Department of Emergency Internal Medicine, Guizhou Provincial People's Hospital, Guiyang City, No. 1 Baoshan South Road, Guiyang City, Guizhou Province, China.
BMC Pulm Med. 2020 Feb 22;20(1):49. doi: 10.1186/s12890-020-1084-3.
Sepsis-induced acute lung injury (ALI) is a clinical syndrome characterized by the injury of alveolar epithelium and pulmonary endothelial cells. This study aimed to investigate the regulation of long noncoding RNA (lncRNA) taurine up-regulated gene 1 (TUG1) in a murine ALI model and in primary murine pulmonary microvascular endothelial cells (PMVECs) stimulated with lipopolysaccharide (LPS).
Adult C57BL/6 mice were intravenously injected with or without TUG1-expressiong adenoviral vector or control vector 1 week before the establishment of ALI model. PMVECs were transfected with TUG1-expressiong or control vectors followed by LPS stimulation. MiR-34b-5p was confirmed as a target of TUG1 using dual-luciferase reporter assay. GRB2 associated binding protein 1 (GAB1) was confirmed as a downstream target of miR-34b-5p using the same method. In the rescue experiment, PMVECs were co-transfected with TUG1-expressing vector and miR-34b-5p mimics (or control mimics) 24 h before LPS treatment.
ALI mice showed reduced levels of TUG1, pulmonary injury, and induced apoptosis and inflammation compared to the control group. The overexpression of TUG1 in ALI mice ameliorated sepsis-induced pulmonary injury, apoptosis and inflammation. TUG1 also showed protective effect in LPS-treated PMVECs. The expression of MiR-34b-5p was negatively correlated with the level of TUG1. TUG1-supressed apoptosis and inflammation in LPS-stimulated PMVECs were restored by miR-34b-5p overexpression. GAB1 was inversely regulated by miR-34b-5p but was positively correlated with TUG1 expression.
TUG1 alleviated sepsis-induced inflammation and apoptosis via targeting miR-34b-5p and GAB1. These findings suggested that TUG1 might be served as a therapeutic potential for the treatment of sepsis-induced ALI.
脓毒症诱导的急性肺损伤（ALI）是一种以肺泡上皮和肺内皮细胞损伤为特征的临床综合征。本研究旨在探讨长链非编码 RNA（lncRNA）牛磺酸上调基因 1（TUG1）在小鼠 ALI 模型中的调控作用，以及在脂多糖（LPS）刺激的原代小鼠肺微血管内皮细胞（PMVECs）中的作用。
成年 C57BL/6 小鼠在建立 ALI 模型前 1 周静脉注射 TUG1 表达腺病毒载体或对照载体。用 TUG1 表达载体或对照载体转染 PMVECs，然后用 LPS 刺激。双荧光素酶报告实验证实 miR-34b-5p 是 TUG1 的靶基因。同样的方法证实 GRB2 相关结合蛋白 1（GAB1）是 miR-34b-5p 的下游靶基因。在挽救实验中，PMVECs 在 LPS 处理前 24 小时共转染 TUG1 表达载体和 miR-34b-5p 模拟物（或对照模拟物）。
与对照组相比，ALI 小鼠的 TUG1 水平降低，肺损伤、诱导的细胞凋亡和炎症减轻。在 ALI 小鼠中过表达 TUG1 可改善脓毒症引起的肺损伤、细胞凋亡和炎症。TUG1 在 LPS 处理的 PMVECs 中也具有保护作用。miR-34b-5p 的表达与 TUG1 水平呈负相关。过表达 miR-34b-5p 可恢复 TUG1 抑制的 LPS 刺激的 PMVECs 中的细胞凋亡和炎症。GAB1 受 miR-34b-5p 负调控，但与 TUG1 表达呈正相关。
TUG1 通过靶向 miR-34b-5p 和 GAB1 缓解脓毒症引起的炎症和凋亡。这些发现表明，TUG1 可能作为治疗脓毒症诱导的 ALI 的潜在治疗靶点。
