2. Academic Validation
  3. A New Use for an Old Drug: Carmofur Attenuates Lipopolysaccharide (LPS)-Induced Acute Lung Injury via Inhibition of FAAH and NAAA Activities

A New Use for an Old Drug: Carmofur Attenuates Lipopolysaccharide (LPS)-Induced Acute Lung Injury via Inhibition of FAAH and NAAA Activities

  • Front Pharmacol. 2019 Jul 19:10:818. doi: 10.3389/fphar.2019.00818.
Kangni Wu 1,  Yanghui Xiu 2,  Pan Zhou 2 3,  Yan Qiu 2 3,  Yuhang Li 4 5
Affiliations

Affiliations

  • 1 Department of Hematology, The First Affiliated Hospital of Xiamen University, Xiamen, China.
  • 2 Eye Institute & Affiliated Xiamen Eye Center, Xiamen University, Xiamen, China.
  • 3 Institute of Hematology, Medical College of Xiamem University, Xiamen, China.
  • 4 Xiamen Institute of Rare-earth Materials, Haixi Institutes, Chinese Academy of Sciences, Fujian, China.
  • 5 CAS Key Laboratory of Design and Assembly of Functional Nanostructures, and Fujian Provincial Key Laboratory of Nanomaterials, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fujian, China.
PMID: 31379583 DOI: 10.3389/fphar.2019.00818
Abstract

Acute lung injury (ALI), characterized by a severe inflammatory process, is a complex syndrome that can lead to multisystem organ failure. Fatty acid amide hydrolase (FAAH) and N-acylethanolamine acid amidase (NAAA) are two potential therapeutic targets for inflammation-related diseases. Herein, we identified carmofur, a 5-fluorouracil-releasing drug and clinically used as a chemotherapeutic agent, as a dual FAAH and NAAA inhibitor. In Raw264.7 macrophages, carmofur effectively reduced the mRNA expression of pro-inflammatory factors, including IL-1β, IL-6, iNOS, and TNF-α, and down-regulated signaling proteins of the nuclear transcription factor κB (NF-κB) pathway. Furthermore, carmofur significantly ameliorated the inflammatory responses and promoted resolution of pulmonary injury in lipopolysaccharide (LPS)-induced ALI mice. The pharmacological effects of carmofur were partially blocked by peroxisome proliferator-activated receptor-α (PPARα) antagonist MK886 and Cannabinoid Receptor 2 (CB2) antagonist SR144528, indicating that carmofur attenuated LPS-induced ALI in a PPARα- and CB2-dependent mechanism. Our study suggested that carmofur might be a novel therapeutic agent for ALI, and drug repurposing may provide us effective therapeutic strategies for ALI.

Keywords

N-acylethanolamine acid amidase (NAAA); acute lung injury; carmofur; drug repurposing; fatty acid amide hydrolase (FAAH).

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