GSK3179106 通过靶向 P38 MAPK 改善脂多糖诱导的炎症和急性肺损伤。

IF 5.8 2区 医学 Q1 Medicine Respiratory Research Pub Date : 2024-10-28 DOI:10.1186/s12931-024-03012-9
Bin Zheng, Mengying Li, Enhong Lan, Wenting Ding, Lijiao Gao, Yue Tang, Xinyi Wu, Bing Zhang, Yali Zhang, Xiaona Zhu, Hui Zhang
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引用次数: 0

摘要

急性肺损伤(ALI)是一种严重的急性呼吸道疾病,可导致肺泡-毛细血管屏障破坏和肺水肿、呼吸衰竭及多器官功能障碍综合征。然而,到目前为止,临床上还没有有效的药物。有报道称GSK3179106能缓解肠应激综合征,但GSK3179106对ALI的保护作用尚未阐明。本研究将评估 GSK3179106 对脂多糖(LPS)诱导的炎症和肺损伤的药理活性,并阐明其潜在机制。我们发现,GSK3179106能显著减轻LPS诱导的体内肺损伤,同时抑制炎症细胞的浸润,降低炎症细胞因子的表达。同时,GSK3179106剂量依赖性地降低了LPS诱导的IL-6在巨噬细胞中的蛋白和基因表达。从机理上讲,GSK3179106 可抑制 LPS 诱导的 P38 MAPK 磷酸化。重要的是,研究结果表明 GSK3179106 与 P38 MAPK 之间存在直接的结合。综上所述,我们的研究结果不仅阐明了 GSK3179106 的抗炎活性,还发现了其新的临床适应症。因此,化合物 GSK3179106 可能是治疗急性炎症性疾病的潜在候选药物。
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GSK3179106 ameliorates lipopolysaccharide-induced inflammation and acute lung injury by targeting P38 MAPK.

Acute lung injury (ALI) is a serious acute respiratory disease that can cause alveolar-capillary barrier disruption and pulmonary edema, respiratory failure and multiple organ dysfunction syndrome. However, there is no effective drugs in clinic until now. GSK3179106 has been reported can alleviate intestinal stress syndrome, but the protective effect of GSK3179106 on ALI has not been elucidated. The present study will evaluate the pharmacological activity of GSK3179106 on lipopolysaccharide (LPS)-induced inflammation and lung injury and clarify its underlying mechanism. We found that GSK3179106 significantly attenuated LPS-induced lung injury in vivo, accompanied by inhibited infiltration of inflammatory cells and reduced expression of inflammatory cytokines. Meanwhile, GSK3179106 dose-dependently reduced the LPS-induced IL-6 expression both in protein and gene levels in macrophages. Mechanistically, GSK3179106 could inhibited the phosphorylation of P38 MAPK induced by LPS. Importantly, results showed that there is a direct combination between GSK3179106 and P38 MAPK. Together, our findings not only clarified the anti-inflammatory activity of GSK3179106 but also discovered its new clinical indications. Therefore, compound GSK3179106 may be a potential candidate for the treatment of acute inflammatory diseases.

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来源期刊
Respiratory Research
Respiratory Research RESPIRATORY SYSTEM-
CiteScore
9.70
自引率
1.70%
发文量
314
审稿时长
4-8 weeks
期刊介绍: Respiratory Research publishes high-quality clinical and basic research, review and commentary articles on all aspects of respiratory medicine and related diseases. As the leading fully open access journal in the field, Respiratory Research provides an essential resource for pulmonologists, allergists, immunologists and other physicians, researchers, healthcare workers and medical students with worldwide dissemination of articles resulting in high visibility and generating international discussion. Topics of specific interest include asthma, chronic obstructive pulmonary disease, cystic fibrosis, genetics, infectious diseases, interstitial lung diseases, lung development, lung tumors, occupational and environmental factors, pulmonary circulation, pulmonary pharmacology and therapeutics, respiratory immunology, respiratory physiology, and sleep-related respiratory problems.
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