Recombinant Thrombomodulin Reduce Histone-Induced Rat Lung Transplant Model of Primary Graft Dysfunction

Abstract

Purpose In ISHLT 2018, we reported a rat lung transplant model of primary graft dysfunction (PGD) by histone administration. Recombinant thrombomodulin is clinically used antiinflammation and anticoagulation agent and previously reported that it reduces histone-induced endothelial damage and coagulation. We hypothesized that recombinant thrombomodulin administration reduced histone-induced PGD after lung transplantation. Methods Donor rats were randomly assigned to receive calf thymus histone (40 mg/kg) (Histone group), calf thymus histone (40 mg/kg) and recombinant thrombomodulin (3mg/kg) (Histone+rhTM group) or phosphate buffered saline (PBS) (control group). They were administered intravenously to the donor rats, then left lungs were explanted 3 hours after the administration. Immediately after the procurements of the donor lungs, orthotropic lung transplantations were performed. Donor and recipient rats were evaluated for lung functions and tissue damages by means of blood gas analysis, X-ray, real-time RT-PCR, plasma protein analysis and histopathological assessment. Results In the donor assessment, there were no significant differences in the blood gas analysis, chest X-ray nor histology between the groups. Gene expressions of inflammatory cytokines in lung tissue and plasma level of inflammation protein significantly increase in Histone group and Histone+rhTM group (figure A). However, there was marked worsening of gas exchanges in the Histone group after lung transplantation and recovery in Histone+rhTM group (figure B). Histopathologic evaluation revealed lung injury in Histone group and recovery in Histone+rhTM group (figure C). Radiograph taken after autopsy showed reduced radiolucency in Histone group and recovery in Histone+rhTM group (figure D). Conclusion Recombinant thrombomodulin administration reduced PGD like reaction in lung transplantation. It may indicate a possibility of novel treatment for PGD in lung transplantation.