Berghausen Eva, ten Freyhaus Henrik, Rosenkranz Stephan
Klinik III für Innere Medizin, Herzzentrum der Universität zu Köln, Cologne, Germany.
Handb Exp Pharmacol. 2013;218:381-408. doi: 10.1007/978-3-642-38664-0_16.
Despite recent advances in the management of patients with pulmonary arterial hypertension (PAH), this disease remains a devastating condition with limited survival. While the current therapies primarily target the vasoconstrictor/vasodilator imbalance in the pulmonary circulation, there is currently no cure for PAH, and pulmonary vascular remodeling-representing the underlying cause of the disease-is only modestly affected. Hence, novel therapeutic approaches directly targeting the vascular remodeling process are warranted. Recent studies provided compelling evidence that peptide growth factors, which elicit their signals via receptor tyrosine kinases, are important contributors to the development and progression of PAH. In particular, platelet-derived growth factor (PDGF) is a strong mitogen for pulmonary vascular smooth muscle cells and protects these cells from apoptosis, thus representing an important mediator of pulmonary vascular remodeling. PDGF ligand and receptors are upregulated in PAH, and experimental studies have shown that inhibition of PDGF receptor signaling by pharmacological or genetic approaches prevents the development of PAH in animal models and is even able to reverse pulmonary vascular remodeling once it has been established. Consistently, results from phase II and phase III clinical trials indicate that the tyrosine kinase inhibitor imatinib mesylate, which potently inhibits the PDGF receptor, is effective in improving exercise capacity and pulmonary hemodynamics as add-on therapy in patients with severe PAH (i.e., pulmonary vascular resistance >800 dynes s cm(-5)). Future studies will evaluate the long-term clinical efficacy and safety of imatinib, including patients with less impaired hemodynamics. Based on the current knowledge, targeting of PDGFR signaling is likely to become an anti-proliferative treatment option for patients with PAH and has the potential to at least partially correct the pathology of the disease.
尽管肺动脉高压（PAH）患者的治疗最近取得了进展，但这种疾病仍然是一种具有毁灭性的疾病，生存率有限。虽然目前的治疗主要针对肺循环中的血管收缩剂/血管扩张剂失衡，但目前PAH尚无治愈方法，而作为该疾病根本原因的肺血管重塑仅受到轻微影响。因此，有必要采用直接针对血管重塑过程的新型治疗方法。最近的研究提供了令人信服的证据，表明通过受体酪氨酸激酶发出信号的肽生长因子是PAH发生和发展的重要促成因素。特别是，血小板衍生生长因子（PDGF）是肺血管平滑肌细胞的强有丝分裂原，并保护这些细胞免于凋亡，因此是肺血管重塑的重要介质。PAH中PDGF配体和受体上调，实验研究表明，通过药理学或遗传学方法抑制PDGF受体信号传导可防止动物模型中PAH的发生，并且一旦肺血管重塑形成，甚至能够逆转它。一致地，II期和III期临床试验的结果表明，强力抑制PDGF受体的酪氨酸激酶抑制剂甲磺酸伊马替尼作为重度PAH（即肺血管阻力>800达因·秒·厘米(-5)）患者的附加治疗，在改善运动能力和肺血流动力学方面是有效的。未来的研究将评估伊马替尼的长期临床疗效和安全性，包括血液动力学受损较轻的患者。基于目前的知识，靶向PDGFR信号传导可能成为PAH患者的一种抗增殖治疗选择，并有可能至少部分纠正该疾病的病理状况。
