Abstract
IntruoductionHigh mobility group box 1 (HMGB1), a ubiquitous nuclear protein, induces several inflammatory diseases and functions as a fatal factor when released extracellularly. The effect of HMGB1 on vascular reactivity during sepsis remains to be clarified.MethodsA rat model of abdominal sepsis was produced by cecal ligation and puncture (CLP) under sevoflurane anesthesia (n = 28). Anti-HMGB1 antibody at a dose of 4 or 0.4 mg/kg, or normal saline was injected twice intravenously, i.e., immediately after the CLP surgery and 4 h thereafter. Rats in the sham group underwent laparotomy, and the cecum was manipulated but not ligated or punctured. The descending thoracic aorta was excised 12 h after the CLP surgery and cut into rings of approximately 3 mm in length. Changes in the expression of HMGB1 and vascular reactivity were examined in the rings shortly after harvest and 4 h thereafter.ResultsHMGB1 was identified immunohistochemically and by Western blotting in the nuclei of vascular endothelial and smooth muscle cells in all groups shortly after excision of the aorta, but its expression was augmented only in the CLP groups 4 h thereafter. Degenerated smooth muscle cells were also observed after CLP. Anti-HMGB1 antibody dose-dependently inhibited the augmentation of HMGB1 expression and the morphological changes induced by CLP. The expression of HMGB1 partly correlated with suppression of vascular reactivity.ConclusionThe present results strongly suggest that HMGB1 plays an important role in vascular malfunction from an early phase of sepsis.
Highlights
High mobility group box 1 (HMGB1) is a ubiquitous nuclear protein present in many eukaryotic cells that stabilizes nucleosomes and enables gene transcription by binding to DNA [1]
The present results strongly suggest that HMGB1 plays an important role in vascular malfunction from an early phase of sepsis
HMGB1 was expressed in the nuclei of the endothelium in all groups even shortly after the preparation, the number of HMGB1-positive endothelial cells in the cecal ligation and puncture (CLP) groups (23 ± 2 in the CLP ? normal saline (NS) group, ± 6 in the CLP ? 4 mgAb group, and ± 7 in the CLP ? 0.4 mgAb group) was significantly greater than that in the sham group (4 ± 3; Fig. 1b)
Summary
High mobility group box 1 (HMGB1) is a ubiquitous nuclear protein present in many eukaryotic cells that stabilizes nucleosomes and enables gene transcription by binding to DNA [1]. HMGB1 is actively released by monocytes/macrophages more than 8 h after stimulation with endotoxin, TNF-a, or IL-1 [2, 4]. HMGB1 ligates three receptors expressed on the surface of endothelial and smooth muscle cells: the receptor for advanced glycation end products (RAGE), the toll-like receptor (TLR) 2, and TLR4 [5,6,7]. Endothelial cells stimulated with HMGB1 show increased expression of intercellular and vascular adhesion molecules and RAGE receptor, as well as increased secretion of TNF-a and chemokines, resulting in endothelial cell activation and injury [8]. HMGB1 and RAGE are known to regulate transendothelial migration of monocytes/macrophages [9], and cytoskeleton reorganization in smooth muscle cells [10]
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