Pretreatment with phosphatase and tensin homolog deleted on chromosome 10 (PTEN) inhibitor SF1670 augments the efficacy of granulocyte transfusion in a clinically relevant mouse model
Pretreatment with phosphatase and tensin homolog deleted on chromosome 10 (PTEN) inhibitor SF1670 augments the efficacy of granulocyte transfusion in a clinically relevant mouse model
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DOI：
10.1182/blood-2010-09-309864
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发表时间：
2011-06-16
期刊：
影响因子：
20.3
通讯作者：
Luo, Hongbo R.
中科院分区：
文献类型：
--
作者：
Li, Yitang;Prasad, Amit;Luo, Hongbo R.
粒细胞输注治疗的临床效果常常受到离体保质期短、炎症部位募集效率低以及移植的中性粒细胞杀灭病原体能力差等因素的影响。在这里，使用最近开发的小鼠粒细胞输血模型，我们发现，通过使用 10 号染色体 (PTEN) 抑制剂 SF1670 上缺失的特定磷酸酶和张力蛋白同源物来增强细胞内磷脂酰肌醇 (3,4,5) 三磷酸信号传导，可以显着提高粒细胞输血的功效。用 SF1670 处理的中性粒细胞对化学引诱剂刺激非常敏感。 SF1670 治疗后，中性粒细胞的吞噬作用、氧化爆发、极化和趋化作用等功能得到增强。经过 SF1670 预处理的输注中性粒细胞向发炎的腹膜腔和肺部的募集显着增加。此外，输注 SF1670 处理的中性粒细胞可增强中性粒细胞减少性腹膜炎和细菌性肺炎受体小鼠的杀菌能力（减少细菌负荷）。因此，这减轻了中性粒细胞减少症相关肺炎的严重程度并降低了死亡率。总之，这些观察结果表明，通过使用 PTEN 抑制剂 SF1670 增强输注的中性粒细胞中的磷脂酰肌醇 (3,4,5)-三磷酸，可以增强先天免疫反应并减轻中性粒细胞减少症相关感染的严重程度，从而为提高粒细胞输注功效提供了一种治疗策略。 （血。2011；117(24):6702-6713）
The clinical outcome of granulocyte transfusion therapy is often hampered by short ex vivo shelf life, inefficiency of recruitment to sites of inflammation, and poor pathogen-killing capability of transplanted neutrophils. Here, using a recently developed mouse granulocyte transfusion model, we revealed that the efficacy of granulocyte transfusion can be significantly increased by elevating intracellular phosphatidylinositol (3,4,5)trisphosphate signaling with a specific phosphatase and tensin homolog deleted on chromosome 10 (PTEN) inhibitor SF1670. Neutrophils treated with SF1670 were much sensitive to chemoattractant stimulation. Neutrophil functions, such as phagocytosis, oxidative burst, polarization, and chemotaxis, were augmented after SF1670 treatment. The recruitment of SF1670-pretreated transfused neutrophils to the inflamed peritoneal cavity and lungs was significantly elevated. In addition, transfusion with SF1670-treated neutrophils led to augmented bacteria-killing capability (decreased bacterial burden) in neutropenic recipient mice in both peritonitis and bacterial pneumonia. Consequently, this alleviated the severity of and decreased the mortality of neutropenia-related pneumonia. Together, these observations demonstrate that the innate immune responses can be enhanced and the severity of neutropenia-related infection can be alleviated by augmenting phosphatidylinositol (3,4,5)-trisphosphate in transfused neutrophils with PTEN inhibitor SF1670, providing a therapeutic strategy for improving the efficacy of granulocyte transfusion. (Blood. 2011;117(24):6702-6713)