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  3. An indoloquinolinone 3a alleviates lipopolysaccharide-induced acute lung injury by modulating the NF-κB and AMPK/Nrf2 signaling pathways

An indoloquinolinone 3a alleviates lipopolysaccharide-induced acute lung injury by modulating the NF-κB and AMPK/Nrf2 signaling pathways

  • Int Immunopharmacol. 2026 Apr 1:174:116398. doi: 10.1016/j.intimp.2026.116398.
Wenyue Tian 1,  Zhiyan Liu 1,  Jiazheng Liu 1,  Lingkai Kong 2,  Hongyan Qin 3,  Guo-Yuan Zhu 4,  Wei Zhang 4,  Jing Jin 5,  Xiaojian Wang 5,  Zhi-Hong Jiang 6,  Li-Ping Bai 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Mechanism and Quality of Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau 999078, China.
  • 2 State Key Laboratory of Mechanism and Quality of Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau 999078, China; School of Chemistry and Chemical Engineering, Linyi University, Linyi, Shandong 276000, China.
  • 3 School of Chinese Medicine, Hong Kong Baptist University, Hong Kong Special Administrative Region of China; School of First Clinical Medicine, Lanzhou University, Lanzhou, China.
  • 4 State Key Laboratory of Mechanism and Quality of Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau 999078, China; Guangdong-Macao Joint Laboratory for Innovative Drug Research on TCM and Natural-Derived Small RNAs, Macau University of Science and Technology, Taipa, Macau 999078, China; Zhuhai M.U.S.T. Science and Technology Research Institute, Hengqin New District, Zhuhai, Guangdong 519031, China.
  • 5 State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050, China.
  • 6 State Key Laboratory of Mechanism and Quality of Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau 999078, China; Guangdong-Macao Joint Laboratory for Innovative Drug Research on TCM and Natural-Derived Small RNAs, Macau University of Science and Technology, Taipa, Macau 999078, China. Electronic address: [email protected].
  • 7 State Key Laboratory of Mechanism and Quality of Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau 999078, China; Guangdong-Macao Joint Laboratory for Innovative Drug Research on TCM and Natural-Derived Small RNAs, Macau University of Science and Technology, Taipa, Macau 999078, China; Zhuhai M.U.S.T. Science and Technology Research Institute, Hengqin New District, Zhuhai, Guangdong 519031, China. Electronic address: [email protected].
PMID: 41698296 DOI: 10.1016/j.intimp.2026.116398
Abstract

Acute lung injury (ALI) is a pulmonary disorder characterized by refractory hypoxemia, with acute respiratory distress syndrome (ARDS) representing the most severe form. In the post-pandemic era, ARDS remains associated with significant morbidity and mortality. Uncontrolled inflammatory responses and oxidative stress are recognized as key pathogenic mechanisms driving ALI. In this study, indoloquinolinone 3a, an indole-fused pirfenidone derivative, was investigated for its protective effect on lipopolysaccharide (LPS)-induced ALI, along with the underlying molecular mechanisms. In vivo, 3a notably attenuated pulmonary histological damage, decreased the lung wet/dry weight ratio and total protein concentration in bronchoalveolar lavage fluid (BALF), upregulated ZO-1 expression, suppressed neutrophil infiltration and myeloperoxidase (MPO) activity, decreased TNF-α, IL-6, IL-1β levels, downregulated cyclooxygenase-2 (COX-2) expression, and reduced PGE2 content in ALI mice. In vitro, 3a markedly inhibited the LPS-stimulated inflammatory response by suppressing the NF-κB signaling pathway in both bone marrow-derived macrophages (BMDMs) and RAW 264.7 cells. Additionally, 3a enhanced anti-oxidant defense capacity in ALI mice by increasing glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) levels, while reducing Reactive Oxygen Species (ROS) and malondialdehyde (MDA) levels. In LPS-stimulated macrophages, 3a also prevented ROS production via AMPK activation and upregulation of Nrf2 and key anti-oxidant Enzymes. Moreover, AMPK inhibition abolished 3a's suppressive effects on LPS-stimulated NF-κB p65 phosphorylation as well as iNOS and COX-2 expression in macrophages. Taken together, indoloquinolinone 3a ameliorated LPS-induced ALI, and the AMPK-mediated NF-κB inhibition and Nrf2 activation in macrophages may be responsible for the anti-inflammatory and anti-oxidant effects of indoloquinolinone 3a on LPS-induced ALI.

Keywords

AMPK/Nrf2 pathway; Acute lung injury; Indoloquinolinone 3a; Inflammation; NF-κB pathway; Oxidative stress.

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