弹性蛋白酶抑制剂对野百合碱诱导的肺动脉高压干预作用的研究

目的　探讨丝氨酸弹性蛋白酶抑制剂ZD 0 892对野百合碱性肺动脉高压的逆转作用。方法　利用野百合碱建立大鼠肺动脉高压模型。 2 1天后 ,治疗组给予ZD 0 892管饲 ,剂量按2 4 0mg/(kg·d)分 2次给予 ,模型组按同样剂量管饲ZD 0 892的溶媒 ;而正常对照组管饲同样剂量的生理盐水。于实验第 2 1、2 8、35天 ,使用荧光分光光度计检测肺动脉弹性蛋白的离解活性 ,通过右心导管法测定肺动脉压力 ;并在上述时间点 ,采用钡明胶灌注的技术对周围肺动脉进行组织病理学分析。结果　注射野百合碱后的 2 1天 ,大鼠肺动脉高压已经形成 ,肺动脉弹性蛋白酶的活性明显升高。经ZD 0 892治疗 1周后 ,肺动脉弹性蛋白酶的活性显著下降 ,肺动脉压力、周围肺动脉的肌化数、肌性肺动脉的中膜厚度也相应减低 ;治疗 2周后 ,弹性蛋白酶的活性降低至正常水平 ,肺动脉压力及结构也随之恢复正常。结论　内源性血管弹性蛋白酶在肺动脉高压的发生及发展中起重要作用 ,ZD 0 892能有效地抑制其活性 ,进而可使野百合碱诱导的严重肺动脉高压完全逆转。

Effect of elastase inhibitor on pulmonary hypertension induced by monocrotaline

Objective Pulmonary hypertension is a proliferative vascular disease characterized by pulmonary vascular structural remodeling. Until now, the pathogenesis of pulmonary hypertension is still not fully understood. Although considerable progress has been made, there is, to date, no cure for advanced pulmonary vascular disease. Recently, a number of studies suggest that endogenous vascular elastase (EVE) play a role in the vascular changes associated with pulmonary hypertension. The purpose of the study was to determine whether an elastase inhibitor might reverse advanced pulmonary vascular disease produced in rats by injection of monocrotaline.Methods One hundred and twenty male Sprague-Dawley rats were used in this study.The rats were divided into three groups: control, model and ZD-0892 groups. In the model and ZD-0892 groups,the rats were subjected to a single subcutaneous injection of monocrotaline (60 mg/kg) in the hind flank, while the rats in control group received an equivalent volume of 0.9% saline. From day 21, the rats in the ZD-0892 and model groups received twice-daily gavage tube feedings of either ZD-0892 at a dose of 240 mg/kg per day or its administration vehicle, while the rats in control group were subjected to an equivalent volume of 0.9% saline. On days 21, 28 and 35 post-injection, the elastolytic activity was measured with a fluorescence microplate reader and pulmonary artery pressure was detected via catheterization. Meanwhile, the lungs were evaluated morphologically, using the barium-gelatin perfusion technique. Results The injection of monocrotaline led to severe pulmonary hypertension in rats 21 days later and pulmonary artery elastolytic activity increased remarkably. A 1-week treatment with ZD-0892 resulted in declines in elastase activity. This was associated with significant declines in pulmonary artery pressure, decreases in muscularization of peripheral arteries and reductions in medial hypertrophy. After 2 weeks, elastase activity returned to normal level. Pulmonary artery pressure and structure were normalized. Conclusion Increased elastase activity is important in the development of vascular changes and progressive pulmonary hypertension. ZD-0892 can suppress the elastase activity and completely reverse the fatal pulmonary hypertension induced by monocrotaline in rats.