Sinomenine blocks tissue remodeling in a rat model of chronic cardiac allograft rejection.
BACKGROUND
Chronic rejection (CR) with graft vasculopathy is recognized as a major cause of graft loss over time. Sinomenine (SN) has anti-inflammatory, antirheumatic, and immunomodulatory effects. Previously, we demonstrated antimacrophage and anti-T cell effects of SN in acute rejection. In the current study, we investigated the effect of SN in a rat cardiac allograft model of CR.


METHODS
After a brief course of cyclosporine A (CsA), Lewis recipients of F344 hearts were treated with SN alone, CsA alone, or a combination of both drugs. Grafts were analyzed morphometrically and by immunohistochemistry. Expression of basic fibroblast growth factor (bFGF), vascular endothelial growth factor, and endothelin 1 was assessed by reverse transcription-polymerase chain reaction. Antidonor IgM formation was investigated by FACS.


RESULTS
Cardiac grafts from SN-treated rats showed less pronounced vasculopathy in comparison with untreated rats or CsA-treated recipients. After treatment with a combination of both drugs, rats had significantly less graft vasculopathy than rats receiving either drug alone. Treatment with CsA alone led to a decrease in bFGF expression, whereas SN alone did not affect gene expression. SN in combination with CsA, however, markedly reduced expression of bFGF, vascular endothelial growth factor, and endothelin 1. SN alone did not inhibit antidonor antibody formation.


CONCLUSIONS
These studies demonstrate for the first time the therapeutic value of SN in a model of chronic cardiac allograft rejection. SN in combination with low-dose T cell-targeted immunosuppression is effective in controlling tissue remodeling in the context of CR and is associated with inhibition of intragraft expression of mediators involved in angiogenesis, vascular tone, and tissue remodeling.
Mark
Walter
W
Department of Transplant Surgery, University Hospital Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria. Walter.Mark@uibk.ac.at
Schneeberger
Stefan
S
Seiler
Rüdiger
R
Stroka
Deborah M
DM
Amberger
Albert
A
Offner
Felix
F
Candinas
Daniel
D
Margreiter
Raimund
R
D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D002908:Chronic Disease; D016572:Cyclosporine / Q000627:therapeutic use; D016207:Cytokines / Q000378:metabolism; D004359:Drug Therapy, Combination; D006084:Graft Rejection / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control; D006133:Growth Substances / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D016027:Heart Transplantation; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008297:Male; D009019:Morphinans / Q000627:therapeutic use*; D009206:Myocardium / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344; D014184:Transplantation, Homologous; D020257:Ventricular Remodeling / Q000187:drug effects*
D000276:Adjuvants, Immunologic; D016207:Cytokines; D006133:Growth Substances; D007166:Immunosuppressive Agents; D009019:Morphinans; C009271:sinomenine; D016572:Cyclosporine