Shuangdan Jiedu Decoction improved LPS-induced acute lung injury by regulating both cGAS-STING pathway and inflammasome

Ethnopharmacological relevance: Shuangdan Jiedu Decoction (SJD) is a formula composed of six Chinese herbs with heat-removing and detoxifying, antibacterial, and anti-inflammatory effects, which is clinically used in therapy of various inflammatory diseases of the lungs including COVID-19, but the therapeutic material basis its action as well as its molecular mechanism are still unclear. Aim of the study: The study attempted to determine the therapeutic effect of SJD on LPS-induced acute lung injury (ALI), as well as to investigate its mechanism of action and assess its therapeutic potential for the cure inflammation-related diseases in the clinical setting. Materials and methods: We established an ALI model by tracheal drip LPS, and after the administration of SJD, collected the bronchoalveolar lavage fluid (BALF) and lung tissues of mice and examined the expression of flammatory factors in them. In addition, we evaluated the effects of SJD on the cyclic guanosine monophosphateadenosine monophosphate synthase -stimulator of interferon genes (cGAS-STING) and inflammasome immunoblotting and real-time quantitative polymerase chain reaction (RT-qPCR). Results: We demonstrated that SJD was effective in alleviating LPS-induced ALI by suppressing the levels of inflammatory cytokines in the BALF, improving the level of lung histopathology and the number of neutrophils, as well as decreasing the inflammatory factor-associated gene expression. Importantly, we found that SJD could inhibit multiple stimulus-driven activation of cGAS-STING and inflammasome. Further studies showed that Chinese herbal medicines in SJD had no influence on the cGAS-STING pathway and inflammasome alone at formulated dose. By increasing the concentration of these herbs, we observed inhibitory effects on the cGASSTING pathway and inflammasome, and the effect exerted was maximal when the six herbs were combined, indicating that the synergistic effects among these herbs plays a crucial role in the anti-inflammatory effects SJD. Conclusions: Our research demonstrated that SJD has a favorable protective effect against ALI, and its mechanism of effect may be associated with the synergistic effect exerted between six Chinese medicines to inhibit the cGASSTING and inflammasome abnormal activation. These results are favorable for the wide application of SJD in clinic as well as for the development of drugs for ALI from herbal formulas.