Zolty Ronald
Director Cardiovascular Pulmonary Hypertension Program, University of Nebraska Medical Center, Lied Transplant Center, Omaha, USA.
Expert Opin Drug Discov. 2023 Apr;18(4):445-466. doi: 10.1080/17460441.2023.2192919. Epub 2023 Apr 3.
Distal pulmonary arterial remodeling and elevated pulmonary vascular resistance are characteristic of pulmonary arterial hypertension (PAH). Current approved vasodilator-specific PAH therapy that includes phosphodiesterase-5 inhibitors, soluble guanylate cyclase stimulators, endothelin receptor antagonists, and prostanoids has demonstrated dramatic enhancement in functional capacity, quality of life, and invasive hemodynamics. However, none of these treatments are curative, underscoring the need to identify new pathophysiologic signaling pathways.
The author provides a comprehensive review on current knowledge and recent development in the understanding of PAH. Furthermore, the author discusses PAH potential genetic causes as well as novel molecular signaling pathways. This article also reviews the currently approved PAH specific therapy based on pivotal clinical trials and ongoing clinical trials using novel compounds that specifically target PAH pathogenesis.
The discovery of novel signaling pathways - growth factors, tyrosine kinases, BMPs, estrogen, and serotonin - involved in the PAH pathobiology will lead within the next 5 years to the approval of new therapeutic agents targeting these different pathways. If proven beneficial, these new agents may reverse or at least prevent the progression of this devastating and lethal disease.
远端肺动脉重塑和肺血管阻力升高是肺动脉高压（PAH）的特征。目前获批的用于治疗PAH的血管扩张剂，包括磷酸二酯酶-5抑制剂、可溶性鸟苷酸环化酶刺激剂、内皮素受体拮抗剂和前列腺素，已显示出在功能能力、生活质量和有创血流动力学方面有显著改善。然而，这些治疗方法均无法治愈该疾病，这凸显了识别新的病理生理信号通路的必要性。
作者对目前关于PAH的认识及最新进展进行了全面综述。此外，作者还讨论了PAH潜在的遗传病因以及新的分子信号通路。本文还基于关键临床试验以及使用专门针对PAH发病机制的新型化合物的正在进行的临床试验，对目前获批的PAH特异性治疗进行了综述。
参与PAH病理生物学过程的新信号通路——生长因子、酪氨酸激酶、骨形态发生蛋白、雌激素和5-羟色胺——的发现，将在未来5年内促使针对这些不同通路的新型治疗药物获批。如果证明有益，这些新药可能会逆转或至少阻止这种毁灭性致命疾病的进展。
