Mulberry (Morus alba l.) leaf improves arachidonic acid metabolism disorder in chronic obstructive pulmonary disease

Background: Chronic obstructive pulmonary disease (COPD) cannot be fully assessed in severity using current diagnostic methods and spirometry. Previous studies indicate that arachidonic acid (ARA) metabolic dysregulation is closely linked to inflammation and oxidative stress, yet its association with COPD remains unclear.

Purpose: This study aims to investigate the relationship between ARA metabolism and COPD, as well as the intervention mechanism of mulberry (Morus alba l.) leaves, using functional metabolomics.

Methods: We employed ultra-performance liquid chromatography-tandem mass spectrometry to measure serum ARA and its 11 metabolite concentrations in clinical samples (91 healthy subjects and 191 COPD patients) and in COPD rats. Metabolomic techniques were utilized to screen differential metabolites. Additionally, malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and Glutathione Peroxidase (GSH-Px) levels in serum from both COPD patients and rats were quantified using assay kits. Hematoxylin-eosin staining and ELISA were applied to observe pulmonary morphology and serum levels of interleukin (IL)-10, IL-6, IL-1β, and tumor necrosis factor (TNF)-α in rats, respectively. Real-time polymerase chain reaction was used to measure mRNA expression of cyclooxygenase (COX), Lipoxygenase (LOX), and soluble Epoxide Hydrolase in rat lung.

Results: Five differential metabolites, (±)12-hydroxyeicosa-tetraenoic acid (HETE), 15(S)-HETE, (±)11-HETE, prostaglandin E2 (PGE2), and thromboxane B2 (TXB2), were identified in COPD patients and rats. Among these, (±)12-HETE, 15(S)-HETE, and (±)11-HETE showed significant positive correlations with COPD assessment test scores and negative correlations with eosinophil percentages, with high diagnostic sensitivities and specificities. When combined with aminophylline (APL), mulberry leaf water extract (MLWE) intervention significantly improved pulmonary function parameters in COPD rats, outperforming APL or high-dose MLWE alone. MLWE also reduced interstitial inflammatory cell infiltration, lowered mean linear intercept, downregulated COX-2 and 5/12/15-LOX mRNA expression in lung tissue, decreased serum levels of IL-6, IL-1β, and TNF-α, and elevated IL-10. Furthermore, MLWE enhanced SOD, CAT, and GSH-Px activities while reducing MDA levels, indicating mitigation of oxidative stress.

Conclusions: ARA metabolic dysregulation contributes to COPD pathogenesis, and (±)12-HETE, 15(S)-HETE, and (±)11-HETE may serve as potential biomarkers for COPD. MLWE exert therapeutic effects by modulating ARA metabolism, ameliorating oxidative stress, and suppressing inflammatory responses, offering a novel strategy for COPD prevention and treatment.

Arachidonic acid metabolism; Chronic obstructive pulmonary disease; Functional metabolomics; Mulberry leaf; Ultra-performance liquid chromatography-tandem mass spectrometry.