Abstract
Background: Acute lung injury (ALI) is a life-threatening disease without effective chemotherapy at present. Liang-Ge-San (LGS) is a famous traditional Chinese medicine formula, which is used to treat ALI in China. However, only a few studies have addressed the mechanisms of LGS in ALI. Purpose: To evaluate the anti-inflammatory effects of LGS on lipopolysaccharide (LPS)-induced ALI, and to explore its underlying molecular mechanism. Methods: Murine RAW264.7 cells were treated with LGS and LPS (1 μg/ml). The generation of IL-6, TNF-α, IL-1β was detected by ELISA. The protein expressions of STAT3 and P-STAT3 (Tyr705) were determined by Western blotting and fluorescence confocal microscopy. STAT3 transcriptional activity was investigated by luciferase reporter gene assay. qPCR was used to detect the expressions of microRNA-21 (miR-21), STAT3, and IL-6. DSS cross-linking assay was used to assess the change of STAT3 dimer. In vivo anti-inflammatory effects of LGS were evaluated in an ALI mouse model induced by tracheal instillation of LPS (3 mg/kg). The anti-ALI effects were evaluated by ELISA, qPCR, Western blotting, BCA, and H&E assays. Results: LGS suppressed LPS-stimulated IL-6, TNF-α, and IL-1β generation in murine macrophages RAW264.7. Moreover, LGS down-regulated protein levels of P-STAT3 (Tyr705) and STAT3, inhibited STAT3 transcriptional activity, and up-regulated miR-21. Furthermore, blockage of miR-21 antagonized the inhibitory effects of LGS on the production of IL-6 and the expressions of P-STAT3 (Tyr705) and STAT3 as well as the formation of STAT3 dimer. Critically, LGS up-regulated the expression of miR-21 and inhibited the protein expressions of STAT3 and P-STAT3 (Tyr705) to reduce the release of IL-6 and inflammatory cell infiltration as well as the degree of edema in LPS-induced ALI mice. Conclusion: LGS inhibited LPS-induced ALI through up-regulating miR-21 and subsequently inhibiting the STAT3 signaling pathway, thereby decreasing the release of IL-6.
Highlights
Acute lung injury (ALI) is a life-threatening syndrome with 30% to 50% mortality, which is mainly caused by sepsis, trauma, and infection
Blockage of miR-21 antagonized the inhibitory effects of LGS on the production of IL-6 and the expressions of P-STAT3 (Tyr705) and STAT3 as well as the formation of STAT3 dimer
LGS up-regulated the expression of miR-21 and inhibited the protein expressions of STAT3 and P-STAT3 (Tyr705) to reduce the release of IL-6 and inflammatory cell infiltration as well as the degree of edema in LPS-induced ALI mice
Summary
Acute lung injury (ALI) is a life-threatening syndrome with 30% to 50% mortality, which is mainly caused by sepsis, trauma, and infection. Studies have demonstrated that inhibition of STAT3 pathway significantly suppresses peripheral inflammatory responses. Research has proved that STAT3 inhibitors are effective in suppressing inflammation, which is related to diminish infiltration of inflammatory cells, and decrease level of neutrophils, inflammatory cytokines (IL1β, IL-6, and TNF-α), and chemokines (Zhao et al, 2016). The suppression of STAT3 signaling pathway can reduce ALI. It has been reported that lung vascular permeability, lung myeloperoxidase accumulation as well as inflammatory cells from serum and bronchoalveolar lavage fluid (BALF) are markedly reduced in the inhibition of STAT3 murine model during ALI (Ju et al, 2015). Acute lung injury (ALI) is a life-threatening disease without effective chemotherapy at present. Purpose: To evaluate the anti-inflammatory effects of LGS on lipopolysaccharide (LPS)induced ALI, and to explore its underlying molecular mechanism
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