Lee Jooyeon, Park Jeong-Ran, Lee Hanbyeol, Hong Seok-Ho, Kim Woo Jin, Eickelberg Oliver, Park Sung-Min, Ryu Semin, Cho Sung Joon, Kim Seung-Jin, Yang Se-Ran
Department of Thoracic and Cardiovascular Surgery, Kangwon National University, Chuncheon, Gangwon, South Korea.
Department of Internal Medicine, Kangwon National University, Chuncheon, Gangwon, South Korea.
Lab Anim Res. 2025 May 7;41(1):12. doi: 10.1186/s42826-025-00245-7.
Acute lung injury (ALI), including its most severe form, acute respiratory distress syndrome (ARDS), is a common cause of acute hypoxemic respiratory failure. Although its clinical characteristics have been well characterized, the relevant mechanism remains unclear. An imbalance in autophagy leads to alveolar remodeling and triggers the pathogenesis of ARDS. In this study, we assessed the therapeutic efficacy of the STAT1 inhibitor fludarabine (Fluda) in ALI. C57BL6 mice were exposed to lipopolysaccharide (LPS), and their lung tissues were analyzed via next-generation transcriptome sequencing.
Western blotting revealed that interferon regulatory factor 1 (IRF1) was highly expressed and STAT1 was phosphorylated following LPS exposure. Fluda significantly decreased the protein expression of STAT1/IRF1 and inhibited the alveolar infiltration of neutrophils and macrophages. Nitric oxide (NO), inducible nitric oxide synthase, tumor necrosis factor-α (TNF-α), interferon-γ, and interleukin-6 (IL-6) release was decreased in the lungs of mice and RAW264.7 macrophages following Fluda treatment. In LPS-induced GFP-LC3 transgenic mice treated with Fluda, the counts of LC3-expressing neutrophils and macrophages in bronchoalveolar (BAL) fluid were significantly decreased. Furthermore, Fluda decreased LC3 and p62 protein expression, thereby inhibiting the release of NO, IL-6, and TNF-α in BAL. In RAW264.7 cells, the inhibition of STAT1/IRF1 by Fluda decreased LPS-induced ERK and NF-κB p65 phosphorylation.
The inhibition of STAT1/IRF1 by Fluda plays a pivotal role in modulating dysregulated autophagy by suppressing the MAPK and NF-κB p65 pathways in ALI.
急性肺损伤（ALI），包括其最严重的形式急性呼吸窘迫综合征（ARDS），是急性低氧性呼吸衰竭的常见原因。尽管其临床特征已得到充分描述，但其相关机制仍不清楚。自噬失衡会导致肺泡重塑并引发ARDS的发病机制。在本研究中，我们评估了STAT1抑制剂氟达拉滨（Fluda）对ALI的治疗效果。将C57BL6小鼠暴露于脂多糖（LPS），并通过下一代转录组测序分析其肺组织。
蛋白质印迹分析显示，LPS暴露后干扰素调节因子1（IRF1）高表达且STAT1磷酸化。Fluda显著降低了STAT1/IRF1的蛋白表达，并抑制了中性粒细胞和巨噬细胞的肺泡浸润。氟达拉滨治疗后，小鼠肺组织和RAW264.7巨噬细胞中一氧化氮（NO）、诱导型一氧化氮合酶、肿瘤坏死因子-α（TNF-α）、干扰素-γ和白细胞介素-6（IL-6）的释放减少。在用Fluda治疗的LPS诱导的GFP-LC3转基因小鼠中，支气管肺泡灌洗液（BAL）中表达LC3的中性粒细胞和巨噬细胞数量显著减少。此外，Fluda降低了LC3和p62蛋白表达，从而抑制了BAL中NO、IL-6和TNF-α的释放。在RAW264.7细胞中，Fluda对STAT1/IRF1的抑制降低了LPS诱导的ERK和NF-κB p65磷酸化。
Fluda对STAT1/IRF1的抑制通过抑制ALI中的MAPK和NF-κB p65途径，在调节自噬失调中起关键作用。
