Circulating histones are major mediators of systemic inflammation and cellular injury in patients with acute liver failure.
Circulating histones are major mediators of systemic inflammation and cellular injury in patients with acute liver failure.
复制标题
循环组蛋白是急性肝衰竭患者全身炎症和细胞损伤的主要介质
DOI：
10.1038/cddis.2016.303
复制
发表时间：
2016-09-29
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
急性肝功能衰竭（ALF）是一种危及生命的全身性疾病。在此，我们研究了循环组蛋白（最近发现的炎症介质）对ALF小鼠模型和患者全身炎症和肝损伤的影响。我们分析了62例ALF患者、60例慢性肝病患者和30例健康志愿者血液样本中的组蛋白水平。我们将患者血清与人L02肝细胞和单核细胞U937细胞孵育，以评估细胞损伤和细胞因子产生。分别给予D-氨基半乳糖加脂多糖（GalN/LPS）、刀豆球蛋白A（ConA）和对乙酰氨基酚（APAP）诱导C57 BL/6 N小鼠肝损伤，研究循环组蛋白的致病作用。此外，通过体内和离体研究评价了可结合组蛋白的非抗凝肝素的保护作用。我们观察到ALF患者的循环组蛋白显著增加，并与疾病严重程度和死亡率相关。在ALF患者中也存在显著的全身炎症，这与组蛋白水平相关。ALF患者血清诱导L02细胞死亡，刺激U937细胞产生细胞因子，这些细胞因子可被非抗凝肝素消除。此外，在GalN/LPS、ConA和APAP处理的小鼠中，循环组蛋白均显著释放，并且与高水平的炎性细胞因子相关。肝素可减少小鼠的全身炎症和肝损伤，表明其可干扰组蛋白相关的肝损伤。总的来说，这些研究结果表明，循环组蛋白是ALF中全身炎症和细胞损伤的关键介质，这可能是潜在的临床应用。
Acute liver failure (ALF) is a life-threatening systemic disorder. Here we investigated the impact of circulating histones, recently identified inflammatory mediators, on systemic inflammation and liver injury in murine models and patients with ALF. We analyzed histone levels in blood samples from 62 patients with ALF, 60 patients with chronic liver disease, and 30 healthy volunteers. We incubated patients' sera with human L02 hepatocytes and monocytic U937 cells to assess cellular damage and cytokine production. d-galactosamine plus lipopolysaccharide (GalN/LPS), concanavalin A (ConA), and acetaminophen (APAP) were given to C57BL/6N mice to induce liver injury, respectively, and the pathogenic role of circulating histones was studied. Besides, the protective effect of nonanticoagulant heparin, which can bind histones, was evaluated with in vivo and ex vivo investigations. We observed that circulating histones were significantly increased in patients with ALF, and correlated with disease severity and mortality. Significant systemic inflammation was also pronounced in ALF patients, which were associated with histone levels. ALF patients’ sera induced significant L02 cell death and stimulated U937 cells to produce cytokines, which were abrogated by nonanticoagulant heparin. Furthermore, circulating histones were all released remarkably in GalN/LPS, ConA, and APAP-treated mice, and associated with high levels of inflammatory cytokines. Heparin reduced systemic inflammation and liver damage in mice, suggesting that it could interfere with histone-associated liver injury. Collectively, these findings demonstrate that circulating histones are critical mediators of systemic inflammation and cellular damage in ALF, which may be potentially translatable for clinical use.
登录
查看更多内容
影响因子：
3.8
作者：
Jaeschke, H;Gores, GJ;Lemasters, JJ
通讯作者：
Lemasters, JJ
影响因子：
6.7
作者：
Craig, Darren G. N.;Lee, Patricia;Simpson, Kenneth J.
通讯作者：
Simpson, Kenneth J.
粉防己碱通过抑制 NF-kappaB 激活来保护小鼠免受伴刀豆球蛋白 A 诱导的肝炎。
影响因子：
4.4
作者：
Feng, Dechun;Mei, Yunhua;Xu, Lingyun
通讯作者：
Xu, Lingyun
影响因子：
4.6
作者：
Nakamura, T;Vollmar, B;Schäfers, HJ
通讯作者：
Schäfers, HJ
影响因子：
13.5
作者：
Rolando, N;Wade, J;Williams, R
通讯作者：
Williams, R