激活的TAFI促进了慢性血栓栓塞性肺动脉高压的发展：一种可能的新治疗靶点。
文献 Activated TAFI Promotes the Development of Chronic Thromboembolic Pulmonary Hypertension: A Possible Novel Therapeutic Target 于 2017年 发表在 Circulation Research 原文链接
Abstract
RATIONALE:
Pulmonary hypertension is a fatal disease; however, its pathogenesis still remains to be elucidated. Thrombin-activatable fibrinolysis inhibitor (TAFI) is synthesized by the liver and inhibits fibrinolysis. Plasma TAFI levels are significantly increased in chronic thromboembolic pulmonary hypertension (CTEPH) patients.
OBJECTIVE:
To determine the role of activated TAFI (TAFIa) in the development of CTEPH.
METHODS AND RESULTS:
Immunostaining showed that TAFI and its binding partner thrombomodulin (TM) were highly expressed in the pulmonary arteries (PAs) and thrombus in patients with CTEPH. Moreover, plasma levels of TAFIa were increased 10-fold in CTEPH patients compared with controls. In mice, chronic hypoxia caused a 25-fold increase in plasma levels of TAFIa with increased plasma levels of thrombin and TM, which led to thrombus formation in PA, vascular remodeling, and pulmonary hypertension. Consistently, plasma clot lysis time was positively correlated with plasma TAFIa levels in mice. Additionally, overexpression of TAFIa caused organized thrombus with multiple obstruction of PA flow and reduced survival rate under hypoxia in mice. Bone marrow transplantation showed that circulating plasma TAFI from the liver, not in the bone marrow, was activated locally in PA endothelial cells through interactions with thrombin and TM. Mechanistic experiments demonstrated that TAFIa increased PA endothelial permeability, smooth muscle cell proliferation, and monocyte/macrophage activation. Importantly, TAFIa inhibitor and peroxisome proliferator-activated receptor-α agonists significantly reduced TAFIa and ameliorated animal models of pulmonary hypertension in mice and rats.
CONCLUSIONS:
These results indicate that TAFIa could be a novel biomarker and realistic therapeutic target of CTEPH.
摘要
基本原理：
肺动脉高压是一种致命的疾病，然而它的发病机理仍有待阐明。凝血活化纤溶抑制因子（TAFI）是由肝脏合成的，可抑制纤维蛋白溶解。在慢性血栓栓塞性肺动脉高压（CTEPH）患者的血浆中，TAFI水平显著增加。
目的：
确定激活的TAFI（TAFIa）在慢性血栓栓塞性肺动脉高压发展中的作用。
方法和结果：
免疫染色结果表明，TAFI和它的结合蛋白凝血素（TM）在慢性血栓栓塞性肺动脉高压患者的肺动脉（PAs）和血栓中高表达。此外，与对照组相比，慢性血栓栓塞性肺动脉高压患者的血浆中，TAFIa表达水平增加了10倍。在小鼠中，慢性缺氧使TAFIa在血浆中的表达水平增加了25倍，凝血酶和凝血素血浆水平也升高了，导致了肺动脉的血栓形成、血管重建和肺动脉高压。与此一致的，小鼠中，血浆凝块溶解时间与血浆中TAFIa的水平呈正相关。此外，在小鼠缺氧的情况下，过表达TAFIa导致了组织血栓，伴随着肺动脉血液流动的多重阻碍，降低了存活率。骨髓移植显示，来源于肝，而不是骨髓中的循环血浆TAFI通过与凝血酶和凝血素的相互作用能在肺动脉内皮细胞中被局部激活。机制实验表明，TAFIa增强了肺动脉内皮的渗透性，平滑肌细胞的增殖，以及单核细胞/巨噬细胞的激活。重要的是，在小鼠和大鼠中，TAFIa抑制剂和过氧化物酶增生物激活受体α激动剂显著减少了TAFIa，并改善了肺动脉高压动物模型。
结论:
这些结果表明，TAFIa可能是慢性血栓栓塞性肺动脉高压的一个新生物标志物和治疗靶标。
使用试剂原文信息：Thrombin-antithrombin complex (TAT) and D-dimer were quantified by commercially available ELISA kits (USCN Life Science).