Intravenous thrombolysis using recombinant tissue plasminogen activator (tPA) remains the primary treatment for patients with acute ischemic stroke (AIS). However, the mechanism of tPA-related hemorrhagic transformation (HT) remains poorly understood. Elevation of histidine-rich glycoprotein (HRG) expression was detected by nano-liquid chromatography tandem mass spectrometry at 1 h following tPA infusion as compared to baseline prior to tPA infusion (discovery cohort, n = 10), which was subsequently confirmed in a validation cohort (n = 157) by ELISA. Surprisingly, no elevation of HRG was detected in individuals who subsequently developed HT. During in vitro experiments, HRG reduced neutrophil NETosis, inflammatory cytokine production, and migration across the blood-brain barrier induced by tPA. In a photothrombotic murine AIS model, HRG administration ameliorated HT with delayed thrombolysis, by inhibiting neutrophil immune infiltration and downregulating pro-inflammatory signaling pathways. Neutrophil depletion or NETosis inhibition also alleviated HT, whereas HRG siRNA treatment exacerbated HT. In conclusion, fluctuations in HRG levels may reflect tPA therapy and its associated HT. The inhibitory effect of HRG on neutrophils may counteract tPA-induced immune abnormalities and HT in patients with AIS.

中文翻译：

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富含组氨酸的糖蛋白调节中性粒细胞和溶栓相关的出血转化。


使用重组组织纤溶酶原激活剂（tPA）进行静脉溶栓仍然是急性缺血性卒中（AIS）患者的主要治疗方法。然而，tPA 相关的出血转化 (HT) 机制仍知之甚少。与 tPA 输注前的基线相比，在 tPA 输注后 1 小时，通过纳米液相色谱串联质谱法检测到富含组氨酸的糖蛋白 (HRG) 表达升高（发现队列，n = 10），随后在验证中得到证实通过 ELISA 检测队列（n = 157）。令人惊讶的是，在随后发生 HT 的个体中没有检测到 HRG 升高。在体外实验中，HRG 减少了中性粒细胞 NETosis、炎性细胞因子的产生以及 tPA 诱导的穿过血脑屏障的迁移。在光血栓小鼠 AIS 模型中，HRG 通过抑制中性粒细胞免疫浸润和下调促炎信号通路，改善 HT 并延迟溶栓。中性粒细胞耗竭或 NETosis 抑制也能减轻 HT，而 HRG siRNA 治疗则加剧 HT。总之，HRG 水平的波动可能反映了 tPA 治疗及其相关的 HT。 HRG 对中性粒细胞的抑制作用可能会抵消 tPA 诱导的 AIS 患者的免疫异常和 HT。