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

Acute 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 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 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

Acute 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 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 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

The 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.