Marine Surfactin Modulates Neutrophilic Inflammation in ARDS via FPR1 Inhibition

Acute Respiratory Distress Syndrome (ARDS) is a severe pulmonary condition with a high mortality rate. It is caused by lung injuries, such as pneumonia or aspiration, and indirect lung injuries, including sepsis, severe trauma, or transfusion-related acute lung injury. It is a significant challenge in critical care medicine and finding a treatment has been a focal point of research with the aim is to discover pharmacological treatment that can inhibit inflammation, improve lung function, and prevent secondary infections. Despite numerous clinical trials, few drugs have shown a clear benefit in reducing mortality.  To this account, a new study published in British Journal of Pharmacology and led by Professor Tsong-Long Hwang from Chang Gung University of Science and Technology in Taiwan and conducted by Shun-Chin Yang, Yi-Hsuan Wang, Chiu-Ming Ho, Yung-Fong Tsai, Ping-Jyun Sung, and Tony Eight Lin, the researchers explored the therapeutic potential of anteiso-C13-surfactin (IA-1), a cyclic lipopeptide derived from marine bacterium Bacillus amyloliquefaciens, in the treatment of ARDS. They also investigated the anti-inflammatory mechanisms of IA-1, and it’s targeting the formyl peptide receptor 1 (FPR1) pathway in neutrophils, which is a critical mediator of inflammatory responses and plays a central role in the pathogenesis of ARDS by increased neutrophilic inflammation and tissue damage.

Initially, the research team isolated IA-1 from Bacillus amyloliquefaciens using bioactivity-directed fractionation and isolation techniques. They employed chromatography and spectroscopy (including mass spectrometry and nuclear magnetic resonance) for structural elucidation which identified IA-1 as a cyclic lipopeptide with anti-inflammatory properties. The authors found that IA-1 significantly inhibited respiratory burst, degranulation, and CD11b expression in neutrophils stimulated with FPR1 agonists, highlighting its ability to dampen neutrophil-mediated inflammatory responses by interfering with FPR1 activation. The study employed competitive binding assays using FPR1 agonists and a fluorescently labeled analogue of fMLP, alongside transfection experiments in HEK293 cells expressing human FPR1, to investigate IA-1’s interaction with FPR1. Additionally, intracellular calcium mobilization and the activation of downstream signaling pathways (MAP kinases and Akt) were assessed. IA-1 acted as a competitive antagonist to FPR1, effectively inhibiting the binding of FPR1 agonists to the receptor and subsequently attenuating downstream signaling events that lead to neutrophil activation.

The researchers used the lipopolysaccharide (LPS)-induced ARDS mouse model to assess the therapeutic potential of IA-1 in vivo and examined the effects of IA-1 on neutrophil infiltration, lung tissue damage, oxidative stress, and cytokine production in the lungs of LPS-treated mice. They found that in IA-1 treated mice has significant reduction in lung tissue damage, neutrophil infiltration and oxidative stress, and decreased levels of pro-inflammatory cytokines in the lungs. These in vivo results confirmed the in vitro findings, and showed the therapeutic potential of IA-1 in ARDS by modulating neutrophilic inflammation through FPR1 inhibition.

Overall, marine bacteria are a largely untapped reservoir of bioactive compounds with potential for therapeutic drug development and the research work by Professor Hwang and colleagues highlighted the power of marine natural products in drug discovery, particularly in inflammatory diseases where conventional treatments fall short and a significant step forward in the search for novel ARDS therapeutics. They demonstrated successfully the therapeutic promise of marine-derived compounds, particularly in modulating neutrophilic inflammation via FPR1 inhibition lipopeptides and the need for further clinical investigation to advance the therapeutic potential of IA-1 in ARDS and potentially other inflammatory conditions.