Targeting formyl peptide receptor 1 with anteiso‐C13‐surfactin for neutrophil‐dominant acute respiratory distress syndrome

Abstract

Background and PurposeAcute respiratory distress syndrome (ARDS) is a catastrophic pulmonary inflammatory dysfunction with a high mortality rate. An overwhelming immune response by neutrophils is a key feature in infective or sterile ARDS. The formyl peptide receptor 1 (FPR1) is a crucial damage‐sensing receptor for inflammatory reactions in the initiation and progression of neutrophil‐mediated ARDS. However, effective targets for controlling dysregulated neutrophilic inflammatory injuries in ARDS are limited.Experimental ApproachHuman neutrophils were used to explore the anti‐inflammatory effects of cyclic lipopeptide anteiso‐C13‐surfactin (IA‐1) from marine Bacillus amyloliquefaciens. The lipopolysaccharide‐induced model of ARDS in mice was used to determine the therapeutic potential of IA‐1 in ARDS. Lung tissues were harvested for histology analyses.Key ResultsThe lipopeptide IA‐1 inhibited immune responses of neutrophils, including respiratory burst, degranulation, and expression of adhesion molecules. IA‐1 inhibited the binding of N‐formyl peptides to FPR1 in human neutrophils and in hFPR1‐transfected HEK293 cells. We identified IA‐1 as a competitive FPR1 antagonist, thus diminishing the downstream signalling pathways involving calcium, mitogen‐activated protein kinases and Akt. Furthermore, IA‐1 ameliorated the inflammatory damage to lung tissue, by decreasing neutrophil infiltration, reducing elastase release and oxidative stress in endotoxemic mice.Conclusion and ImplicationsThe lipopeptide IA‐1 could serve as a therapeutic option for ARDS by inhibiting FPR1‐mediated neutrophilic injury.