PDF(Pubmed)
Abstract：
Systemic allergic reaction is characterized by vasodilation and vascular leakage, which causes a rapid, precipitous and sustained decrease in arterial blood pressure with a concomitant decrease of cardiac output. Histamine is a major mediator released by mast cells in allergic inflammation and response. It causes a cascade of inflammation and strongly increases vascular permeability within minutes through its four G-protein-coupled receptors (GPCRs) on endothelial cells. High mobility group box-1 (HMGB1), a nonhistone chromatin-binding nuclear protein, can be actively secreted into the extracellular space by endothelial cells. HMGB1 has been reported to exert pro-inflammatory effects on endothelial cells and to increase vascular endothelial permeability. However, the relationship between histamine and HMGB1-mediated signaling in vascular endothelial cells and the role of HMGB1 in anaphylactic-induced hypotension have never been studied.
EA.hy 926 cells were treated with different concentrations of histamine for the indicated periods. The results showed that histamine induced HMGB1 translocation and release from the endothelial cells in a concentration- and time-dependent manner. These effects of histamine were concentration-dependently inhibited by d-chlorpheniramine, a specific H1 receptor antagonist, but not by H2 or H3/4 receptor antagonists. Moreover, an H1-specific agonist, 2-pyridylethylamine, mimicked the effects of histamine, whereas an H2-receptor agonist, 4-methylhistamine, did not. Adrenaline and noradrenaline, which are commonly used in the clinical treatment of anaphylactic shock, also inhibited the histamine-induced HMGB1 translocation in endothelial cells. We therefore established a rat model of allergic shock by i.v. injection of compound 48/80, a potent histamine-releasing agent. The plasma HMGB1 levels in compound 48/80-injected rats were higher than those in controls. Moreover, the treatment with anti-HMGB1 antibody successfully facilitated the recovery from compound 48/80-induced hypotension.
Histamine induces HMGB1 release from vascular endothelial cells solely through H1 receptor stimulation. Anti-HMGB1 therapy may provide a novel treatment for life-threatening systemic anaphylaxis.
EA.hy 926 cells were treated with different concentrations of histamine for the indicated periods. The results showed that histamine induced HMGB1 translocation and release from the endothelial cells in a concentration- and time-dependent manner. These effects of histamine were concentration-dependently inhibited by d-chlorpheniramine, a specific H1 receptor antagonist, but not by H2 or H3/4 receptor antagonists. Moreover, an H1-specific agonist, 2-pyridylethylamine, mimicked the effects of histamine, whereas an H2-receptor agonist, 4-methylhistamine, did not. Adrenaline and noradrenaline, which are commonly used in the clinical treatment of anaphylactic shock, also inhibited the histamine-induced HMGB1 translocation in endothelial cells. We therefore established a rat model of allergic shock by i.v. injection of compound 48/80, a potent histamine-releasing agent. The plasma HMGB1 levels in compound 48/80-injected rats were higher than those in controls. Moreover, the treatment with anti-HMGB1 antibody successfully facilitated the recovery from compound 48/80-induced hypotension.
Histamine induces HMGB1 release from vascular endothelial cells solely through H1 receptor stimulation. Anti-HMGB1 therapy may provide a novel treatment for life-threatening systemic anaphylaxis.
摘要：
全身过敏反应的特点是血管舒张和血管渗漏，这导致了一个快速的，动脉血压急剧持续下降，心输出量随之下降。组胺是肥大细胞在过敏性炎症和反应中释放的主要介质。它通过内皮细胞上的四个G蛋白偶联受体（GPCRs）引起炎症级联反应，并在几分钟内强烈增加血管通透性。高移动性组盒-1(HMGB1)，一种非组蛋白染色质结合核蛋白，能被内皮细胞主动分泌到细胞外空间。已报道HMGB1对内皮细胞发挥促炎作用并增加血管内皮通透性。然而,组胺与血管内皮细胞中HMGB1介导的信号传导之间的关系以及HMGB1在过敏性低血压中的作用从未被研究过.
EA。将hy926细胞用不同浓度的组胺处理指定的时期。结果表明，组胺以浓度和时间依赖性方式诱导HMGB1易位和从内皮细胞释放。组胺的这些作用被d-氯苯那敏浓度依赖性地抑制，一种特定的H1受体拮抗剂，但不是H2或H3/4受体拮抗剂。此外，H1特异性激动剂，2-吡啶基乙胺,模仿组胺的作用，而H2受体激动剂，4-甲基组胺,没有。肾上腺素和去甲肾上腺素,这是临床上常用的过敏性休克的治疗方法,还抑制了组胺诱导的HMGB1在内皮细胞中的易位。因此,我们通过静脉内注射化合物48/80(一种有效的组胺释放剂)建立了过敏性休克的大鼠模型。注射化合物48/80的大鼠的血浆HMGB1水平高于对照组。此外，抗HMGB1抗体治疗成功促进了化合物48/80诱导的低血压的恢复.
组胺仅通过H1受体刺激诱导血管内皮细胞释放HMGB1。抗HMGB1治疗可能为危及生命的全身性过敏反应提供新的治疗方法。
EA。将hy926细胞用不同浓度的组胺处理指定的时期。结果表明，组胺以浓度和时间依赖性方式诱导HMGB1易位和从内皮细胞释放。组胺的这些作用被d-氯苯那敏浓度依赖性地抑制，一种特定的H1受体拮抗剂，但不是H2或H3/4受体拮抗剂。此外，H1特异性激动剂，2-吡啶基乙胺,模仿组胺的作用，而H2受体激动剂，4-甲基组胺,没有。肾上腺素和去甲肾上腺素,这是临床上常用的过敏性休克的治疗方法,还抑制了组胺诱导的HMGB1在内皮细胞中的易位。因此,我们通过静脉内注射化合物48/80(一种有效的组胺释放剂)建立了过敏性休克的大鼠模型。注射化合物48/80的大鼠的血浆HMGB1水平高于对照组。此外，抗HMGB1抗体治疗成功促进了化合物48/80诱导的低血压的恢复.
组胺仅通过H1受体刺激诱导血管内皮细胞释放HMGB1。抗HMGB1治疗可能为危及生命的全身性过敏反应提供新的治疗方法。
