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Butyrolactone I from Aspergillus fungi blocks neutrophil FPR1 to alleviate acute respiratory distress syndrome
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DOI：10.1016/j.bcp.2025.117348.png)
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Abstract
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Formyl peptide receptor 1 (FPR1), activated by N-formyl peptides, significantly contributes to neutrophil activation and the development of acute respiratory distress syndrome (ARDS). This study showed that butyrolactone I (BLI), a secondary metabolite of Aspergillus terreus, effectively blocks FPR1 and reduces the severity of ARDS. BLI selectively inhibited superoxide anion production, elastase release, cluster of differentiation molecule 11b (CD11b) expression, and chemotaxis in human neutrophils activated by N-formyl peptides derived from bacteria and mitochondria. The FPR1 receptor-binding and molecular docking assays confirmed that BLI acted as an FPR1 inhibitor. Pharmacological experiments demonstrated that BLI selectively inhibited FPR1 downstream signals in human neutrophils, including calcium mobilization and phosphorylation of protein kinase B (Akt), c-Jun N-terminal kinases (JNK), extracellular regulated protein kinases (ERK), and p38 mitogen-activated protein kinases (p38). In a mouse model of ARDS, treatment with BLI reduced neutrophil infiltration, oxidative damage, and levels of elastase and interleukin-1 beta (IL-1β) in the lungs. The fungal compound BLI could serve as a potential treatment for ARDS by blocking FPR1 and reducing neutrophil-induced injury.
Keywords:
Acute respiratory distress syndrome
Aspergillus terreus
butyrolactone I
Formyl peptide receptor
Neutrophil
4-HNE
4-Hydroxynonenal
ABTS
2,2-Azinobis-(3-ethylbenzothiazoline-6-sulfonate
Akt
Protein kinase B
ARDS
Acute respiratory distress syndrome
BLI
Butyrolactone I
cAMP
Cyclic adenosine monophosphate
CB
Cytochalasin B
CD11b
Cluster of differentiation molecule 11b
CD66b
Cluster of differentiation 66
CDKs
Cyclin-dependent kinases
COVID-19
Coronavirus disease 2019
DMSO
Dimethyl sulfoxide
DPPH
1,1-Diphenyl-2-picrylhydrazyl
ERK
Extracellular signal-regulated kinase
FBS
Fetal bovine serum
fMLF
N-Formyl-methionyl-leucyl-phenylalanine
fMMYALF
N-Formyl-Met-Met-Tyr-Ala-Leu-Phe
FNLFNYK
N-Formyl-Nle-Leu-Phe-Nle-Tyr-Lys-fluorescein
FPRs
Formyl-peptide receptors
FPR1
Formyl peptide receptor 1
FRP2
Formyl peptide receptor 2
GPCRs
G protein-coupled receptors
HBSS
Hank’s balanced salt solution
HE
Hematoxylin and eosin
HEK-293
Human embryonic kidney cells
IHC
Immunohistochemical
IL-1β
Interleukin-1 beta
IL-8
Interleukine-8
JNK
c-Jun N-terminal kinases
LDH
Lactate dehydrogenase
LPS
Lipopolysaccharide
LTB4
leukotriene B4
Ly6G
Lymphocyte antigen 6 family member G
MPO
Myeloperoxidase
NADPH
Nicotinamide adenine dinucleotide phosphate
NaF
Sodium fluoride
NET
Neutrophil extracellular trap
p38
p38 mitogen-activated protein kinase
PMA
Phorbol 12-myristate 13-acetate
ROS
Reactive oxygen species
RNS
Reactive nitrogen species
THP-1
Human monocytic leukemia cells
Tween 20
Sorbitan monolaurate
Vit E
Vitamin E
WST-1
2-(4-Iodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium monosodium salt
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