Emergency Department, The Fourth Sanatorium Area of Hangzhou Special Service Sanatorium Center of Air Force, Nanjing City, Jiangsu Province, China.
Convalescent Department, The Fourth Sanatorium Area of Hangzhou Special Service Sanatorium Center of Air Force, Nanjing City, Jiangsu Province, China.
J Surg Res. 2021 Sep;265:323-332. doi: 10.1016/j.jss.2021.03.006. Epub 2021 May 7.
Nowadays, there is no approved targeted agent for lung injury induced by sepsis. S1PR2 is confirmed to be a promising diagnosis and treatment target. JTE-013 as S1PR2 antagonists may be an agent of great potential. In this research, we sought to determine the functional role of JTE-013 in lung injury induced by sepsis.
Seventy-two rats were assigned into normal group, sepsis model group and JTE-013 group. The animal model of lung injury induced by sepsis was constructed by cecal ligation and puncture. The human pulmonary microvascular endothelial cells (HPMECs) were divided into control, LPS and LPS + JTE-013 group. HPMECs induced by LPS served as the cell model of lung injury induced by sepsis. HE staining assay was performed for assessment of the pathological condition and Evans blue was applied for assessment of pulmonary tissue permeability. Wet/dry ratio was measured as indicators of pulmonary edema degree and neutrophil count was measured as indicators of infection status. The levels of inflammatory factors were detected by corresponding kits, cell survival by CCK-8 assay and protein expression level by western blot.
S1PR2 was highly expressed in vivo model of lung injury induced by sepsis. It was observed that JTE-013 as antagonist of S1PR2 alleviated the lung tissue injury, endothelial dysfunction and pulmonary edema induced by sepsis. In addition, JTE-013 reduced neutrophil count and levels of inflammatory factors. Moreover, results confirmed that JTE-013 enhanced cell viability and mitigated inflammatory response in cell model of sepsis.
Overall, JTE-013 as an antagonist of S1PR2 could relieve inflammatory injury and endothelial dysfunction induced by sepsis in vivo and vitro, resulting in attenuation of lung injury. These findings elucidated that JTE-013 may be a promising targeted agent for lung injury induced by sepsis.
目前，针对脓毒症引起的肺损伤尚无批准的靶向药物。S1PR2 已被证实是一个有前途的诊断和治疗靶点。S1PR2 拮抗剂 JTE-013 可能是一种极具潜力的药物。本研究旨在确定 JTE-013 在脓毒症诱导的肺损伤中的作用。
72 只大鼠随机分为正常组、脓毒症模型组和 JTE-013 组。盲肠结扎穿孔法构建脓毒症肺损伤模型。将人肺微血管内皮细胞（HPMEC）分为对照组、LPS 组和 LPS+JTE-013 组，用 LPS 诱导 HPMEC 建立脓毒症肺损伤细胞模型。HE 染色法评估肺组织病理改变，伊文思蓝法评估肺组织通透性，干湿重法评估肺组织水肿程度，中性粒细胞计数评估感染状态。采用相应试剂盒检测炎症因子水平，CCK-8 法检测细胞存活率，Western blot 法检测蛋白表达水平。
S1PR2 在脓毒症诱导的肺损伤体内模型中高表达。S1PR2 拮抗剂 JTE-013 可减轻脓毒症引起的肺组织损伤、内皮功能障碍和肺水肿。此外，JTE-013 降低了中性粒细胞计数和炎症因子水平。此外，研究结果证实 JTE-013 可增强细胞活力，减轻细胞模型中脓毒症引起的炎症反应。
总之，S1PR2 拮抗剂 JTE-013 可减轻体内和体外脓毒症引起的炎症损伤和内皮功能障碍，从而减轻肺损伤。这些发现表明 JTE-013 可能是一种有前途的脓毒症肺损伤靶向药物。
