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

• Published in: British journal of pharmacology 2023-08, Vol.180 (16), p.2120-2139
• Main Authors: Yang, Shun‐Chin, Wang, Yi‐Hsuan, Ho, Chiu‐Ming, Tsai, Yung‐Fong, Sung, Ping‐Jyun, Lin, Tony Eight, Hwang, Tsong‐Long
• Format: Article
• Language: English
• Subjects: AKT protein; Animals; ARDS; Calcium signalling; Degranulation; Elastase; Formyl peptides; FPR1; HEK293 Cells; Humans; Immune response; Inflammation; Kinases; Leukocytes (neutrophilic); lipopeptide; Lipopeptides - pharmacology; Lipopolysaccharides; Lungs; marine Bacillus; Mice; Neutrophils; N‐formyl peptides; Oxidative stress; Peptides; Receptors, Formyl Peptide - metabolism; Respiratory burst; Respiratory distress syndrome; Respiratory Distress Syndrome - drug therapy; Signal transduction; Surfactin
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.16073

Background and Purpose 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 Results 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. Conclusion and Implications The lipopeptide IA‐1 could serve as a therapeutic option for ARDS by inhibiting FPR1‐mediated neutrophilic injury. Anteiso‐C13‐surfactin from marine Bacillus amyloliquefaciens inhibits neutrophilic immune responses through blocking FPR1 and attenuates lung inflammatory injury in neutrophil‐dominant ARDS.