Butyrolactone I from Aspergillus fungi blocks neutrophil FPR1 to alleviate acute respiratory distress syndrome

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology Pub Date : 2025-09-21 DOI:10.1016/j.bcp.2025.117348

Chun-Yu Chen , Yu-Ting Kuo , Chih-Chuang Liaw , Yi-Hsuan Wang , Shih-Hsin Chang , Yung-Fong Tsai , Kai-Cheng Hsu , Tony Eight Lin , Tsong-Long Hwang

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Abstract

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.

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来自曲霉真菌的丁内酯I阻断中性粒细胞FPR1以减轻急性呼吸窘迫综合征。

甲酰基肽受体1 （FPR1）被n -甲酰基肽激活，在中性粒细胞活化和急性呼吸窘迫综合征（ARDS）的发生中起重要作用。本研究表明，土曲霉的次级代谢物丁内酯I （BLI）可有效阻断FPR1，降低ARDS的严重程度。BLI选择性地抑制由细菌和线粒体衍生的n -甲酰基肽激活的人中性粒细胞的超氧阴离子产生、弹性蛋白酶释放、分化分子簇11b （CD11b）表达和趋化性。FPR1受体结合和分子对接实验证实BLI是FPR1抑制剂。药理实验表明，BLI可选择性抑制人中性粒细胞中FPR1的下游信号，包括钙动员和蛋白激酶B （Akt）、c-Jun n末端激酶（JNK）、细胞外调节蛋白激酶（ERK）和p38丝裂原活化蛋白激酶（p38）的磷酸化。在ARDS小鼠模型中，BLI治疗可降低肺中性粒细胞浸润、氧化损伤以及弹性蛋白酶和白细胞介素-1β (IL-1β)水平。真菌化合物BLI可能通过阻断FPR1和减少中性粒细胞诱导的损伤而成为ARDS的潜在治疗方法。

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来源期刊

Biochemical pharmacology 医学-药学

CiteScore

10.30

自引率

1.70%

发文量

420

审稿时长

17 days

期刊介绍： Biochemical Pharmacology publishes original research findings, Commentaries and review articles related to the elucidation of cellular and tissue function(s) at the biochemical and molecular levels, the modification of cellular phenotype(s) by genetic, transcriptional/translational or drug/compound-induced modifications, as well as the pharmacodynamics and pharmacokinetics of xenobiotics and drugs, the latter including both small molecules and biologics. The journal''s target audience includes scientists engaged in the identification and study of the mechanisms of action of xenobiotics, biologics and drugs and in the drug discovery and development process. All areas of cellular biology and cellular, tissue/organ and whole animal pharmacology fall within the scope of the journal. Drug classes covered include anti-infectives, anti-inflammatory agents, chemotherapeutics, cardiovascular, endocrinological, immunological, metabolic, neurological and psychiatric drugs, as well as research on drug metabolism and kinetics. While medicinal chemistry is a topic of complimentary interest, manuscripts in this area must contain sufficient biological data to characterize pharmacologically the compounds reported. Submissions describing work focused predominately on chemical synthesis and molecular modeling will not be considered for review. While particular emphasis is placed on reporting the results of molecular and biochemical studies, research involving the use of tissue and animal models of human pathophysiology and toxicology is of interest to the extent that it helps define drug mechanisms of action, safety and efficacy.