Simonson Michael S, Robinson Ann V, Schulak James A, Hricik Donald E
Department of Medicine, School of Medicine, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, OH 44106, USA.
Transplantation. 2002 Apr 15;73(7):1054-9. doi: 10.1097/00007890-200204150-00007.
In animal models, endothelin-1 (ET-1) blockade attenuates transplant vasculopathy and chronic allograft dysfunction even in the absence of cyclosporine (CsA). As CsA has side effects and ET-1 antagonism alone has significant benefits, we postulated that allograft survival could be significantly improved by combining an endothelin-converting enzyme inhibitor with low-dose CsA.
Survival of Lewis to Fisher 344 rat heterotopic cardiac allografts was determined in untreated animals and compared with those treated with high-dose CsA (62 mg/kg i.m. on day 2), low-dose CsA (25 mg/kg), an endothelin-converting enzyme inhibitor, phosphoramidon (PA, 10 mg/kg/day), or low-dose CsA + PA.
Untreated allografts had a median survival of 16 days compared with 20 days for low-dose CsA. Grafts treated with PA survived for 28 days, and combination of PA and low-dose CsA improved median survival to 47 days (P<0.01). Median survival with combination therapy was similar to that for high-dose CsA (42 days). To explore mechanisms underlying the benefits of combination therapy, cardiac allografts treated as above (n=4 each group) were explanted at 20 d and analyzed for parenchymal rejection, neointimal vasculopathy, myocardial fibrosis, and macrophage infiltration. Low-dose CsA alone but not PA improved parenchymal rejection; in contrast, PA alone but not low-dose CsA improved vasculopathy. Both parenchymal rejection and vasculopathy were improved by combination therapy with low-dose CsA and PA. Unlike CsA, inhibition of ET-1 biosynthesis significantly reduced myocardial fibrosis in allografts.
These results suggest that the combination of low-dose CsA and endothelin-converting enzyme inhibition may prove useful to improve long-term graft survival while minimizing potential side effects of CsA.
在动物模型中，即使在没有环孢素（CsA）的情况下，内皮素-1（ET-1）阻断也能减轻移植血管病变和慢性移植物功能障碍。由于CsA有副作用，而单独使用ET-1拮抗剂有显著益处，我们推测将内皮素转换酶抑制剂与低剂量CsA联合使用可显著提高移植物存活率。
测定未治疗动物中Lewis到Fisher 344大鼠异位心脏移植的存活率，并与接受高剂量CsA（第2天肌肉注射62 mg/kg）、低剂量CsA（25 mg/kg）、内皮素转换酶抑制剂磷酰胺（PA，10 mg/kg/天）或低剂量CsA + PA治疗的动物进行比较。
未治疗的移植物中位存活时间为16天，低剂量CsA治疗的为20天。用PA治疗的移植物存活28天，PA与低剂量CsA联合使用可将中位存活时间提高到47天（P<0.01）。联合治疗的中位存活时间与高剂量CsA治疗的相似（42天）。为探究联合治疗益处的潜在机制，将上述治疗的心脏移植物（每组n = 4）在第20天取出，分析实质排斥、内膜血管病变、心肌纤维化和巨噬细胞浸润情况。单独使用低剂量CsA而非PA可改善实质排斥；相反，单独使用PA而非低剂量CsA可改善血管病变。低剂量CsA和PA联合治疗可同时改善实质排斥和血管病变。与CsA不同，抑制ET-1生物合成可显著减少移植物中的心肌纤维化。
这些结果表明，低剂量CsA与内皮素转换酶抑制联合使用可能有助于提高移植物长期存活率，同时将CsA的潜在副作用降至最低。
