부산대학교 도서관

PURPOSE OF STUDY: Sepsis is a major cause of neonatal morbidity and mortality, but the mechanisms linking neonatal susceptibility to infection and mortality are unclear. Elevated serum levels of the dual-function cytokine HMGB1, a late mediator of septic shock that signals through the Receptor for Advanced Glycation End Products (RAGE), are associated with adult mortality during sepsis, but recent studies have shown that absence of HMGB1 signalling in the context of endotoxemia is also detrimental to survival. STAT1-mediated HMGB1 acetylation is essential for HMGB1 nuclear release in the context of inflammatory stress; however, the mechanisms by which STAT1-mediated HMGB1 nuclear release might contribute to neonatal susceptibility to endotoxemia are unknown. The objective of this study was to determine the mechanisms regulating HMGB1 signalling in endotoxemic neonatal mice. METHODS USED: To induce endotoxemia, neonatal (PN0) and adult (8–10 wk) mice were exposed to LPS(5 mg/kg, IP). Expression of the STAT1 agonist IFNβ was assessed by qPCR. Circulating IFNβ was measured by serum ELISA, and pulmonary STAT1 signalling assessed by Western Blot. Expression of RAGE target genes was assessed by qPCR. To interrogate the mechanisms of STAT1-mediated HMGB1 nuclear release, RAW 264.7 cells were exposed to LPS (1 µg/ml) or IFNβ (100–1000 U/ml) and STAT1 signalling and HMGB1 expression were assessed by Western blot. SUMMARY OF RESULTS: In contrast to adult endotoxemic mice, expression of IFNβ was attenuated in neonatal mice. This was associated with significantly reduced STAT1 signalling in neonatal pulmonary cytosolic extracts (p<0.05), and significantly reduced neonatal pulmonary expression of RAGE-dependent target genes TNFα, MCP1, and MIP1α (p<0.05) compared to the adult. Thus, the HMGB1/RAGE signalling axis is attenuated in the neonatal lung via a STAT1-dependent mechanism. CONCLUSIONS: Multiple factors result in impaired neonatal HMGB1/RAGE signalling following systemic inflammatory stress. In adults, exaggerated HMGB1 release is late-mediator of mortality associated with sepsis. In contrast, attenuated HMGB1/RAGE signalling complicates neonatal endotoxemia. These results suggest that targeting nuclear release of HMGB1 may be beneficial during neonatal sepsis.