Recombinant Antithrombin Alleviated Pulmonary Injury and Inflammation in LPS-Induced ARDS by Inhibiting IL17a/NF-κB Signaling.

BACKGROUND: Recombinant antithrombin (rAT) has been shown to protect lungs from ARDS and modulate immune responses, but its anti-inflammatory mechanisms remain unclear. This study aimed to explore the immunomodulatory effects and mechanisms of rAT in LPS-induced ARDS mice. METHODS: ARDS mouse model was established by intraperitoneally administration of 20 mg/kg LPS. After 3 hours of LPS administration, rAT or PBS was injected intravenously. Lung injury, alveolar permeability, serum inflammatory cytokines, immune cell infiltration in lung tissue, and the proportion of Th17 were assessed 36 hours after rAT administration. The functional roles of the differential expressed genes (DEGs), obtained from LPS-induced ARDS mice treated with or without rAT, were analyzed by GO, KEGG and GSEA enrichment analysis. The activation of NF-κB and NLRP3 inflammasome was evaluated by Western blot and immunofluorescence staining. RESULTS: We found that rAT alleviated lung injury, reduced pulmonary permeability, decreased serum inflammatory cytokines, and suppressed immune cell infiltration and NLRP3 inflammasome activation. Moreover, rAT decreased the proportion of Th17 cells in lung tissues and peripheral blood, downregulated IL17a expression, and inhibited NF-κB signaling pathway in lung tissues. Additionally, the administration of IL-17A diminished the efficacy of rAT in mitigating lung injury, suppressing the immune response, and inhibiting the activation of the NF-κB signaling pathway in LPS-induced ARDS mice. CONCLUSION: The findings of this study suggest that rAT alleviates lung injury and suppresses inflammatory responses by inhibiting the IL17a/NF-κB signaling axis, suggesting that rAT may serve as a potential therapeutic agent for mitigating pulmonary inflammation and improving the prognosis of ARDS induced by sepsis. Furthermore, this study provides important research data and theoretical basis for the clinical translation and application of rAT.