Harada Tatsuhiko, Shimomura Yasuyo, Nishida Osamu, Maeda Munenori, Kato Yu, Nakamura Tomoyuki, Kuriyama Naohide, Komura Hidefumi
Department of Anesthesiology and Critical Care Medicine, Fujita Health University, School of Medicine, Toyoake, Aichi, Japan.
Fujita Med J. 2023 Aug;9(3):225-230. doi: 10.20407/fmj.2022-026. Epub 2022 Dec 27.
Sepsis is a life-threatening condition characterized by multi-organ dysfunction due to host immune system dysregulation in response to an infection. During sepsis, neutrophils release neutrophil extracellular traps (NETs) as part of the innate immune response. However, excessive NETs play a critical role in the development of organ failure during sepsis. Although recombinant human soluble thrombomodulin (rTM) can inhibit NET formation in the lungs and liver of a mouse model of endotoxin shock, its effects on the kidneys are unclear.
The specific effects of NETs and rTM on the renal cortex and renal medulla were examined in a mouse model of endotoxin shock generated by intraperitoneal (i.p.) injection of lipopolysaccharide (LPS), followed by i.p. injection of rTM or an identical volume of saline 1 h later.
LPS injection increased serum creatinine, blood urea nitrogen, and histone H3 levels. However, rTM administration significantly decreased histone H3 and citrullinated histone H3 (citH3) levels. Immunohistochemical analysis revealed no significant changes in citH3 quantity in the renal cortex of any group. However, in the renal medulla, the increase in citH3 induced by LPS was abolished in the LPS+rTM group.
Our findings demonstrate that rTM can suppress NETs in the renal medulla of mice with endotoxin-induced acute kidney injury.
脓毒症是一种危及生命的病症，其特征为由于宿主免疫系统对感染的失调反应而导致多器官功能障碍。在脓毒症期间，中性粒细胞释放中性粒细胞胞外陷阱（NETs）作为固有免疫反应的一部分。然而，过量的NETs在脓毒症期间器官衰竭的发展中起关键作用。尽管重组人可溶性血栓调节蛋白（rTM）可抑制内毒素休克小鼠模型肺和肝脏中的NET形成，但其对肾脏的影响尚不清楚。
通过腹腔注射脂多糖（LPS）建立内毒素休克小鼠模型，1小时后腹腔注射rTM或等体积的生理盐水，研究NETs和rTM对肾皮质和肾髓质的具体影响。
注射LPS可使血清肌酐、血尿素氮和组蛋白H3水平升高。然而，给予rTM可显著降低组蛋白H3和瓜氨酸化组蛋白H3（citH3）水平。免疫组织化学分析显示，任何组的肾皮质中citH3数量均无显著变化。然而，在肾髓质中，LPS + rTM组消除了LPS诱导的citH3增加。
我们的研究结果表明，rTM可抑制内毒素诱导的急性肾损伤小鼠肾髓质中的NETs。
