Janus激酶抑制剂促进体外人全血中前列腺素的生物合成:心血管副作用和预防策略的含义。

IF 20.3 1区 医学 Q1 RHEUMATOLOGY
Sabreen Alabbasi, Stefania Tacconelli, Mirjam de Vries, Iva Gunnarsson, Vilija Oke, Marika Kvarnström, Alessandra De Michele, Patrizia Di Gregorio, Paola Patrignani, Helena Idborg, Per-Johan Jakobsson
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引用次数: 0

摘要

目的:Janus激酶抑制剂(JAKis)有效治疗慢性炎症性疾病,但通过未知的机制与心血管副作用相关。本研究旨在探讨JAKis对人全血(WB)中血栓原素(TX)A2生成的影响及其可能的机制。方法:我们评估了4种JAKis-托法替尼、巴西替尼、非格替尼和upadacitinib (0.04-20.0 μM)对健康人凝血WB中TXB2生物合成的影响,作为血小板TXA2生成的标志物。此外,我们评估了这些JAKis在24小时脂多糖(LPS)刺激后对健康人、系统性红斑狼疮(SLE)患者和treatment-naïve轴性脊柱炎(axSpA)患者血清中TXB2生成的影响,作为血小板和白细胞类前列腺素生物合成的标志物。结果:所有JAKis均增加凝血WB的血清TXB2生成,但不呈浓度依赖性。在lps刺激下的WB中,托法替尼(1 μM)显著增加了健康受试者(hs)(42%±33%,n = 17)、SLE患者(57%±39%,n = 12)和axSpA患者(31%±23%,n = 15)的TXB2生成。Baricitinib (1 μM)也能使HSs的TXB2升高(30%±22%,n = 10)。Upadacitinib有增加TXB2的趋势(46%±40%,n = 7),而filgotinib没有(21%±19%,n = 7)。在所有JAKis存在的情况下,阿司匹林(100 μM)几乎完全降低了血清TXB2。结论:血小板中TXA2生物合成的增强(白细胞的少量贡献)可能与JAKis相关的心血管风险增加有关。低剂量阿司匹林可能具有保护作用,值得进一步研究。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Janus kinase inhibitors enhance prostanoid biosynthesis in human whole blood in vitro: implications for cardiovascular side effects and prevention strategies.

Objectives: Janus kinase inhibitors (JAKis) effectively treat chronic inflammatory diseases but are associated with cardiovascular side effects through unknown mechanisms. This study aimed to investigate the impact of JAKis on prothrombotic thromboxane (TX)A2 production in human whole blood (WB) as a possible mechanism.

Methods: We evaluated the effects of 4 JAKis- tofacitinib, baricitinib, filgotinib, and upadacitinib (0.04-20.0 μM)-on TXB2 biosynthesis in clotting WB from healthy subjects, serving as a marker for platelet TXA2 generation. Additionally, we assessed the impact of these JAKis on TXB2 production in WB from healthy subjects, patients with systemic lupus erythematosus (SLE), and treatment-naïve patients with axial spondyloarthritis (axSpA) after 24-hour lipopolysaccharide (LPS) stimulation, as a marker of platelet and leukocyte prostanoid biosynthesis.

Results: All JAKis increased serum TXB2 production in clotting WB, although not in a concentration-dependent manner. In LPS-stimulated WB, tofacitinib (1 μM) significantly increased TXB2 production in healthy subjects (HSs) (42% ± 33%, n = 17), patients with SLE (57% ± 39%, n = 12), and patients with axSpA (31% ± 23%, n = 15). Baricitinib (1 μM) also increased TXB2 in HSs (30% ± 22%, n = 10). Upadacitinib showed a trend towards increased TXB2 (46% ± 40%, n = 7), while filgotinib did not (21% ± 19%, n = 7). Aspirin (100 μM) almost completely reduced serum TXB2 in the presence of all JAKis.

Conclusions: The enhanced biosynthesis of TXA2 in platelets, with a minor contribution from leukocytes, may contribute to the increased cardiovascular risk associated with JAKis. Low-dose aspirin may offer a protective effect, warranting further investigations.

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来源期刊
Annals of the Rheumatic Diseases
Annals of the Rheumatic Diseases 医学-风湿病学
CiteScore
35.00
自引率
9.90%
发文量
3728
审稿时长
1.4 months
期刊介绍: Annals of the Rheumatic Diseases (ARD) is an international peer-reviewed journal covering all aspects of rheumatology, which includes the full spectrum of musculoskeletal conditions, arthritic disease, and connective tissue disorders. ARD publishes basic, clinical, and translational scientific research, including the most important recommendations for the management of various conditions.
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