliance, and airway resistance. In addition, Hematoxylin and Eosin staining of the lungs and assays of rat IgM, IgG, and anti-C3 deposition were carried out after perfusion. Results: The duration of satisfactory pulmonary function after the start of perfusion was significantly increased in Group XF. CH50 in Group XF decreased significantly than in Group X. In addition, FUT-175 suppressed both the increase in pulmonary arterial pressure and airway resistance, and the decrease in dynamic pulmonary compliance. In Group XF, intraalveolar hemorrhage and the thickening of the arterial wall were not observed. Groups X and XF showed deposition of IgM, IgG, and C3 at the endothelium of the pulmonary arteries but less in Group I. Conclusions: This study suggests that FUT-175 inhibited complement activation including the alternative pathway and improved lung xenograft pulmonary function. FUT-175 ameliorates hyperacute rejection in a guinea pig-to-rat ex vivo xenogeneic lung perfusion model.

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