Dexmedetomidine mitigates lipopolysaccharide-induced acute lung injury by modulating heat shock protein A12B to inhibit the toll-like receptor 4/nuclear factor-kappa B signaling pathway.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS): Life-threatening medical conditions characterized by high morbidity and mortality rates, where the inflammatory process plays a crucial role in lung tissue damage, especially in models induced by lipopolysaccharide (LPS). Heat shock protein A12B (HSPA12B) has strong anti-infammatory properties However, it is unknown whether increased HSPA12B is protective against LPS-induced ALI. And Dexmedetomidine (DEX) is a potent α2-adrenergic receptor (α2-AR) agonist that has been shown to protect against sepsis-induced lung injury, however, the underlying mechanisms of this protection are not fully understood. This study utilized bioinformatics analysis and an LPS-induced ALI model to explore how DEX alleviates lung injury by modulating HSPA12B and inhibiting the Toll-like receptor 4/nuclear factor-kappa B (TLR4/NF-κB) signaling pathway. Results indicate that HSPA12B overexpression and DEX pre-treatment markedly mitigated LPS-induced lung injury, which was evaluated by the deterioration of histopathology, histologic scores, the W/D weight ratio, and total protein expression, tumor necrosis factor-alpha (TNF-α), and interleukin-1ß (IL-1ß) in the BALF, and the levels of NO, MDA,SOD and MPO in the lung. Moreover, HSPA12B overexpression and DEX pre-treatment significantly reduces lung injury and inflammation levels by upregulating HSPA12B and inhibiting the activation of the TLR4/NF-κB signaling pathway. On the contrary, when the expression of HSPA12B is inhibited, the protective effect of DEX pre-treatment on lung tissue is significantly weakened.In summary, our research demonstrated that the increased expression of AAV-mediated HSPA12B in the lungs of mice inhibits acute inflammation and suppresses the activation of TLR4/NF-κB pathway in a murine model of LPS-induced ALI. DEX could enhance HSPA12B and inhibit the initiation and development of inflammation through down-regulating TLR4/NF-κB pathway.These findings highlight the potential of DEX as a therapeutic agent for treating ALI and ARDS, offering new strategies for clinical intervention.

Gelsevirine ameliorates sepsis-associated encephalopathy by inhibiting the STING signalling-mediated pyroptosis pathway in microglia.

BACKGROUND: Sepsis-associated encephalopathy (SAE) is among the most prevalent and deadly complications associated with sepsis, but satisfactory treatments and therapeutic agents are lacking. Gelsevirine, an active ingredient derived from Gelsemium elegans Benth., has shown promising effects in animal models of anxiety, ischaemic stroke and osteoarthritis. However, its protective effect against SAE and its mechanism of action are still unknown. PURPOSE: To elucidate the efficacy of gelsevirine against SAE and the mechanism of its protective effect through the STING signalling-mediated pyroptosis pathway. METHODS: We constructed a mouse model of caecum ligation and puncture (CLP)-induced sepsis and explored the protective effects of gelsevirine in mice with SAE by assessing survival rates and behavioural alterations. To further explore its mechanism of action, we investigated the modulatory effects of gelsevirine on the levels of inflammatory factors, microglial activation and pyroptosis by Western blotting, immunohistochemistry staining and PCR. STING knockout mice were used to verify the protective effect of gelsevirine against SAE through the STING pathway. RESULTS: Gelsevirine increased the survival rate of mice with SAE. The Morris water maze and open field tests revealed that gelsevirine significantly alleviated cognitive dysfunction and increased exploratory behaviour in mice with SAE. Gelsevirine inhibited the activation of microglia and decreased inflammatory factor levels in the hippocampus of mice with SAE. In mice with SAE and in vitro BV2 microglia, gelsevirine reduced levels of inflammatory factors and inhibited STING protein phosphorylation and microglial pyroptosis. However, after STING knockout, the inhibitory effect of gelsevirine on microglial pyroptosis was significantly weakened, and gelsevirine-mediated protective effects were abolished. CONCLUSIONS: Gelsevirine increased the survival rate, ameliorated cognitive impairment, inhibited glial cell activation and reduced inflammation in the hippocampi of mice with SAE; the mechanism may be related to the inhibition of STING signalling pathway-mediated pyroptosis in microglia.