抑制质子传感器GPR68可以抑制内皮功能障碍和急性肺损伤,这些损伤是由 Staphylococcus aureus 细菌颗粒引起的
Pratap Karki1, Yunbo Ke2, Chen-Ou Zhang1
1Division of Pulmonary and Critical Care, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.
概括
这项研究揭示了G蛋白结合受体68 (GPR68) 中介于由黄金葡萄球菌引起的肺损伤. 一种GPR68抑制剂,OGM-8345,在急性肺损伤 (ALI) 模型中有效降低了炎症和屏障功能障碍.
科学领域:
- 细胞生物学 细胞生物学
- 免疫学 免疫学 免疫学
- 病理生理学 病理生理学
背景情况:
- 医院获得的肺炎和其他肺部细菌感染给公共卫生带来了重大挑战.
- 内皮细胞 (EC) 暴露于热杀死的金黄色葡萄球菌 (HKSA) 可以引发炎症反应,导致急性肺损伤 (ALI).
- G蛋白结合受体68 (GPR68),是一种质子感应受体,在pH值降低时涉及病态细胞反应.
研究的目的:
- 调查GPR68在HKSA引起的EC功能障碍和ALI中的作用.
- 评估GPR68抑制剂OGM-8345在细菌诱导ALI的临床前模型中的治疗潜力.
主要方法:
- 在暴露于HKSA的人类肺部EC中评估了GPR68mRNA水平和活性.
- 在细胞和小鼠模型中使用了选择性GPR68抑制剂 (OGM-8345).
- 测量了EC透性,细胞结合完整性,炎症基因表达和细胞因子分泌.
- 通过内HKSA注射在小鼠中诱导ALI,并评估肺血管泄漏和炎症.
主要成果:
- 在肺部EC中,HKSA增加了GPR68的表达和活性.
- OGM-8345减弱了HKSA诱导的EC透性,保持了细胞结的完整性,并减少了炎症标志物.
- GPR68的激活 (通过Ogerin或酸性介质) 加剧了HKSA诱导的EC功能障碍,而OGM-8345反转了这种情况.
- 在小鼠中,OGM-8345显著降低了HKSA诱导的ALI,血管泄漏和肺炎.
结论:
- GPR68在调解HKSA诱导的肺损伤和内皮细胞功能障碍方面发挥着关键作用.
- GPR68抑制剂OGM-8345在治疗细菌病原体诱导的ALI方面表现出强大的治疗潜力,特别是在组织酸化的情况下.
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