In this study, we report that 1,25(OH)<sub>2</sub>D<sub>3</sub> treatment has beneficial effects and improves the survival rate in LPS-induced mouse sepsis model by blocking the secretion of high-mobility group box 1 (HMGB1), a key late regulator of sepsis.
Following the initiation of sepsis, serum HMGB1 continued to increase in the sepsis group and was significantly elevated at 24 h (P<0.05), whereas urine HMGB1 levels decreased significantly at 12 and 24 h (P<0.05).
In addition, rTM administered prior to or after LPS suppressed the level of pro-inflammatory cytokine TNF-α in sera at 1-3 h after LPS injection, whereas only the administration of rTM after LPS suppressed the levels of HMGB1 and nucleosome (late-phase mediators of sepsis) (9-12 h) in sera after the LPS injection.
Moreover, we suggested that miR-181a-5p may play a role in regulating DC responses to HMGB1 and serve as evidence indicating that novel therapies targeting miRNAs may be useful for treating immune dysfunction in the setting of sepsis.
We used a CLP model of sepsis and in vitro LPS or HMGB1-treated NR8383 cells to examine the effects of GL on expression of HMGB1 and proinflammatory cytokines.
Administration of glutathione and thioredoxin inhibitors to cell cultures enhanced HMGB1 oxidation during sepsis in endothelial and proximal tubule cells, respectively.
These findings demonstrate that anti-HMGB1 antibodies alter inflammation in murine sepsis models and reduce sepsis mortality without potentiating immunosuppression.
Inflammatory response genes; TLR4, late onset inflammatory mediator HMGB1, genes associated with antigen presentation; MICB, PSMB2, PSMB8, PSME2, epigenetic regulators; DNMT3B, HDAC1, HDAC2 were significantly down regulated, whereas the anti-inflammatory gene; IL4 was up regulated in melioidosis patients compared to sepsis cases caused by other pathogens.
The mechanism of immunomodulation by mung bean has not been described until today except for a report which identified HMGB1 suppression as a pathway underlying the protective effect against sepsis.
Deciphering the mechanism of Huang-Lian-Jie-Du-Decoction on the treatment of sepsis by formula decomposition and metabolomics: Enhancement of cholinergic pathways and inhibition of HMGB-1/TLR4/NF-κB signaling.
Therefore, our study clearly demonstrates that the regulation of HMGB1 release using small molecules is a promising strategy for the treatment of sepsis.
Taken together, our data suggest that HMGB1 accumulation in the late phase of sepsis plays a specific role in the development of postsepsis immunosuppression and specifically affects neutrophil-dependent antibacterial defense mechanisms.
Plasma and sputum HMGB1 levels did not correlate to disease severity (pneumonia severity index or presence of sepsis), but high sputum HMGB1 level was correlated to pneumococcal aetiology (p = 0.002).