Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China.
Int J Mol Med. 2018 Apr;41(4):2159-2168. doi: 10.3892/ijmm.2018.3443. Epub 2018 Jan 30.
Acute lung injury (ALI) is a critical illness with a high morbidity and mortality rate due to severe inflammation in the lungs. The effects and underlying mechanism of the triggering receptor expressed on myeloid cells‑1 (TREM‑1)‑like transcript‑1‑derived peptide (LR12) on ALI remain unclear. The aim of the present study was to determine whether LR12 attenuates lipopolysaccharide (LPS)‑induced ALI and elucidate the mechanism underlying it. Male C57BL/6 mice were randomly assigned to three groups as follows: Sham group, LPS + scramble group and LPS + LR12 group. Normal saline (NS) or LPS was administrated by intratracheal instillation, and NS, LR12 or LR12 scramble was administered intraperitoneally 30 min later. The treatment was repeated every 3 h three times. Mice were sacrificed 24 h later. Pulmonary pathological changes, the lung wet/dry weight ratio, the macrophage and neutrophil counts in bronchoalveolar lavage fluid and myeloperoxidase (MPO) activity in the lung tissues were observed. The inflammatory cytokines were evaluated by enzyme‑linked immunosorbent assay and lung neutrophil infiltration was detected by immunohistochemistry. Nuclear factor (NF)‑κB p65 and TREM‑1 were analyzed by western blotting, and the activation of NF‑κB was detected by electrophoretic mobility shift assay. LPS‑induced pathohistological injury, edema and neutrophil infiltration were significantly alleviated by TREM‑1 inhibitor, LR12. The proinflammatory cytokines [interleukin (IL)‑6, IL‑1β, tumor necrosis factor‑α] and chemokines (keratinocyte chemokine and monocyte chemoattractant protein‑1) were significantly reduced, whereas the anti‑inflammatory cytokines, IL‑10 were significantly increased by LR12. LR12 was identified to significantly decrease p65 expression levels in the nucleus and inhibit the activity of NF‑κB. Furthermore, LR12 alleviated LPS‑induced ALI by reducing the expression of TREM‑1, increasing the release of soluble TREM‑1 and inhibiting activation of the NF-κB signaling pathway.
急性肺损伤 (ALI) 是一种严重的肺部炎症导致的高发病率和高死亡率的危重病。触发髓样细胞表达的受体重组蛋白 1 (TREM-1)-样转录物-1 衍生肽 (LR12) 对 ALI 的作用及其潜在机制尚不清楚。本研究旨在确定 LR12 是否减轻脂多糖 (LPS) 诱导的 ALI，并阐明其作用机制。雄性 C57BL/6 小鼠随机分为三组：假手术组、LPS+乱序组和 LPS+LR12 组。通过气管内滴注给予生理盐水 (NS) 或 LPS，30min 后给予 NS、LR12 或 LR12 乱序腹腔内注射。每 3h 重复治疗一次，共 3 次。24h 后处死小鼠。观察肺组织病理变化、肺湿/干重比、支气管肺泡灌洗液中巨噬细胞和中性粒细胞计数以及肺组织髓过氧化物酶 (MPO) 活性。采用酶联免疫吸附试验检测炎性细胞因子，免疫组织化学法检测肺中性粒细胞浸润。Western blot 分析核因子 (NF)-κB p65 和 TREM-1 的表达，电泳迁移率改变试验检测 NF-κB 的激活。TREM-1 抑制剂 LR12 显著减轻 LPS 诱导的组织病理学损伤、水肿和中性粒细胞浸润。促炎细胞因子[白细胞介素 (IL)-6、IL-1β、肿瘤坏死因子-α]和趋化因子(角质形成细胞趋化因子和单核细胞趋化蛋白-1)显著降低，抗炎细胞因子 IL-10 显著增加。LR12 显著降低核内 p65 表达水平并抑制 NF-κB 活性。此外，LR12 通过降低 TREM-1 的表达、增加可溶性 TREM-1 的释放和抑制 NF-κB 信号通路的激活，减轻 LPS 诱导的 ALI。
