Luteolin inhibits inflammation and M1 macrophage polarization in the treatment of Pseudomonas aeruginosa-induced acute pneumonia through suppressing EGFR/PI3K/AKT/NF-κB and EGFR/ERK/AP-1 signaling pathways
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引用次数: 0
Abstract
Background
The opportunistic pathogen Pseudomonas aeruginosa primarily causes infections in immunocompromised individuals. Luteolin, a natural flavonoid, is widely present in plants, which exerts various pharmacological activities, including anti-inflammatory and antimicrobial activities.
Purpose
This study aimed to explore the therapeutic efficacy of luteolin and the underlying molecular mechanisms in treating the P. aeruginosa-induced acute pneumonia.
Methods
Network pharmacology was utilized to identify the core targets of luteolin for treating acute P. aeruginosa pneumonia. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed to dissect the potential effects of luteolin and the involved signaling pathways. Surface plasmon resonance (SPR) assay and molecular docking were employed for studying the binding affinities of luteolin with the key targets. Furthermore, we applied a mouse model of bacterial pneumonia for assessing the therapeutic effects of luteolin in vivo, and an in vitro infection model for specifically investigating the effects of luteolin on macrophages as well as the underlying mechanisms upon P. aeruginosa infection.
Results
Network pharmacology identified TNF, IL-6, EGFR and AKT1 as the key targets of luteolin for treating acute P. aeruginosa pneumonia. Moreover, as revealed by GO and KEGG enrichment analysis, EGFR, MAPK and PI3K/AKT pathways were the potential pathways regulated the P. aeruginosa-induced inflammatory response. According to the in vivo results, luteolin effectively mitigated the P. aeruginosa-induced acute lung injury through reducing the pulmonary permeability, neutrophil infiltration, proinflammatory cytokine production (IL-1β, IL-6, TNF and MIP-2) and bacterial burden in lung tissues, which led to increased survival rate of mice. Furthermore, the luteolin-treated mice had diminished EGFR, PI3K, AKT, IκBα, NF-κB p65, ERK, c-Jun and c-Fos phosphorylation, down-regulated M1 macrophage marker levels (iNOS, CD86 and IL-1β) but up-regulated M2 macrophage marker levels (Ym1, CD206 and Arg1) in lung tissues. Consistently, the luteolin-pretreated macrophages exhibited reduced phosphorylation of these regulatory proteins, diminished proinflammatory cytokine production, and down-regulated expression of M1 macrophage markers, but up-regulated expression of IL-10 and M2 macrophage markers.
Conclusion
luteolin effectively suppressed the inflammatory responses and M1 macrophage polarization through inhibiting EGFR/PI3K/AKT/NF-κB and EGFR/ERK/AP-1 signaling pathways in the treatment of acute P. aeruginosa pneumonia. This study suggests that luteolin could be a promising candidate for development as a therapeutic agent for acute bacterial pneumonia.
期刊介绍:
Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.