西地那非改善内皮祖细胞治疗野百合碱诱导的大鼠肺动脉高压的长期疗效。
Sildenafil improves long-term effect of endothelial progenitor cell-based treatment for monocrotaline-induced rat pulmonary arterial hypertension.
机构信息
Department of Biological Science and Technology, National Pingtung University of Science and Technology, Pingtung, Taiwan.
出版信息
Cytotherapy. 2013 Feb;15(2):209-23. doi: 10.1016/j.jcyt.2012.09.002. Epub 2012 Dec 11.
BACKGROUND AIMS
We hypothesized that the long-term therapeutic effect of combined sildenafil and bone marrow-derived endothelial progenitor cells (BMDEPCs) on monocrotaline (MCT)-induced rat pulmonary arterial hypertension (PAH) is superior to either treatment alone.
METHODS
Male Sprague-Dawley rats (n = 40) were equally divided into normal controls, MCT (65 mg/kg, subcutaneously) only, MCT + sildenafil (25 mg/kg/day, orally), MCT + BMDEPCs (2.0 × 10(6) autologous cells, intravenously) and MCT + sildenafil+ BMDEPCs. BMDEPCs and sildenafil were given on day 21 after MCT administration. Animals were sacrificed by day 90 after MCT administration.
RESULTS
The apoptotic (caspase 3, Bax) and inflammatory (tumor necrosis factor-α, matrix metalloproteinase-9) biomarkers in right ventricle and lung and pulmonary expressions of fibrotic biomarkers (transforming growth factor-β, p-Smad3) and connexin 43 protein were lower in monotherapy groups (i.e., MCT + sildenafil and MCT + BMDEPCs) and further decreased in normal controls and combined treatment groups (i.e., MCT + sildenafil + BMDEPCs) compared with untreated animals (i.e., MCT only) (all P < 0.01). Expressions of anti-fibrotic biomarkers (bone morphogenetic protein-2, p-Smad1/5) and numbers of alveolar sacs and arterioles in lung were higher in monotherapy groups and further increased in normal controls and combined treatment groups compared with untreated animals (all P < 0.005). In right ventricle, connexin 43 and α-myosin heavy chain (MHC) expressions were higher in the monotherapy groups and further elevated in normal controls and combined treatment groups compared with untreated animals, whereas β-MHC exhibited the opposite pattern (all P < 0.01). Right ventricular systolic pressure and weight were lower in the monotherapy animals and further reduced in normal controls and combined treatment groups compared with untreated animals (all P < 0.0001).
CONCLUSIONS
Combined therapy with BMDEPCs and sildenafil was superior to either treatment alone in attenuating rodent MCT-induced PAH.
背景目的
我们假设联合使用西地那非和骨髓来源的内皮祖细胞（BMDEPCs）治疗野百合碱（MCT）诱导的大鼠肺动脉高压（PAH）的长期治疗效果优于单独治疗。
方法
雄性 Sprague-Dawley 大鼠（n = 40）平均分为正常对照组、MCT（65 mg/kg，皮下注射）组、MCT+西地那非（25 mg/kg/天，口服）组、MCT+BMDEPCs（2.0×10(6) 个自体细胞，静脉注射）组和 MCT+西地那非+BMDEPCs 组。在 MCT 给药后第 21 天给予 BMDEPCs 和西地那非。在 MCT 给药后第 90 天处死动物。
结果
与未治疗组（即 MCT 组）相比，在单一治疗组（即 MCT+西地那非组和 MCT+BMDEPCs 组）中，右心室和肺中的凋亡（半胱氨酸天冬氨酸蛋白酶 3、Bax）和炎症（肿瘤坏死因子-α、基质金属蛋白酶-9）生物标志物以及肺纤维化生物标志物（转化生长因子-β、磷酸化 Smad3）和连接蛋白 43 蛋白的表达均较低，而在正常对照组和联合治疗组（即 MCT+西地那非+BMDEPCs 组）中进一步降低（均 P<0.01）。与未治疗组（即 MCT 组）相比，在单一治疗组中，抗纤维化生物标志物（骨形态发生蛋白-2、磷酸化 Smad1/5）和肺泡囊及肺小动脉的数量均较高，而在正常对照组和联合治疗组中进一步增加（均 P<0.005）。在右心室中，连接蛋白 43 和α-肌球蛋白重链（MHC）的表达在单一治疗组中较高，而在正常对照组和联合治疗组中进一步升高，而β-MHC 则呈现相反的模式（均 P<0.01）。与未治疗组相比，在单一治疗动物中，右心室收缩压和重量较低，而在正常对照组和联合治疗组中进一步降低（均 P<0.0001）。
结论
与单独治疗相比，联合使用 BMDEPCs 和西地那非治疗野百合碱诱导的大鼠 PAH 效果更好。
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