Cowan K N, Heilbut A, Humpl T, Lam C, Ito S, Rabinovitch M
Division of Cardiovascular Research/Departments of Pediatrics, Laboratory Medicine and Pathobiology, and Medicine, Hospital for Sick Children/University of Toronto, 555 University Avenue, Toronto, Ontario, Canada, M5G 1X8.
Nat Med. 2000 Jun;6(6):698-702. doi: 10.1038/76282.
Progression of pulmonary hypertension is associated with increased serine elastase activity and the proteinase-dependent deposition of the extracellular matrix smooth muscle cell survival factor tenascin-C (refs. 1,2). Tenascin-C amplifies the response of smooth muscle cells to growth factors, which are also liberated through matrix proteolysis. Recent organ culture studies using hypertrophied rat pulmonary arteries have shown that elastase inhibitors suppress tenascin-C and induce smooth muscle cell apoptosis. This initiates complete regression of the hypertrophied vessel wall by a coordinated loss of cellularity and extracellular matrix. We now report that elastase inhibitors can reverse advanced pulmonary vascular disease produced in rats by injecting monocrotaline, an endothelial toxin. We began oral administration of the peptidyl trifluoromethylketone serine elastase inhibitors M249314 or ZD0892 21 days after injection of monocrotaline. A 1-week treatment resulted in 92% survival, compared with 39% survival in untreated or vehicle-treated rats. Pulmonary artery pressure and muscularization were reduced by myocyte apoptosis and loss of extracellular matrix, specifically elastin and tenascin-C. After 2 weeks, pulmonary artery pressure and structure normalized, and survival was 86%, compared with 0% in untreated or vehicle-treated rats. Although concomitant treatment with various agents can reduce pulmonary hypertension, we have documented complete regression after establishment of malignant monocrotaline-induced disease.
肺动脉高压的进展与丝氨酸弹性蛋白酶活性增加以及细胞外基质平滑肌细胞存活因子腱生蛋白-C的蛋白酶依赖性沉积有关（参考文献1,2）。腱生蛋白-C会增强平滑肌细胞对生长因子的反应，而这些生长因子也是通过基质蛋白水解作用释放出来的。最近利用肥大的大鼠肺动脉进行的器官培养研究表明，弹性蛋白酶抑制剂可抑制腱生蛋白-C并诱导平滑肌细胞凋亡。这会通过细胞和细胞外基质的协同减少引发肥大血管壁的完全消退。我们现在报告，弹性蛋白酶抑制剂能够逆转由注射内皮毒素野百合碱在大鼠中引发的晚期肺血管疾病。在注射野百合碱21天后，我们开始口服肽基三氟甲基酮丝氨酸弹性蛋白酶抑制剂M249314或ZD0892。为期1周的治疗使存活率达到92%，相比之下，未治疗或接受赋形剂治疗的大鼠存活率为39%。通过心肌细胞凋亡以及细胞外基质（特别是弹性蛋白和腱生蛋白-C）的减少，肺动脉压力和肌化程度降低。2周后，肺动脉压力和结构恢复正常，存活率为86%，相比之下，未治疗或接受赋形剂治疗的大鼠存活率为0%。尽管联合使用各种药物可以降低肺动脉高压，但我们已经证明在恶性野百合碱诱导的疾病形成后可以实现完全消退。
