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Tangeretin alleviates LPS-induced acute lung injury by inhibiting ferroptosis of macrophage via Nrf2 pathways

ABSTRACT: Sepsis-induced acute lung injury (ALI) is a severe clinical condition with a high mortality rate. Tangeretin, widely found in citrus fruits, has been reported to exert antioxidant and anti-inflammatory properties. However, whether Tangeretin protects against sepsis-induced ALI and the potential mechanisms remain unclear.We established ALI model via intraperitoneally injected with 5 mg/kg lipopolysaccharides (LPS) for 12 h. Tangeretin was applied intraperitoneally 30 min before LPS treatment. The lung tissue samples from both the LPS and LPS + TAN groups were subjected to RNA sequencing analysis, conducted by OE Biotech Co., Ltd. (Shanghai, China). We performed differential gene expression analysis using RNA-seq data between LPS and LPS/Tangeretin group.GSEA analysis between LPS and LPS/Tangeretin group showed that IL6_JAK_STAT3_SIGNALING, INFLAMMATORY_RESPONSE, TNFA_SIGNALING_VIA_NFKB were significantly enriched (Fig.3C-E). These results identified the anti-inflammatory effect of Tangeretin against sepsis-induced ALI.

ORGANISM(S): Mus musculus

PROVIDER: GSE252755 | GEO | 2024/01/20

REPOSITORIES: GEO

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Project description:Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is an inflammatory process of the lungs characterized by increased permeability of the alveolar-capillary membrane with subsequent interstitial/alveolar edema and diffuse alveolar damage. ALI/ARDS can be the results of either direct or indirect lung injury, with pneumonia being the most common direct pulmonary insult and sepsis the most common extra-pulmonary cause. In this study, we employed the murine lipopolysaccharide (LPS)-induced direct and indirect lung injury model to explore the pathogenic mechanisms of pulmonary and extra-pulmonary ARDS, using an unbiased, discovery and quantitative proteomic approach. A total of 1,017 proteins were both identified and quantified in bronchoalveolar lavage fluid (BALF) from control, intratracheal LPS (I.T. LPS, 0.1 mg/kg) and intraperitoneal LPS (I.P. LPS, 5 mg/kg) treated mice. The two LPS groups shared 13 up-regulated and 22 down-regulated proteins compared to the control group. Among them, molecules related to bronchial and type II alveolar epithelial cell functions including cell adhesion molecule 1 and surfactant protein B were reduced, whereas lactotransferrin and resistin like alpha involved in lung innate immunity were upregulated in both LPS groups. Proteomic profiling also identified significant differences in BALF proteins between I.T. and I.P. LPS groups. Ingenuity pathway analysis revealed that acute-phase response signaling was activated by both I.T. and I.P. LPS, however, the magnitude of activation is much greater in I.T. LPS group compared to I.P. LPS group. Intriguingly, two canonical signaling pathways, liver X receptor/retinoid X receptor activation and the production of nitric oxide and reactive oxygen species in macrophages, were activated by I.T. LPS but suppressed by I.P. LPS. In addition, CXCL15 (also known as lungkine) was also up-regulated by I.T LPS but down-regulated by I.P. LPS. In conclusion, our quantitative discovery-based proteomic approach identified commonalities as well as significant differences in BALF protein expression profiles in LPS-induced direct and indirect lung injury, and importantly, LPS-induced indirect lung injury results in suppression of select components of lung innate immunity, which could contribute to the so-called “immunoparalysis” in sepsis patients.

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Tangeretin alleviates LPS-induced acute lung injury by inhibiting ferroptosis of macrophage via Nrf2 pathways

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