Inserm U999, Université Paris XI, Hôpital Marie Lannelongue, Le Plessis-Robinson, France.
J Thorac Cardiovasc Surg. 2010 Sep;140(3):677-83. doi: 10.1016/j.jtcvs.2010.01.004.
In patients with chronic thromboembolic pulmonary hypertension, high flow in unobstructed lung regions may induce small-vessel damage responsible for persistent pulmonary hypertension after pulmonary thromboendarterectomy. In piglets, closure of an experimental aortopulmonary shunt reverses the flow-induced vascular lesions and diminishes the elevated levels of messenger RNA (mRNA) expression for endothelin-1 and endothelin receptor A (ETA). We wanted to study the effect of the ETA antagonist TBC 3711 on reversal of flow-induced pulmonary vascular lesions.
Twenty piglets were studied. In 15 piglets, pulmonary vasculopathy was induced by creating an aortopulmonary shunt. After 5 weeks of shunting, some animals were studied (n = 5); others underwent shunt closure for 1 week with (n = 5) or without (n = 5) TBC3711 treatment. Anti-ETA treatment started 1 week before and ended 1 week after the shunt closure. The controls were sham-operated animals (n = 5).
High blood flow led to medial hypertrophy of the distal pulmonary arteries (54.9% +/- 1.3% vs 35.3% +/- 0.9%; P < .0001) by stimulating smooth muscle cell proliferation (proliferating cell nuclear antigen) and increased the expression of endothelin-1, ETA or endothelin receptor type A or endothelin receptor A, angiopoietin 1, and Tie2 (real-time polymerase chain reaction). One week after shunt closure, gene expression levels were normal and smooth muscle cells showed increased apoptosis (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) without proliferation. However, pulmonary artery wall thickness returned to control values only in the group given TBC3711 (33.2% +/- 8% with and 50.3% +/- 1.3% without; P < .05).
Anti-ETA therapy accelerated the reversal of flow-induced pulmonary arterial disease after flow correction. In patients with chronic thromboembolic pulmonary hypertension and severe distal pulmonary vasculopathy, anti-ETA agents may prove useful for preventing persistent pulmonary hypertension after pulmonary thromboendarterectomy.
在慢性血栓栓塞性肺动脉高压患者中，通畅肺区的高血流可能导致小血管损伤，导致肺血栓内膜剥脱术后持续性肺动脉高压。在小猪中，实验性体肺分流术的关闭可逆转血流诱导的血管病变，并降低内皮素-1 和内皮素受体 A（ETA）信使 RNA（mRNA）表达水平的升高。我们希望研究 ETA 拮抗剂 TBC 3711 对逆转血流诱导的肺血管病变的影响。
研究了 20 头小猪。在 15 头小猪中，通过创建体肺分流术诱导肺血管病。分流 5 周后，对一些动物进行了研究（n = 5）；其他动物进行了分流关闭 1 周，同时（n = 5）或不（n = 5）接受 TBC3711 治疗。ETA 治疗于分流关闭前 1 周开始，并于分流关闭后 1 周结束。对照组为假手术动物（n = 5）。
高血流通过刺激平滑肌细胞增殖（增殖细胞核抗原）导致远端肺动脉的中膜肥厚（54.9%±1.3%比 35.3%±0.9%；P<0.0001），并增加内皮素-1、ETA 或内皮素受体 A 或内皮素受体 A、血管生成素 1 和 Tie2 的表达（实时聚合酶链反应）。分流关闭 1 周后，基因表达水平正常，平滑肌细胞出现凋亡增加（末端脱氧核苷酸转移酶介导的 dUTP 缺口末端标记）而无增殖。然而，只有在给予 TBC3711 的组中，肺动脉壁厚度才恢复到对照值（有和无 TBC3711 分别为 33.2%±8%和 50.3%±1.3%；P<0.05）。
ETA 拮抗剂治疗加速了血流纠正后血流诱导性肺动脉疾病的逆转。在慢性血栓栓塞性肺动脉高压和严重远端肺血管病患者中，ETA 抑制剂可能有助于预防肺血栓内膜剥脱术后持续性肺动脉高压。
