Inhibition of TBK1 by amlexanox attenuates paraquat-induced acute lung injury.

Abstract

The specific mechanism of paraquat (PQ)-induced acute lung injury (ALI) is unclear, though inflammation is a likely contributor. Amlexanox, a TANK binding kinase 1 (TBK1) inhibitor, is a strong anti-inflammatory drug. We investigated the role of TBK1 and the potential therapeutic effect of amlexanox in the pathogenesis of PQ-induced ALI. After 30 mg/kg PQ treatment for 72 h, mouse lung pathological injury occurred, and the protein concentration in alveolar lavage fluid was increased. Next, RAW264.7 mouse macrophages were treated with 100 μM PQ for 24 h, which decreased cell viability. PQ induced oxidative damage and increased IL-1β, IFNβ, NF-κBp65, IRF3, and pTBK1/TBK1 levels in mouse lungs and RAW264.7 cells. Inhibiting the activation of TBK1 with amlexanox (100 mg/kg in mice and 50 μM in RAW264.7 cells) attenuated mouse lung injury and decreased the protein concentration in alveolar lavage fluid. Further, amlexanox relieved the oxidative damage in mouse lungs and RAW264.7 cells, reduced the levels of inflammatory factors such as IL-1β and IFNβ, and inhibited the activation of NF-κBp65 and IRF3. These results suggest that TBK1 plays a key role in the pathogenesis of PQ-induced ALI. Further, amlexanox treatment alleviates PQ-induced ALI by inhibiting the TBK1-NF-κB/IRF3 signalling pathway. Our study provides evidence that TBK1 inhibition by amlexanox alleviates PQ-induced ALI and may be a new therapeutic strategy.

• Authors: Na Wang, Yuhua Li, Xiaofeng Wang, Zhongliang Ma, Yunwen Wang, Chen Zhang, Yuan Yuan, Min Zhao
• Journal: Toxicology (Toxicology) Vol. 443 Pg. 152555 (10 2020) ISSN: 1879-3185 [Electronic] Ireland
• PMID: 32763286 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier B.V. All rights reserved.

Chemical References

• Aminopyridines
• Anti-Inflammatory Agents
• Herbicides
• IL1B protein, mouse
• Interferon Regulatory Factor-3
• Interleukin-1beta
• Irf3 protein, mouse
• Protein Kinase Inhibitors
• Transcription Factor RelA
• Interferon-beta
• amlexanox
• Tbk1 protein, mouse
• Protein Serine-Threonine Kinases
• Paraquat

Topics

• Acute Lung Injury (chemically induced, drug therapy, genetics, metabolism)
• Aminopyridines (pharmacology, therapeutic use)
• Animals
• Anti-Inflammatory Agents (pharmacology, therapeutic use)
• Bronchoalveolar Lavage Fluid (chemistry)
• Cell Survival (drug effects)
• Herbicides
• Interferon Regulatory Factor-3 (metabolism)
• Interferon-beta (genetics)
• Interleukin-1beta (genetics)
• Male
• Mice
• Mice, Inbred C57BL
• Paraquat
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• RAW 264.7 Cells
• Transcription Factor RelA (metabolism)