Recombinant human soluble thrombomodulin is associated with attenuation of sepsis-induced renal impairment by inhibition of extracellular histone release
Recombinant human soluble thrombomodulin is associated with attenuation of sepsis-induced renal impairment by inhibition of extracellular histone release
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DOI：
10.1371/journal.pone.0228093
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发表时间：
2020-01-23
期刊：
影响因子：
3.7
通讯作者：
Yamakage, Michiaki
中科院分区：
文献类型：
--
作者：
Akatsuka, Masayuki;Masuda, Yoshiki;Yamakage, Michiaki
脓毒症所致的多器官功能障碍常涉及肾脏损伤。细胞外组蛋白对损伤相关的分子模式的反应被认为促进了脓毒症引起的器官功能障碍。重组人可溶性血栓调节蛋白(RHTM)及其凝集素样结构域(D1)具有抗炎作用，并中和损伤相关的分子模式。然而，重组人TM和D1对细胞外组蛋白H3水平和肾脏损伤的影响仍然知之甚少。我们的目的是探讨细胞外组蛋白H3水平与脓毒症大鼠肾脏损伤的关系，并阐明重组人TM和D1对脓毒症大鼠细胞外组蛋白H3水平、肾脏损伤和存活的影响。本研究采用盲肠结扎和穿刺法建立大鼠脓毒症模型。观察大鼠盲肠结扎和穿孔后24 h组蛋白H3水平、肾脏组织病理学变化及存活率。盲肠结扎和穿孔后，组蛋白H3水平随时间增加。组织病理学分析表明，肾小管上皮细胞中变性灶的分布和组蛋白H3的水平同时增加。与赋形剂治疗组相比，给予重组人TM和D1可显著降低组蛋白H3水平，并改善肾脏损伤。Rh TM组和d1组大鼠存活率明显高于赋形剂组。这项研究的结果表明，重组人TM及其D1类似地降低了升高的组蛋白H3水平，从而减轻了急性肾损伤。我们的研究结果还表明，rhTM和D1有可能成为脓毒症合并急性肾损伤的新的治疗策略。
Multiple organ dysfunction induced by sepsis often involves kidney injury. Extracellular histones released in response to damage-associated molecular patterns are known to facilitate sepsis-induced organ dysfunction. Recombinant human soluble thrombomodulin (rhTM) and its lectin-like domain (D1) exert anti-inflammatory effects and neutralize damage-associated molecular patterns. However, the effects of rhTM and D1 on extracellular histone H3 levels and kidney injury remain poorly understood. Our purpose was to investigate the association between extracellular histone H3 levels and kidney injury, and to clarify the effects of rhTM and D1 on extracellular histone H3 levels, kidney injury, and survival in sepsis-induced rats. Rats in whom sepsis was induced via cecal ligation and puncture were used in this study. Histone H3 levels, histopathology of the kidneys, and the survival rate of rats at 24 h after cecal ligation and puncture were investigated. Histone H3 levels increased over time following cecal ligation and puncture. Histopathological analyses indicated that the distribution of degeneration foci among tubular epithelial cells of the kidney and levels of histone H3 increased simultaneously. Administration of rhTM and D1 significantly reduced histone H3 levels compared with that in the vehicle-treated group and improved kidney injury. The survival rates of rats in rhTM- and D1-treated groups were significantly higher than that in the vehicle-treated group. The results of this study indicated that rhTM and its D1 similarly reduce elevated histone H3 levels, thereby reducing acute kidney injury. Our findings also proposed that rhTM and D1 show potential as new treatment strategies for sepsis combined with acute kidney injury.