Sphingolipid metabolism contributes to sex dimorphism in COPD pathogenesis

Sex-specific mechanisms in chronic obstructive pulmonary disease (COPD) remain poorly defined. Sphingolipids are bioactive mediators that regulate airway epithelial integrity, inflammation, and bronchial smooth muscle tone, and their dysregulation contributes to airway hyperresponsiveness. We tested whether sphingolipid metabolism is regulated by sex in COPD. Lung tissue and paired plasma from female and male never-smoking controls (NSC), ever-smoking controls (SC), and COPD subjects were analyzed for sphingolipid enzyme expression and metabolite levels. Bronchial rings from mice and human bronchial smooth muscle cells (HBSMCs) were exposed to estradiol or cigarette smoke extract (CSE) ± ceramidase or sphingosine kinase inhibitors. Expression of sphingolipid regulators ASAH1 and ORMDL3 was increased in COPD airways, significantly higher in women, and correlated with airway smooth muscle remodeling. Plasma from females with COPD showed increased sphingosine-1-phosphate (S1P), whereas males exhibited higher ceramide levels. Female mice displayed greater CSE-induced bronchial reactivity, attenuated by sphingosine kinase inhibition. In male-donor HBSMCs, estradiol increased ASAH1, ORMDL3, S1P, and smooth muscle protein expression and enhanced contractility. CSE further augmented molecular responses in estradiol-treated cells but reduced collagen-gel contraction, whereas ceramidase inhibition attenuated estradiol-dependent effects. These findings suggest that estrogen-dependent alterations in sphingolipid metabolism contribute to airway hyperreactivity and remodeling in females with COPD.