NEW TREATMENT FOR PULMONAY HYPERTENSION

(1)野百合碱注射后1周和4周，每隔7天向大鼠股肌肉注射编码前列环素合成酶(PGIS)基因的裸质粒。PGIS基因转移增加了肌肉内和血清中6-酮-前列腺素F2-α，前列环素的稳定代谢物。在野百合碱治疗的大鼠中，重复的PGIS基因转移显著降低了肺动脉压，改善了右室肥厚和肺动脉重塑。在正常大鼠中，3%的骨髓来源的单个核细胞(BM-MNCs)在细胞移植后1d聚集在肺内。细胞移植2周后，仅有1%的BM-MNCs在肺内检测到。通过逆转录病毒载体介导的PGIs基因转移，建立了高表达PGIs基因并产生前列环素的BM-MNC系。(4)高表达PGIs基因的BM-MNC移植显著降低了肺动脉高压大鼠的肺动脉压，改善了右室肥厚。

(1)Naked plasmid encoding the prostacyclin synthase (PGIS) gene was injected into the thigh muscle every 7 days from 1 week and 4weeks after monocrotaline injection in rats. PGIS gene transfer increased intramuscular and serum 6-keto-prostaglandin F2-alpha, a stable metabolite of prostacyclin. Repeated PGIS gene transfers significantly reduced pulmonary arterial pressure and ameliorated right ventricular hypertrophy and pulmonary arterial remodeling in monocrotaline-treated rats. Furthermore, survival rate was significantly improved by repeated PGIS gene transfers.(2)In normal rats, 3% of intravenously implanted bone marrow-derived mononuclear cells (BM-MNCs) accumulated in the lung 1 day after cell transplantation. Two weeks after cell transplantation, only 1 % of tranplnted BM-MNCs were detected in the lung. In contrast, the rate of lung distribution of transplanted BM-MNCs were remarkably increased in monocrotalin-induced pulmonary hypertension rats (10% and 6% at days 1 and 14, respectively).(3)We established BM-MNC line, which overexpresses PGIS gene and produces prostacyclin, by using a retroviral vector-mediated gene transfer of PGIS.(4)Transplantation of PGIS-overexpressing BM-MNCs significantly reduced pulmonary arterial pressure and ameliorated right ventricular hypertrophy in monocrotaline-induced pulmonary hypertension rats.