Sex-related differences in the response of anti-platelet drug therapies targeting purinergic signaling pathways in sepsis.
Sex-related differences in the response of anti-platelet drug therapies targeting purinergic signaling pathways in sepsis.
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DOI：
10.3389/fimmu.2022.1015577
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发表时间：
2022
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
--
作者：
脓毒症是一种由严重感染引起的复杂临床综合征，是与高死亡率相关的主要卫生保健问题。已经提出了脓毒症免疫反应的性别相关差异，但其机制尚不清楚。嘌呤能信号是免疫细胞生理中一种性别特异性调控机制。我们的研究表明，在脓毒症期间，阻断adp受体P2Y12而非P2Y1受体对雄性小鼠有保护作用，但对雌性小鼠没有保护作用。我们现在假设在脓毒症期间P2Y12或P2Y1信号通路的调节存在性别相关差异。雄性和雌性野生型（WT）、P2Y12敲除（KO）和P2Y1 KO小鼠接受假手术或盲肠结扎穿刺（CLP）诱导脓毒症。脓毒症雄性和雌性小鼠术后腹腔注射P2Y12拮抗剂替格瑞洛或P2Y1拮抗剂MRS2279。术后24小时采集血液、肺和肾。用流式细胞术检测败血症诱导的血小板活化、分泌及血小板与免疫细胞相互作用的变化。用髓过氧化物酶（MPO）比色测定试剂盒测定肺和肾中性粒细胞浸润。与与之对应的CLP WT相比，雄性CLP P2Y12 KO和雌性CLP P2Y1 KO小鼠败血症诱导的血小板活化、分泌和聚集形成减少。脓毒症诱导的MPO活性在雄性CLP P2Y12 KO和雌性CLP P2Y1 KO小鼠中降低。与未治疗的CLP雄性小鼠相比，经替格瑞洛或MRS2279治疗的CLP雄性小鼠显示肺和肾脏败血症诱导的MPO水平、聚集形成和血小板活化降低。雌性CLP小鼠与替格瑞洛或MRS2279治疗的雌性CLP小鼠在肺和肾脏的血小板活化、聚集形成和中性粒细胞浸润方面没有差异。在人类T淋巴细胞中，阻断P2Y1或P2Y12在体外以性别依赖的方式改变细胞生长和分泌，支持在小鼠中获得的数据。总之，靶向嘌呤能信号是一种很有前景的脓毒症治疗方法，但药物靶向嘌呤能信号是性别特异性的，需要研究以确定脓毒症中与性别相关的靶向治疗方法。
Sepsis, a complex clinical syndrome resulting from a serious infection, is a major healthcare problem associated with high mortality. Sex-related differences in the immune response to sepsis have been proposed but the mechanism is still unknown. Purinergic signaling is a sex-specific regulatory mechanism in immune cell physiology. Our studies have shown that blocking the ADP-receptor P2Y12 but not P2Y1 receptor was protective in male mice during sepsis, but not female. We now hypothesize that there are sex-related differences in modulating P2Y12 or P2Y1 signaling pathways during sepsis. Male and female wild-type (WT), P2Y12 knock-out (KO), and P2Y1 KO mice underwent sham surgery or cecal ligation and puncture (CLP) to induce sepsis. The P2Y12 antagonist ticagrelor or the P2Y1 antagonist MRS2279 were administered intra-peritoneally after surgery to septic male and female mice. Blood, lungs and kidneys were collected 24 hours post-surgery. Sepsis-induced changes in platelet activation, secretion and platelet interaction with immune cells were measured by flow cytometry. Neutrophil infiltration in the lung and kidney was determined by a myeloperoxidase (MPO) colorimetric assay kit. Sepsis-induced platelet activation, secretion and aggregate formation were reduced in male CLP P2Y12 KO and in female CLP P2Y1 KO mice compared with their CLP WT counterpart. Sepsis-induced MPO activity was reduced in male CLP P2Y12 KO and CLP P2Y1 KO female mice. CLP males treated with ticagrelor or MRS2279 showed a decrease in sepsis-induced MPO levels in lung and kidneys, aggregate formation, and platelet activation as compared to untreated male CLP mice. There were no differences in platelet activation, aggregate formation, and neutrophil infiltration in lung and kidney between female CLP mice and female CLP mice treated with ticagrelor or MRS2279. In human T lymphocytes, blocking P2Y1 or P2Y12 alters cell growth and secretion in vitro in a sex-dependent manner, supporting the data obtained in mice. In conclusion, targeting purinergic signaling represents a promising therapy for sepsis but drug targeting purinergic signaling is sex-specific and needs to be investigated to determine sex-related targeted therapies in sepsis.
影响因子：
3.7
作者：
Liverani E;Mondrinos MJ;Sun S;Kunapuli SP;Kilpatrick LE
通讯作者：
Kilpatrick LE
DOI：
10.1085/jgp.201611676
发表时间：
2016-09
期刊：
The Journal of general physiology
影响因子：
--
作者：
Björkgren I;Lishko PV
通讯作者：
Lishko PV