Targeting formyl peptide receptor 1 by anteiso-C13-surfactin for neutrophil-dominant acute respiratory distress syndrome.

BACKGROUND AND PURPOSE: Acute respiratory distress syndrome (ARDS) is a catastrophic pulmonary inflammatory dysfunction with a high mortality rate. Overwhelming neutrophilic immunity is a key feature in infective or sterile ARDS. Formyl peptide receptor 1 (FPR1) is a crucial damage sensation receptor for phlogistic reactions in initiation and progression of neutrophil-mediated ARDS. However, effective targets for controlling dysregulated neutrophilic inflammatory injuries in ARDS are limited.

EXPERIMENTAL APPROACH: Human neutrophils were used to explore the anti-inflammatory effects of cyclic lipopeptide anteiso-C13-surfactin (IA-1) from marine Bacillus amyloliquefaciens. The lipopolysaccharide-induced ARDS mouse model was used to determine the therapeutic potential of IA-1 in ARDS. Lung tissues were harvested for histology analyses.

KEY RESULTS: Here, we showed that IA-1 inhibited neutrophilic immunity, including respiratory burst, degranulation, and expression of adhesion molecule. IA-1 inhibited the binding of N-formyl peptides to FPR1 in human neutrophils and hFPR1-transfected HEK293 cells. We identified IA-1 was as a competitive FPR1 antagonist and diminished the FPR1-downstream calcium signaling, mitogen-activated protein kinases, and Akt pathways. Furthermore, IA-1 ameliorated inflamed damage of lung tissue by decreasing neutrophil infiltration, reducing elastase release and oxidative stress in endotoxemic mice.

CONCLUSION AND IMPLICATIONS: IA-1 serves as the therapeutics for treating ARDS by inhibiting FPR1-mediated neutrophilic injury.