雷公藤甲素对实验性肺动脉高压肺脏基质金属蛋白酶MMP2和MMP9的影响

目的：雷公藤甲素能缓解实验性大鼠肺动脉高压，该实验观察雷公藤甲素对肺动脉高压血管重构模型的影响并探讨与基质金属蛋白酶的关系。方法：60只SD大鼠随机分为6组：①正常对照组；②模型组；③连续治疗组；④连续治疗组的安慰剂对照组；⑤延迟治疗组；⑥延迟治疗组的安慰剂对照组。术后5周通过心导管术测得血液动力学指标，并用弹力纤维染色观察肺小动脉的病理学变化。用免疫组织化学染色显示MMP2 和MMP9在肺血管上的阳性分布和半定量，荧光定量PCR（FS-PCR）行肺组织MMP2和MMP9的定量。结果:平均肺动脉压(m PAP） 为38.10±1.20 vs 16.70±1.16 mmHg和心室重量变化［RV/(LV+S)%］为（62.45±5.28）% vs （22.76±3.01）%及血管阻塞积分(VOS） 1.736±0.080 vs 0.000±0.000，②组较①组明显增高(P<0.01)；MMP2和MMP9的表达量在肺血管壁(MMP2为 1.48±0.35 vs 0.00±0.00； MMP9 1.95±0.22 vs 0.00±0.00)和肺组织(MMP2 0.85±0.67 vs 5.50±0.67. MMP9 0.85±0.67 vs 4.95±0.69)均显示②组较①组明显增高（P<0.05）；雷公藤甲素连续治疗组和延迟治疗组各指标均较模型组和各自的安慰剂组减低，且连续治疗效果更好（mPAP 20.80±1.03 vs 26.20±1.03 mmHg，P<0.05）。结论: 雷公藤甲素能延缓大鼠左肺切除加野百合碱注射诱导的肺动脉高压和右心室肥厚，并能抑制新生内膜形成，可能与抑制MMPs的活性增高有关。［中国当代儿科杂志，2007，9（5）：479-483］

Effect of triptolide on the expression of matrix metalloproteinases 2 and 9 in lungs of experimental pulmonary hypertension

OBJECTIVE: It has been shown that triptolide can attenuate pulmonary arterial hypertension in rats. This study was designed to investigate the therapeutic effect of triptolide on pulmonary hypertension in rats and possible mechanisms. METHODS: Sixty Sprague-Dawley (SD) rats were randomly divided into 6 groups: normal control, model, continuous triptolide-treated, delayed triptolide-treated and two placebo groups for continuous and delayed fashions (n=10 each). The rats from the last 5 groups were injected with monocrotaline (MCT, 60 mg/kg) on day 7 after left pneumonectomy. The rats in the continuous triptolide-treated group received therapy from day 5 to 35 with triptolide (0.25 mg/kg intraperitoneally, every other day) and those in the delayed triptolide-treated received therapy with triptolide (0.20 mg/kg intraperitoneally, daily) from day 21 to 35 after operation. The hemodynamic parameters were detected by catheterization and the pathologic changes of small pulmonary arteries were evaluated by light microscopy 5 weeks post-operation. The expression of matrix metalloproteinases (MMPs) was assessed by immunohistochemistry and quantitative fluorescence PCR of relevant (MMP2 and MMP9) mRNAs. RESULTS: By day 35 after operation, the mean pulmonary arterial pressure (mPAP, 38.10±1.20 vs 16.70±1.16 mmHg), the ratio of right ventricle/left ventricle plus septum [RV/(LV+S), 62.45±5.28% vs 22.76±3.01%] and the vessel obstructive scores (VOS, 1.736±0.080 vs 0.000±0.000) increased significantly in the Model group compared with those of the normal control group (P< 0.01). The expression of MMP2 and MMP9 and their mRNA expression in lung tissues obviously also elevated in the Model group (P< 0.05). The continuous and the delayed triptolide-treated groups had significantly lower mPAP (20.80±1.03 and 26.20±1.03 mmHg, respectively) and less right ventricular hypertrophy and pulmonary arterial neointimal formation compared with the model and the placebo groups. The two treated groups also demonstrated decreased expression of MMP2 and MMP9 and their mRNA expression in lung tissues. There were significant differences in mPAP, RV/(LV+S) and VOS between the two triptolide-treated groups. CONCLUSIONS: Triptolide attenuates the development of pulmonary hypertention and right ventricular hypertrophy and promotes regression of pulmonary arterial neointimal formation in pneumonectomized rats that received MCT, possibly through an inhibition of MMPs activity.