Evaluation of Sesquiterpene Lactones in a Rat Model of Paraquat-Induced Acute Lung Injury Using Untargeted Metabolomics.

This study investigated the protective effects and potential mechanisms of sesquiterpene lactones from Eupatorium lindleyanum DC. (SLEL) against paraquat (PQ)-induced acute lung injury (ALI). Male Sprague-Dawley rats were randomly assigned to control, model, SLEL (50, 100, or 200 mg/kg), and dexamethasone (5 mg/kg) groups. ALI was induced by intragastric administration of PQ (200 mg/kg), followed 1 h later by daily administration of SLEL or dexamethasone for 3 consecutive days. Lung injury was evaluated by histopathological examination, pulmonary edema assessment, inflammatory cytokine measurement, Western blotting, quantitative real-time PCR, and untargeted metabolomics. SLEL significantly alleviated PQ-induced histopathological damage and pulmonary edema and reduced inflammatory cytokine levels in serum and bronchoalveolar lavage fluid. SLEL also suppressed TLR4/NF-κB signaling and NLRP3 inflammasome activation while modulating Nrf2/HO-1-associated antioxidant responses. Untargeted metabolomics further revealed that SLEL partially reversed PQ-induced metabolic alterations, particularly those associated with nucleotide metabolism. Quantitatively, high-dose SLEL reduced the lung wet-to-dry ratio from 20.45 ± 2.97 to 12.94 ± 1.71 (p < 0.0001) and decreased serum IL-1β levels from 21.59 ± 2.00 to 16.73 ± 0.95 (p = 0.0001). These findings demonstrate that SLEL attenuates PQ-induced ALI through coordinated regulation of inflammatory responses, oxidative stress, and metabolic disturbances.