Terminalia chebula Extract Alleviates Lipopolysaccharide-Induced Acute Lung Injury by Modulating the Interleukin-17-Dependent Mitogen-Activated Protein Kinase/Nuclear Factor-Kappa B Signaling Pathways.

Abstract

Acute lung injury (ALI), a severe inflammatory disease, is intricately associated with the dysregulation of interleukin (IL)-17-mediated inflammatory responses. Terminalia chebula Retz., a traditional medicinal plant, can modulate inflammatory responses. We evaluated the effect of the prophylactic treatment using T. chebula extract (TCE) on lipopolysaccharide (LPS)-induced ALI and its underlying IL-17-linked mechanism. A mouse ALI model was established to assess TCE efficacy by observing histopathological and inflammatory changes. LC-MS identified its in vitro and absorbed components, followed by target prediction using integrated network pharmacology, molecular docking, and dynamics simulations, with key findings validated by Western blot analysis. ALI mice, pretreated with TCE, demonstrated notable improvements: lung tissue damage was alleviated and levels of pro-inflammatory cytokines (IL-6, tumor necrosis factor [TNF]-α, IL-17A) were reduced. Immunohistochemistry revealed that TCE markedly suppressed the enhanced alveolar expression of IL-17. Phytochemical analysis identified 55 constituents in TCE, with 15 bioactive compounds (e.g., ellagic acid, chebulinic acid) entering systemic circulation. Multi-method computational analysis confirmed that key compounds, particularly ellagic acid, stably interacted with core targets (e.g., IL-6, CXCL8). The KEGG analysis further highlighted significant enrichment in the IL-17 and NF-κB signaling pathways. These physiological adjustments coincided with the inhibition of the IL-17-MAPK/NF-κB pathway, as evidenced by decreased phosphorylation of p65, p38, and IκBα and downregulation of TLR4, MyD88, iNOS, and COX-2. Altogether, TCE pretreatment effectively alleviates ALI. The modulation of the IL-17-dependent signaling axis may enhance the resolution of inflammation, thereby reducing lung injury. These findings highlight the potential of TCE as a promising therapeutic for ALI via targeting the IL-17-MAPK/NF-κB pathway.