Duan_2023_Lab.Invest__100319

Effective inhibition of macrophage activation is critical for resolving inflammation and restoring pulmonary function in patients with chronic obstructive pulmonary disease (COPD). Here, we identified the dual enhanced cyclooxygenase-2 (COX-2)/soluble epoxide hydrolase (sEH) as a novel regulator of macrophage activation in COPD. Both COX-2 and sEH were found to be increased in patients and mice with COPD, as well as in macrophages exposed to cigarette smoke extract (CSE). Pharmacological reduction of the COX-2 and sEH by PTUPB effectively prevented macrophage activation, down-regulated inflammation-related genes, and reduced lung injury, thereby improving respiratory function in a mouse model of COPD induced by cigarette smoke and lipopolysaccharide. Mechanistically, enhanced COX-2/sEH triggered the activation of the NLRP3 inflammasome, leading to the cleavage of pro-IL-1beta into its active form in macrophages and amplifying inflammatory responses. These findings demonstrate that targeting COX-2/sEH-mediated macrophage activation may be a promising therapeutic strategy for COPD. Importantly, our data support the potential use of the dual COX-2 and sEH inhibitor PTUPB as a therapeutic drug for the treatment of COPD.