Emergency Observation Ward, The First People's Hospital of Lianyungang, Lianyungang, Jiangsu 222002, P.R. China.
Emergency Medicine Department, The First People's Hospital of Lianyungang; 3Emergency Medicine Department, The First Affiliated Hospital of Kangda College of Nanjing Medical University, Lianyungang, Jiangsu 222002, P.R. China.
Mol Med Rep. 2021 Dec;24(6). doi: 10.3892/mmr.2021.12473. Epub 2021 Sep 30.
Acute lung injury (ALI) is a respiratory tract disease characterized by increased alveolar/capillary permeability, lung inflammation and structural damage to lung tissues, which can progress and transform into acute respiratory distress syndrome (ARDS). Although there are several treatment strategies available to manage this condition, there is still no specific cure for ALI. Aldo‑keto reductase family 1 member C1 (AKR1C1) is a member of the aldo‑keto reductase superfamily, and is a well‑known Nrf2 target gene and an oxidative stress gene. The aim of the present study was to investigate the effects of AKR1C1 on a lipopolysaccharide (LPS)‑induced ALI model. After mice received LPS treatment, the mRNA expression levels of AKR1C1 in the bronchoalveolar lavage fluid and serum were measured using reverse transcription‑quantitative PCR and its relationship with the inflammatory factors and malondialdehyde levels were determined using correlation analysis. Next, AKR1C1 was overexpressed or knocked out in mice, and subsequently ALI was induced in mice using LPS. The severity of ALI, oxidative stress and inflammation in the lungs were measured, and the potential involvement of the Janus kinase 2 (JAK2)/signal transduction activator of transcription 3 (STAT3) signaling pathway was assessed by measuring the changes of lung injury parameters after the agonists of JAK2/STAT3 pathway, including interleukin (IL)‑6 and colivelin, were administrated to mice. The results revealed that AKR1C1 expression was decreased in the LPS‑induced ALI mouse model. AKR1C1 expression was inversely correlated with serum tumor necrosis factor‑α, IL‑6 and malondialdehyde levels, and positively correlated with serum IL‑10 levels. AKR1C1 overexpression significantly attenuated lung injury, as shown by the changes in Evans blue leakage in the lung, lung wet/dry weight ratio, PaO/FIO ratio, survival rate of mice and histological lung changes. In addition, the JAK2/STAT3 signaling pathway was significantly deactivated by AKR1C1. When AKR1C1 mice were treated with JAK2/STAT3 agonists, the effects of AKR1C1 overexpression on lung injury and oxidative stress were abolished. In conclusion, AKR1C1 may protect against oxidative stress and serve as a negative regulator of inflammation in ALI/ARDS. In addition, the JAK2/STAT3 signaling pathway could participate in the protective effects of AKR1C1 against ALI.
急性肺损伤（ALI）是一种以肺泡/毛细血管通透性增加、肺部炎症和肺组织结构损伤为特征的呼吸道疾病，可进展并转化为急性呼吸窘迫综合征（ARDS）。尽管有几种治疗策略可用于治疗这种疾病，但仍没有针对 ALI 的特定治疗方法。醛酮还原酶家族 1 成员 C1（AKR1C1）是醛酮还原酶超家族的成员，是众所周知的 Nrf2 靶基因和氧化应激基因。本研究旨在探讨 AKR1C1 对脂多糖（LPS）诱导的 ALI 模型的影响。用 LPS 处理小鼠后，通过逆转录-定量 PCR 测定支气管肺泡灌洗液和血清中 AKR1C1 的 mRNA 表达水平，并通过相关性分析确定其与炎症因子和丙二醛水平的关系。接下来，在小鼠中过表达或敲除 AKR1C1，然后用 LPS 诱导小鼠发生 ALI。测量肺损伤参数的严重程度，通过测量 JAK2/STAT3 信号通路激动剂（包括白细胞介素（IL）-6 和 colivelin）给药后肺损伤参数的变化，评估 JAK2/STAT3 信号通路的潜在参与。结果表明，在 LPS 诱导的 ALI 小鼠模型中 AKR1C1 的表达降低。AKR1C1 的表达与血清肿瘤坏死因子-α、IL-6 和丙二醛水平呈负相关，与血清 IL-10 水平呈正相关。AKR1C1 的过表达显著减轻了肺损伤，如肺中 Evans 蓝漏出、肺湿/干重比、PaO/FIO 比、小鼠存活率和组织学肺变化的变化所示。此外，AKR1C1 显著抑制 JAK2/STAT3 信号通路。当 AKR1C1 小鼠用 JAK2/STAT3 激动剂治疗时，AKR1C1 过表达对肺损伤和氧化应激的影响被消除。总之，AKR1C1 可能通过抑制炎症发挥保护作用，是 ALI/ARDS 中氧化应激的负调节剂。此外，JAK2/STAT3 信号通路可能参与 AKR1C1 对 ALI 的保护作用。
