Schermuly Ralph Theo, Dony Eva, Ghofrani Hossein Ardeschir, Pullamsetti Soni, Savai Rajkumar, Roth Markus, Sydykov Akylbek, Lai Ying Ju, Weissmann Norbert, Seeger Werner, Grimminger Friedrich
Department of Internal Medicine, Justus-Liebig-University Giessen, Giessen, Germany.
J Clin Invest. 2005 Oct;115(10):2811-21. doi: 10.1172/JCI24838.
Progression of pulmonary hypertension is associated with increased proliferation and migration of pulmonary vascular smooth muscle cells. PDGF is a potent mitogen and involved in this process. We now report that the PDGF receptor antagonist STI571 (imatinib) reversed advanced pulmonary vascular disease in 2 animal models of pulmonary hypertension. In rats with monocrotaline-induced pulmonary hypertension, therapy with daily administration of STI571 was started 28 days after induction of the disease. A 2-week treatment resulted in 100% survival, compared with only 50% in sham-treated rats. The changes in RV pressure, measured continuously by telemetry, and right heart hypertrophy were reversed to near-normal levels. STI571 prevented phosphorylation of the PDGF receptor and suppressed activation of downstream signaling pathways. Similar results were obtained in chronically hypoxic mice, which were treated with STI571 after full establishment of pulmonary hypertension. Moreover, expression of the PDGF receptor was found to be significantly increased in lung tissue from pulmonary arterial hypertension patients compared with healthy donor lung tissue. We conclude that STI571 reverses vascular remodeling and cor pulmonale in severe experimental pulmonary hypertension regardless of the initiating stimulus. This regimen offers a unique novel approach for antire-modeling therapy in progressed pulmonary hypertension.
肺动脉高压的进展与肺血管平滑肌细胞的增殖和迁移增加有关。血小板衍生生长因子（PDGF）是一种有效的促有丝分裂原，并参与这一过程。我们现在报告，PDGF受体拮抗剂STI571（伊马替尼）在两种肺动脉高压动物模型中逆转了晚期肺血管疾病。在使用野百合碱诱导肺动脉高压的大鼠中，在疾病诱导28天后开始每日给予STI571治疗。为期2周的治疗导致100%存活，而假手术治疗的大鼠存活率仅为50%。通过遥测连续测量的右心室压力变化和右心肥大恢复到接近正常水平。STI571可防止PDGF受体磷酸化并抑制下游信号通路的激活。在慢性低氧小鼠中也获得了类似结果，这些小鼠在肺动脉高压完全形成后用STI571进行治疗。此外，与健康供体肺组织相比，发现肺动脉高压患者肺组织中PDGF受体的表达显著增加。我们得出结论，无论起始刺激如何，STI571均可逆转严重实验性肺动脉高压中的血管重塑和肺心病。这种治疗方案为进展性肺动脉高压的抗重塑治疗提供了一种独特的新方法。
