Ginkgolide C attenuates lipopolysaccharide-induced acute lung injury by inhibiting inflammation via regulating the CD40/NF-[kappa]B signaling pathway

• Published in: International journal of molecular medicine 2021-04, Vol.47 (4), p.1
• Main Authors: Zhang, Rui, Guo, Nan, Yan, Genquan, Wang, Qian, Gao, Tiantian, Zhang, Baoke, Hou, Ning
• Format: Article
• Language: English
• Subjects: Analysis; Immunohistochemistry; Inflammation; Lung diseases; Mitogens; Nitric oxide; Scientific equipment and supplies industry; Tumor necrosis factor
• ISSN: 1107-3756
• DOI: 10.3892/ijmm.2021.4895

Excessive lung inflammation caused by endotoxins, including lipopolysaccharide (LPS), mediates the detrimental effects of acute lung injury (ALI), as evidenced by severe alveolar epithelial cell injury. CD40, a member of the tumor necrosis factor receptor superfamily, serves as a central activator in triggering and transducing a series of severe inflammatory events during the pathological processes of ALI. Ginkgolide C (GC) is an efficient and specific inhibitor of CD40. Therefore, the present study aimed to investigate whether GC alleviated LPS-induced ALI, as well as the potential underlying mechanisms. LPS-injured wild-type and CD40 gene conditional knockout mice, and primary cultured alveolar epithelial cells isolated from these mice served as in vivo and in vitro ALI models, respectively. In the present study, histopathological assessment, polymorphonuclear neutrophil (PMN) infiltration, lung injury score, myeloperoxidase activity, wet-to-dry (W/D) weight ratio and hydroxyproline (Hyp) activity were assessed to evaluate lung injury. In addition, immunohistochemistry was performed to evaluate intracellular adhesion molecule-1, vascular cell adhesion molecule-1 and inducible nitric oxide synthase expression levels, and TNF-[alpha], IL-1[beta], IL-6 ELISAs and western blotting were conducted to elucidate the signaling pathway. The results demonstrated that GC alleviated LPS-induced lung injury, as evidenced by improvements in ultrastructural characteristics and histopathological alterations of lung tissue, inhibited PMN infiltration, as well as reduced lung injury score, W/D weight ratio and hydroxyproline content. In LPS-injured alveolar epithelial cells, GC significantly reduced I[kappa]B[alpha] phosphorylation, IKK[beta] activity and NF-[kappa]B p65 subunit translocation via downregulating CD40, leading to a significant decrease in downstream inflammatory cytokine levels and protein expression levels. In conclusion, the results of the present study demonstrated that GC displayed a protective effect against LPS-induced ALI via inhibition of the CD40/NF-[kappa]B signaling pathway; therefore, the present study suggested that the CD40/NF-[kappa]B signaling pathway might serve as a potential therapeutic target for ALI. Key words: Ginkgolide C, CD40, acute lung injury, inflammation, NF-[kappa]B