Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, Askerceva 7, SI-1000, Slovenia.
Institute of Biochemistry, Faculty of Medicine, University of Nis, Bulevar Dr Zorana Djindjica 81, 18000 Nis, Serbia.
Pharmacol Ther. 2019 Sep;201:1-7. doi: 10.1016/j.pharmthera.2019.05.007. Epub 2019 May 13.
Pulmonary hypertension (PH) is a progressive disorder characterized by alterations of the vascular structure and function in the lungs. Despite the success in its stabilisation by targeting pulmonary vascular tone and endothelial dysfunction, the prognosis remains poor and new therapeutic approaches via neglected macromolecular targets are needed. In the pathophysiology of PH the early stages of vascular remodelling are considered to be reversible, while endothelial to mesenchymal transition and proliferation/migration of fibroblasts play a critical role in staging the irreversible phase. Dipeptidyl peptidase-4 (DPP-4)/CD26 is present and active in the lungs and is expressed constitutively on lung fibroblasts, on which it exerts proliferative effects. Further, it is a marker of migrating fibroblasts and of their functional activation, including collagen synthesis and inflammatory cytokine secretion. Inhibiting DPP-4 improves the reversible phases of vascular dysfunction in PH, but is also highly likely to attenuate endothelial to mesenchymal transition and decrease the proliferation and migration of fibroblasts, preventing fibrosis and, consequently, should prolong or even inhibit entrance to the potentially irreversible phase of PH. Proposed mechanisms that support the multifaceted aspects of DPP-4 inhibition in terms of improving PH, involve pathways and mediators in pulmonary vascular and connective tissue remodelling. The latter are affected by the inhibition of this protease resulting in the synergistic beneficial antioxidative, anti-inflammatory and antifibrotic effects. We offer here an evidence-supported hypothesis that DPP-4 inhibitors are likely to be effective in the irreversible phase of remodelling in PH. Accordingly, we propose PH as a possible novel therapeutic indication for existing and new DPP-4 inhibitors.
肺动脉高压（PH）是一种进行性疾病，其特征在于肺部血管结构和功能的改变。尽管通过靶向肺血管张力和内皮功能障碍来稳定 PH 取得了成功，但预后仍然很差，需要通过被忽视的大分子靶点来寻求新的治疗方法。在 PH 的病理生理学中，血管重塑的早期阶段被认为是可逆的，而内皮向间质转化和成纤维细胞的增殖/迁移在分期不可逆转阶段中起着关键作用。二肽基肽酶-4（DPP-4）/CD26 存在于肺部并具有活性，并且在肺成纤维细胞上持续表达，在这些细胞上发挥增殖作用。此外，它是迁移成纤维细胞及其功能激活的标志物，包括胶原合成和炎症细胞因子的分泌。抑制 DPP-4 可改善 PH 中血管功能的可逆阶段，但也极有可能减弱内皮向间质转化，减少成纤维细胞的增殖和迁移，从而防止纤维化，因此应延长甚至抑制进入 PH 的潜在不可逆阶段。支持 DPP-4 抑制在改善 PH 方面具有多方面作用的机制，涉及到肺血管和结缔组织重塑中的途径和介质。这些途径和介质受这种蛋白酶抑制的影响，从而产生协同的有益的抗氧化、抗炎和抗纤维化作用。我们在这里提出一个有证据支持的假设，即 DPP-4 抑制剂可能对 PH 中的重塑不可逆转阶段有效。因此，我们提出 PH 作为现有和新的 DPP-4 抑制剂的一种可能的新的治疗适应证。
