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.
Two polymorphisms were determined as significant risk factors associated with early and late mortality, which may provide insight into the molecular background of SIRS and sepsis, suggesting a possible role for HMGB1 genetics in future prognostic evaluation.
High-mobility group box protein 1 (HMGB1) is a pivotal late mediator involved in the development of sepsis and multiple organ dysfunction syndrome (MODS) in critically ill patients.
Intranuclear proteins, including high mobility group box 1 (HMGB1) and histone H3, released from inflammatory cells activate platelets and the coagulation systems, leading to development of disseminated intravascular coagulation (DIC) in individuals with sepsis.
Highlights of this study include: human SAA is possibly only expressed in a subset of septic patients; SAA induces HMGB1 release via TLR4 and RAGE receptors; SAA supplementation worsens the outcome of lethal endotoxemia; whereas SAA-neutralizing antibodies confer protection against lethal endotoxemia and sepsis.
The pooled mean differences in biomarker concentration (nonsurvivors - survivors), measured at onset of sepsis, are listed as follows: (1) Ang-1: - 2.9 ng/ml (95% CI - 4.1 to - 1.7, p < 0.01); (2) Ang-2: 4.9 ng/ml (95% CI 2.6 to 7.1, p < 0.01); (3) HMGB1: 1.2 ng/ml (95% CI 0.0 to 2.4, p = 0.05); (4) sRAGE: 1003 pg/ml (95% CI 628 to 1377, p < 0.01); (5) sTREM-1: 87 pg/ml (95% CI 2 to 171, p = 0.04); (6) suPAR: 5.2 ng/ml (95% CI 4.5 to 6.0, p < 0.01).
The upregulation of HMGB1 is directly associated with the pathogenesis of cancer, sepsis, ischemia, hemorrhagic shock, anorexia, rheumatic disease, periodontal disease etc.
Taken together, the present results suggest that KC1 and KC3 both reduced HMGB1 release and septic mortality and, thus, may be useful for the treatment of sepsis.
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).
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).
HMGB-1 is considered as an essential facilitator in diseases such as sepsis, collagen disease, atherosclerosis, cancers, arthritis, acute lung injury, epilepsy, myocardial infarction, and local and systemic inflammation.
Serum markers associated with the acute proinflammatory phase of sepsis (TNFα, IL-1β, and IL-6) rapidly increased and then progressively decreased during the 30-day period post-CLP, concomitant with a progressive increase in RAGE ligands (S100B, <i>N</i>ϵ-[carboxymethyl]lysine, HSP70, and HMGB1).
These data indicate that HMGB1 accumulates in renal tissue and enters the urine and the interaction between HMGB1 and TLR4 turns TECs into inflammatory promoters during sepsis.