Elafin, a serine elastase inhibitor, attenuates post-cardiac transplant coronary arteriopathy and reduces myocardial necrosis in rabbits after heterotopic cardiac transplantation
Elafin, a serine elastase inhibitor, attenuates post-cardiac transplant coronary arteriopathy and reduces myocardial necrosis in rabbits after heterotopic cardiac transplantation
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DOI：
10.1172/jci118692
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发表时间：
1996-06-01
影响因子：
15.9
通讯作者：
Rabinovitch, M
中科院分区：
文献类型：
--
作者：
Cowan, B;Baron, O;Rabinovitch, M
我们将实验诱导的心脏移植后冠状动脉病与弹性体溶解活性增加、IL-1β、纤连蛋白介导的炎症和平滑肌细胞 (SMC) 迁移以及 SMC 增殖联系起来。由于我们的体外研究表明丝氨酸弹性蛋白酶释放 SMC 丝裂原并促进 IL-1β 诱导纤连蛋白，我们假设体内给予特定的丝氨酸弹性蛋白酶抑制剂 elafin 会减少心脏移植后冠状动脉的损伤动脉病。喂养胆固醇的兔子接受了异位心脏移植，没有免疫抑制，并接受elafin（9 mg推注后每天连续输注1.79 mg/kg，n = 6）或载体（n = 6）。 1周后，收获心脏进行形态测定、免疫组织化学和生化分析。与对照供体心脏相比，经elafin处理的内膜增厚的冠状动脉总数减少> 70% (P < 0.002)，这与血管弹力分解活性降低相关，血管弹性活性降低通过内弹性层断裂较少来判断(P < 0.03)，免疫反应性纤连蛋白积累较少(P < 0.02)，以及通过增殖细胞核抗原定量的细胞增殖减少(P < 0.03)。 0.0001）。尽管存在心肌淋巴细胞浸润，但与未处理的对照相比，经elafin处理的供体心脏的湿重降低了50%（P < 0.002），并且与心肌细胞完整性的相对保存相关，而不是广泛的心肌坏死（P < 0.004）。这种保护作用与心肌弹力分解活性降低 (P < 0.0001) 和炎症细胞增殖 (P < 0.0001) 以及淋巴细胞中弹性蛋白抑制的弹性蛋白酶相关。因此，丝氨酸弹性蛋白酶活性似乎是心脏移植后冠状动脉病和排斥反应引起的心肌坏死的重要治疗靶点。
We have related experimentally induced post-cardiac transplant coronary arteriopathy to increased elastolytic activity, IL-1 beta, fibronectin-mediated inflammatory and smooth muscle cell (SMC) migration, and SMC proliferation, Since our in vitro studies show that a serine elastase releases SMC mitogens and facilitates IL-1 beta induction of fibronectin, we hypothesized that administration in vivo of the specific serine elastase inhibitor, elafin, would decrease the post-cardiac transplant coronary arteriopathy. Cholesterol-fed rabbits underwent a heterotopic cardiac transplant without immunosuppression and received elafin (1.79 mg/kg per d continuous infusion after a 9 mg bolus, n = 6) or vehicle (n = 6). 1 wk later, hearts were harvested for morphometric, immunohistochemical, and biochemical analyses. A > 70% decrease in the total number of coronary arteries with intimal thickening in elafin-treated compared to control donor hearts (P < 0.002) was associated with reduced vascular elastolytic activity judged by fewer breaks in the internal elastic lamina (P < 0.03), less accumulation of immunoreactive fibronectin (P < 0.02), and reduced cell proliferation quantified by proliferating cell nuclear antigen (P < 0.0001). Despite myocardial lymphocytic infiltration, wet weight of elafin-treated donor hearts was reduced by 50% compared to untreated controls (P < 0.002) and associated with relative preservation of myocyte integrity, instead of extensive myocardial necrosis (P < 0.004). This protective effect correlated with decreased myocardial elastolytic activity (P < 0.0001) and inflammatory cell proliferation (P < 0.0001) and with an elafin-inhibitable elastase in lymphocytes. Serine elastase activity thus appears an important therapeutic target for post-cardiac transplant coronary arteriopathy and myocardial necrosis induced by rejection.