Potent anti-inflammatory effects of an H2S-releasing naproxen (ATB-346) in a human model of inflammation

Article

关键词: HYDROGEN-SULFIDE;    GASEOUS MEDIATORS;    MECHANISMS;    RESOLUTION;    DYSREGULATION;    NEUTROPHILS;    INFECTION;    CLEARANCE;    TOLERANCE;    THERAPY;   

DOI  :  10.1096/fj.201902918RR

来源: SCIE

【 摘 要 】

ATB-346 is a hydrogen sulfide-releasing non-steroidal anti-inflammatory drug (H2S-NSAID) derived from naproxen, which in preclinical studies has been shown to have markedly reduced gastrointestinal adverse effects. However, its anti-inflammatory properties in humans compared to naproxen are yet to be confirmed. To test this, we used a dermal model of acute inflammation in healthy, human volunteers, triggered by ultraviolet-killed Escherichia coll. This robust model allows quantification of the cardinal signs of inflammation along with cellular and humoral factors accumulating within the inflamed skin. ATB-346 was non-inferior to naproxen in terms of its inhibition of cyclooxygenase activity as well as pain and tenderness. ATB-346 significantly inhibited neutrophil infiltration at the site of inflammation at 4 h, compared to untreated controls. Subjects treated with ATB-346 also experienced significantly reduced pain and tenderness compared to healthy controls. Furthermore, both classical and intermediate monocyte subsets infiltrating the site of inflammation at 48 h expressed significantly lower levels of CD14 compared to untreated controls, demonstrating a shift toward an anti-inflammatory phenotype. Collectively, we have shown for the first time in humans that ATB-346 is potently anti-inflammatory and propose that ATB-346 represents the next generation of H2S-NSAIDs, as a viable alternative to conventional NSAIDs, with reduced adverse effects profile.

【 授权许可】

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