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.
Highlights
Acute lung injury (ALI) or its more severe form acute respiratory distress syndrome (ARDS) is a spectrum of lung diseases characterized by a severe inflammatory process, resulting in severe hypoxemia, hypercapnia, diffuse infiltration, and poor pulmonary compliance
To determine whether carmofur can directly regulate the activities of cannabinoid receptor 2 (CB2) and peroxisome proliferator-activated receptor-α (PPARα) receptors, we examined its ability to bind to CB2 and PPARα receptors by the receptors’ competitive binding assay
The results suggested that carmofur did not bind to the ligand-binding domain (LBD) of PPARα and CB2 even at a high dose of 20 μM (Figures 1G, H)
Summary
Acute lung injury (ALI) or its more severe form acute respiratory distress syndrome (ARDS) is a spectrum of lung diseases characterized by a severe inflammatory process, resulting in severe hypoxemia, hypercapnia, diffuse infiltration, and poor pulmonary compliance. ALI may lead to multisystem organ failure and is still a life-threatening disease in critically ill patients (Rubenfeld et al, 2005). Patients diagnosed with ALI are often treated with mechanical ventilation during the course of illness. Mechanical ventilation is helpful for resolving life-threatening hypoxia and hypercapnia, clinical and experimental studies have shown that mechanical ventilation, if performed incautiously, will further damage the lungs due to overinflation, varotrauma, as well as cyclic closing. The mechanism of ventilator-associated lung injury may trigger a pulmonary and systemic inflammatory reaction that may further lead to multiple organ dysfunction or multiple system organ failure. Despite considerable progress has been made in understanding the pathogenesis and pathophysiology of ALI, there is still no effective therapeutic strategy for these diseases
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