Microemulsion cyclosporin inhibits vascular remodelling and attenuates associated changes in profibrotic gene expression in an experimental model of allograft vasculopathy.
BACKGROUND
Chronic allograft dysfunction (CAD), the leading cause of solid organ transplant failure, is characterized by histological evidence of extracellular matrix (ECM) accumulation (fibrosis). The aim of this study was to characterize the changes in fibrosis-associated gene expression in an experimental model of CAD and to measure the effect of the immunosuppressant cyclosporin on these changes.


METHODS
Lewis recipients of F344 rat thoracic to abdominal transplants were administered cyclosporin or no treatment. Vascular remodelling and ECM accumulation (picrosirius red) were measured using computerized histomorphometry. Fibrosis-associated gene expression was studied by semiquantitative reverse transcription-polymerase chain reaction.


RESULTS
Cyclosporin inhibited medial ECM accumulation and vascular remodelling in allografts. This was associated with an attenuation of the graft inflammatory infiltrate and a reduction in intragraft matrix metalloproteinase (MMP) 2 and MMP-9 messenger RNA (mRNA) levels. There was a significant negative correlation between neoadventitial ECM density and MMP-9 expression, as well as with vessel circumference. Neoadventitial ECM density was significantly higher in the cyclosporin-treated group than in animals with untreated allografts, as were mRNA levels of collagen 3 and tissue inhibitor of metalloproteinase 1.


CONCLUSIONS
The alloimmune injury itself may contribute directly to vascular remodelling and fibrosis in allograft vasculopathy. Cyclosporin attenuated this component of the pathophysiology of CAD effectively.
Murphy
G J
GJ
University Department of Surgery, Leicester General Hospital, Leicester, UK. gavinmurphy@hotmail.com
Bicknell
G R
GR
Nicholson
M L
ML
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000473:pathology; D001807:Blood Vessel Prosthesis; D016572:Cyclosporine / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression; D006085:Graft Survival / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014184:Transplantation, Homologous
D007166:Immunosuppressive Agents; D016572:Cyclosporine; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9