Abstract
OBJECTIVES: To evaluate the synergistic protective effect of linezolid (LZD) combined with Xuebijing Injection (XBJ, a traditional Chinese medicine injection) against pneumonia caused by methicillin-resistant Staphylococcus aureus (MRSA) in mice and explore the underlying mechanism. METHODS: Fifty C57BL/6J mice with pneumonia induced by tracheal instillation of MRSA were randomized equally into model group, low- and high-dose XBJ treatment groups (13 and 80 mg·kg(-1)·d(-1), respectively), and combined treatment groups with low- and high-dose XBJ (6.5 and 13 mL·kg(-1)·d(-1), respectively) and LZD (80 mg·kg(-1) ·d(-1)), with 10 PBS-treated mice as the normal control group. The minimum inhibitory concentration (MIC) of XBJ and LZD against MRSA and their effects on bacterial growth and hemolytic activity were assessed in vitro. After the treatments, lung pathologies of the mice were observed withHE staining, and IL-6, TNF-α, IL-1β, and IL-18 levels in lung homogenate were measured using ELISA; the mRNA and protein expressions of Hla, NLRP3, caspase-1, and ASC were detected using qPCR and Western blotting, and pulmonary expressions of NLRP3, caspase-1, and ASC were examined with immunohistochemistry. RESULTS: The combined treatment with LZD and XBJ significantly improved survival rates of the mouse models, reduced inflammatory cell infiltration and lung injury scores, decreased the levels of IL-6, TNF-α, IL-1β, and IL-18, and downregulated mRNA and protein expressions of Hla, NLRP3, caspase-1, and ASC. XBJ alone showed no antibacterial activity against MRSA but inhibited α-hemolysin (Hla) secretion both in vitro and in vivo to suppress NLRP3-mediated inflammation, while LZD did not produce this effect. CONCLUSIONS: LZD combined with XBJ produces enhanced efficacy for improving MRSA pneumonia possibly due to XBJ-induced inhibition of NLRP3-mediated inflammatory response via inhibiting α-hemolysin secretion.