Aspirin Inhibits the Inflammatory Response of Protease-Activated Receptor 1 in Pregnancy Neutrophils: Implications for Treating Women with Preeclampsia.
Aspirin Inhibits the Inflammatory Response of Protease-Activated Receptor 1 in Pregnancy Neutrophils: Implications for Treating Women with Preeclampsia.
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DOI：
10.3390/ijms232113218
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发表时间：
2022-10-30
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
作者：
表达环氧化酶-2 （COX-2）的中性粒细胞广泛浸润子痫前期母体血管，与血管炎症相关。由于妊娠中性粒细胞也表达蛋白酶激活受体1 （PAR-1， F2R凝血酶受体），而非妊娠受试者不表达，因此它们可以被蛋白酶激活。我们测试了阿司匹林的剂量足以抑制COX-2会减少子痫前期中性粒细胞的炎症反应的假设。中性粒细胞从妊娠30周左右的正常孕妇和子痫前期妇女中分离出来。正常妊娠中性粒细胞用弹性酶（一种在子痫前期升高的蛋白酶）或弹性酶加阿司匹林抑制COX-2，或弹性酶加蒎烷血栓素（一种血栓素的生物活性结构类似物和凝血素合成酶抑制剂）处理。用相同剂量的阿司匹林或蒎烷血栓素治疗子痫前期妊娠中性粒细胞。采用免疫荧光共聚焦显微镜检测核因子κB (NF-κB) p65亚基的细胞定位，并测定血栓素浓度评价炎症反应。在未处理的正常孕妇中性粒细胞中，p65定位于细胞质。在弹性酶刺激下，p65从细胞质转移到细胞核，同时增加了血栓素的产生。当中性粒细胞与阿司匹林或蒎烷血栓素共同处理时，弹性蛋白酶不能引起p65的核易位或增加血栓素。在未经治疗的子痫前期女性中性粒细胞中，p65亚基存在于细胞核中，血栓素的产生升高，但当子痫前期中性粒细胞接受阿司匹林或蒎烷血栓素治疗时，p65从细胞核中清除并返回细胞质，同时血栓素的产生减少。这些发现表明COX-2是PAR-1的下游介质，并表明阿司匹林可以抑制PAR-1介导的炎症。鉴于PAR-1和COX-2在子痫前期女性中广泛且普遍表达，应考虑使用足以抑制COX-2的阿司匹林剂量治疗子痫前期女性。
Neutrophils expressing cyclooxygenase-2 (COX-2) extensively infiltrate maternal blood vessels in preeclampsia, associated with vascular inflammation. Because pregnancy neutrophils also express protease-activated receptor 1 (PAR-1, F2R thrombin receptor), which they do not in non-pregnant subjects, they can be activated by proteases. We tested the hypothesis that aspirin at a dose sufficient to inhibit COX-2 would reduce inflammatory responses in preeclampsia neutrophils. Neutrophils were isolated from normal pregnant and preeclamptic women at approximately 30 weeks’ gestation. Normal pregnancy neutrophils were treated with elastase, a protease elevated in preeclampsia, or elastase plus aspirin to inhibit COX-2, or elastase plus pinane thromboxane, a biologically active structural analog of thromboxane and a thromboxane synthase inhibitor. Preeclamptic pregnancy neutrophils were treated with the same doses of aspirin or pinane thromboxane. Confocal microscopy with immunofluorescence staining was used to determine the cellular localization of the p65 subunit of nuclear factor-kappa B (NF-κB) and media concentrations of thromboxane were measured to evaluate the inflammatory response. In untreated neutrophils of normal pregnant women, p65 was localized to the cytosol. Upon stimulation with elastase, p65 translocated from the cytosol to the nucleus coincident with increased thromboxane production. When neutrophils were co-treated with aspirin or pinane thromboxane, elastase was not able to cause nuclear translocation of p65 or increase thromboxane. In untreated neutrophils of preeclamptic women, the p65 subunit was present in the nucleus and thromboxane production was elevated, but when preeclamptic neutrophils were treated with aspirin or pinane thromboxane, p65 was cleared from the nucleus and returned to the cytosol along with decreased thromboxane production. These findings suggest that COX-2 is a downstream mediator of PAR-1 and demonstrate that PAR-1- mediated inflammation can be inhibited by aspirin. Given the extensive and ubiquitous expression of PAR-1 and COX-2 in preeclamptic women, consideration should be given to treating women with preeclampsia using a dose of aspirin sufficient to inhibit COX-2.
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影响因子：
7.3
作者：
Even-Ram, SC;Grisaru-Granovsky, S;Bar-Shavit, R
通讯作者：
Bar-Shavit, R
DOI：
10.1161/hypertensionaha.111.176602
发表时间：
2011-11
期刊：
Hypertension (Dallas, Tex. : 1979)
影响因子：
--
作者：
Mishra N;Nugent WH;Mahavadi S;Walsh SW
通讯作者：
Walsh SW
影响因子：
6
作者：
Lockwood, Charles J.;Toti, Paolo;Schatz, Frederick
通讯作者：
Schatz, Frederick
影响因子：
11.2
作者：
Goerge, Tobias;Barg, Alexej;Schneider, Stefan W.
通讯作者：
Schneider, Stefan W.
影响因子：
2
作者：
Nagelschmitz, J.;Blunck, M.;Hohlfeld, T.
通讯作者：
Hohlfeld, T.