Butyrolactone I from Aspergillus fungi blocks neutrophil FPR1 to alleviate acute respiratory distress syndrome.

Formyl peptide receptor 1 (FPR1), activated by N-formyl peptides, significantly contributes to neutrophil activation and the development of acute respiratory distress syndrome (ARDS). This study showed that butyrolactone I (BLI), a secondary metabolite of Aspergillus terreus, effectively blocks FPR1 and reduces the severity of ARDS. BLI selectively inhibited superoxide anion production, elastase release, cluster of differentiation molecule 11b (CD11b) expression, and chemotaxis in human neutrophils activated by N-formyl peptides derived from bacteria and mitochondria. The FPR1 receptor-binding and molecular docking assays confirmed that BLI acted as an FPR1 inhibitor. Pharmacological experiments demonstrated that BLI selectively inhibited FPR1 downstream signals in human neutrophils, including calcium mobilization and phosphorylation of protein kinase B (Akt), c-Jun N-terminal kinases (JNK), extracellular regulated protein kinases (ERK), and p38 mitogen-activated protein kinases (p38). In a mouse model of ARDS, treatment with BLI reduced neutrophil infiltration, oxidative damage, and levels of elastase and interleukin-1 beta (IL-1β) in the lungs. The fungal compound BLI could serve as a potential treatment for ARDS by blocking FPR1 and reducing neutrophil-induced injury.