Programa de Pesquisa em Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21941-902, Brazil.
Programa de Pós-Graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21941-902, Brazil.
Cells. 2020 Sep 18;9(9):2120. doi: 10.3390/cells9092120.
Pulmonary arterial hypertension (PAH) is characterized by the remodeling of pulmonary arteries, with an increased pulmonary arterial pressure and right ventricle (RV) overload. This work investigated the benefit of the association of human umbilical cord mesenchymal stem cells (hMSCs) with lodenafil, a phosphodiesterase-5 inhibitor, in an animal model of PAH. Male Wistar rats were exposed to hypoxia (10% O) for three weeks plus a weekly i.p. injection of a vascular endothelial growth factor receptor inhibitor (SU5416, 20 mg/kg, SuHx). After confirmation of PAH, animals received intravenous injection of 5.10 hMSCs or vehicle, followed by oral treatment with lodenafil carbonate (10 mg/kg/day) for 14 days. The ratio between pulmonary artery acceleration time and RV ejection time reduced from 0.42 ± 0.01 (control) to 0.24 ± 0.01 in the SuHx group, which was not altered by lodenafil alone but was recovered to 0.31 ± 0.01 when administered in association with hMSCs. RV afterload was confirmed in the SuHx group with an increased RV systolic pressure (mmHg) of 52.1 ± 8.8 normalized to 29.6 ± 2.2 after treatment with the association. Treatment with hMSCs + lodenafil reversed RV hypertrophy, fibrosis and interstitial cell infiltration in the SuHx group. Combined therapy of lodenafil and hMSCs may be a strategy for PAH treatment.
肺动脉高压（PAH）的特征是肺血管重塑，肺动脉压力升高，右心室（RV）负荷过重。本研究探讨了人脐带间充质干细胞（hMSCs）与磷酸二酯酶-5 抑制剂洛地那非联合应用于 PAH 动物模型的益处。雄性 Wistar 大鼠暴露于低氧（10% O）中 3 周，每周腹腔注射血管内皮生长因子受体抑制剂（SU5416，20mg/kg，SuHx）。确认 PAH 后，动物静脉注射 5.10×10^6 hMSCs 或载体，随后口服洛地那非碳酸酯（10mg/kg/天）治疗 14 天。肺动脉加速时间与 RV 射血时间的比值从对照组的 0.42±0.01 降至 SuHx 组的 0.24±0.01，单独使用洛地那非不能改变这一比值，但与 hMSCs 联合使用时可恢复至 0.31±0.01。SuHx 组 RV 后负荷增加，RV 收缩压（mmHg）从 52.1±8.8 升高至治疗后的 29.6±2.2。hMSCs+洛地那非治疗可逆转 SuHx 组的 RV 肥厚、纤维化和间质细胞浸润。洛地那非和 hMSCs 的联合治疗可能是 PAH 治疗的一种策略。
