Zhang Jingli, Liu Lixia
Department of Pharmacy, Taihe County People's Hospital, Fuyang, Anhui 236600, P.R. China.
Department of Respiration, No. 984 Hospital, Joint Logistics Support Force of Chinese People's Liberation Army, Beijing 100094, P.R. China.
Exp Ther Med. 2021 Dec;22(6):1472. doi: 10.3892/etm.2021.10907. Epub 2021 Oct 22.
It has been reported that dipeptidyl peptidase-4 (DPP4) inhibition protects against acute lung injury (ALI). Anagliptin is a novel selective inhibitor of DPP4 but its role in ALI has not been studied. The present study aimed to investigate the effects of anagliptin on lipopolysaccharide (LPS)-induced human pulmonary microvascular endothelial cell (HPMVEC) injury, as well as its underlying mechanism. HPMVECs were exposed to LPS in the presence or absence of anagliptin co-treatment. MTT assay was used to evaluate cell viability and nitric oxide (NO) production was detected using a commercial kit. DPP4 and pro-inflammatory cytokine expression levels, apoptosis and migration were assessed via reverse transcription-quantitative PCR, western blotting, TUNEL staining and wound healing assay, respectively. Western blot analysis was performed to assess expression levels of proteins involved in NF-κB signaling, cell apoptosis and migration, as well as high mobility group box 1 (HMGB1)/receptor for advanced glycation end products (RAGE). LPS decreased cell viability and NO production, but elevated expression of DPP4 in HPMVECs. LPS promoted pro-inflammatory cytokine expression, NF-κB activation and cell apoptosis, but inhibited cell migration and phosphorylated-AKT/endothelial NO synthase expression. Anagliptin co-treatment significantly restored all of these effects. Mechanistically, the upregulation of HMGB1/RAGE expression induced by LPS was markedly blocked by anagliptin. In conclusion, anagliptin alleviated inflammation, apoptosis and endothelial dysfunction in LPS-induced HPMVECs via modulating HMGB1/RAGE expression. These data provide a basis for use of anagliptin in ALI treatment.
据报道，二肽基肽酶-4（DPP4）抑制可预防急性肺损伤（ALI）。阿格列汀是一种新型的DPP4选择性抑制剂，但其在ALI中的作用尚未得到研究。本研究旨在探讨阿格列汀对脂多糖（LPS）诱导的人肺微血管内皮细胞（HPMVEC）损伤的影响及其潜在机制。将HPMVECs在有或无阿格列汀共同处理的情况下暴露于LPS。采用MTT法评估细胞活力，并使用商用试剂盒检测一氧化氮（NO）的产生。分别通过逆转录定量PCR、蛋白质印迹法、TUNEL染色和伤口愈合试验评估DPP4和促炎细胞因子的表达水平、细胞凋亡和迁移情况。进行蛋白质印迹分析以评估参与NF-κB信号传导、细胞凋亡和迁移的蛋白质以及高迁移率族蛋白B1（HMGB1）/晚期糖基化终产物受体（RAGE）的表达水平。LPS降低了HPMVECs的细胞活力和NO产生，但提高了DPP4的表达。LPS促进促炎细胞因子表达、NF-κB激活和细胞凋亡，但抑制细胞迁移以及磷酸化-AKT/内皮型一氧化氮合酶的表达。阿格列汀共同处理显著恢复了所有这些效应。机制上，LPS诱导的HMGB1/RAGE表达上调被阿格列汀显著阻断。总之，阿格列汀通过调节HMGB1/RAGE表达减轻了LPS诱导的HPMVECs中的炎症、细胞凋亡和内皮功能障碍。这些数据为阿格列汀用于ALI治疗提供了依据。
