Department of Pulmonary and Critical Medicine, The First Clinical Medical College of Three Gorges University, Yichang Central People’s Hospital, Yi Chang, Hubei 443000, China.
Department of Critical Care Medicine, The First Clinical Medical College of Three Gorges University, Yichang Central People’s Hospital, Yi Chang, Hubei 443000, China.
Aging (Albany NY). 2024 Feb 9;16(3):2978-2988. doi: 10.18632/aging.205527.
Acute lung injury (ALI) is one of the most common high-risk diseases associated with a high mortality rate and is still a challenge to treat effectively. Netrin-1 (NT-1) is a novel peptide with a wide range of biological functions, however, its effects on ALI have not been reported before. In this study, an ALI model was constructed using lipopolysaccharide (LPS) and treated with NT-1. Pulmonary function and lung wet to dry weight ratio (W/D) were detected. The expressions of pro-inflammatory cytokines and chemokines interleukin-8 (IL-8), interleukin-1β (IL-1β), and chemokine (C-X-C motif) ligand 2 (CXCL2) were measured using real-time polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). We found that the levels of NT-1 were reduced in the LPS-induced ALI mice model. Administration of NT-1 improved histopathological changes of lung tissues and lung function in LPS-challenged ALI mice. We also report that NT-1 decreased Myeloperoxidase (MPO) activity and ameliorated pulmonary edema. Additionally, treatment with NT-1 reduced the levels of pro-inflammatory cytokines and chemokines such as IL-8, IL-1β, and CXCL2 in lung tissues of LPS-challenged ALI mice. Importantly, NT-1 reduced cell count in BALF and mitigated oxidative stress (OS) by reducing the levels of MDA and increasing the levels of GSH. Mechanistically, it is shown that NT-1 reduced the levels of Toll-like receptor 4 (TLR4) and prevented nuclear translocation of nuclear factor-κB (NF-κB) p65. Our findings indicate that NT-1 is a promising agent for the treatment of ALI through inhibiting TLR4/NF-κB signaling.
急性肺损伤（ALI）是一种常见的高危疾病，死亡率高，目前仍难以有效治疗。轴突导向因子 Netrin-1（NT-1）是一种具有广泛生物学功能的新型肽，但尚未有关于其对 ALI 作用的报道。在本研究中，我们构建了脂多糖（LPS）诱导的 ALI 模型，并给予 NT-1 进行治疗。检测肺功能和肺湿重/干重比（W/D）。采用实时聚合酶链反应（RT-PCR）和酶联免疫吸附试验（ELISA）检测促炎细胞因子和趋化因子白细胞介素-8（IL-8）、白细胞介素-1β（IL-1β）和趋化因子（C-X-C 基序）配体 2（CXCL2）的表达。结果发现，LPS 诱导的 ALI 小鼠模型中 NT-1 水平降低。给予 NT-1 可改善 LPS 刺激的 ALI 小鼠的肺组织病理变化和肺功能。我们还报告称，NT-1 降低髓过氧化物酶（MPO）活性并改善肺水肿。此外，NT-1 降低了 LPS 刺激的 ALI 小鼠肺组织中促炎细胞因子和趋化因子（如 IL-8、IL-1β 和 CXCL2）的水平。重要的是，NT-1 通过降低 MDA 水平和增加 GSH 水平来减少 BALF 中的细胞计数并减轻氧化应激（OS）。机制上，结果表明 NT-1 通过降低 Toll 样受体 4（TLR4）水平并防止核因子-κB（NF-κB）p65 核转位来减轻 OS。我们的研究结果表明，NT-1 通过抑制 TLR4/NF-κB 信号通路可能成为治疗 ALI 的一种有前途的药物。
