Nishihara Masaaki, Shinohara Keisuke, Ikeda Shota, Akahoshi Tomohiko, Tsutsui Hiroyuki
Emergency and Critical Care Center, Kyushu University Hospital, Fukuoka, Japan.
Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
J Intensive Care. 2024 Sep 2;12(1):31. doi: 10.1186/s40560-024-00742-2.
Sympathetic nerve activity (SNA) plays a central role in the pathogenesis of several diseases such as sepsis and chronic kidney disease (CKD). Activation of microglia in the paraventricular nucleus of the hypothalamus (PVN) has been implicated in SNA. The mechanisms responsible for the adverse prognosis observed in sepsis associated with CKD remain to be determined. Therefore, we aimed to clarify the impact of increased SNA resulting from microglial activation on hemodynamics and organ damage in sepsis associated with CKD.
In protocol 1, male Sprague-Dawley rats underwent either nephrectomy (Nx) or sham surgery followed by cecal ligation and puncture (CLP) or sham surgery. After CLP, Nx-CLP rats exhibited decreased blood pressure, increased heart rate, elevated serum creatinine and bilirubin levels, and decreased platelet count compared to Nx-Sham rats. Heart rate variability analysis revealed an increased low to high frequency (LF/HF) ratio in Nx-CLP rats, indicating increased SNA. Nx-CLP rats also had higher creatinine and bilirubin levels and lower platelet counts than sham-CLP rats after CLP. In protocol 2, Nx-CLP rats were divided into two subgroups: one received minocycline, an inhibitor of microglial activation, while the other received artificial cerebrospinal fluid (CSF) intracerebroventricularly via an osmotic minipump. The minocycline-treated group (Nx-mino-CLP) showed attenuated hypotensive and increased heart rate responses compared to the CSF-treated group (Nx-CSF-CLP), and the LF/HF ratio was also decreased. Echocardiography showed larger left ventricular dimensions and inferior vena cava in the Nx-mino-CLP group. In addition, creatinine and bilirubin levels were lower and platelet counts were higher in the Nx-mino-CLP group compared to the Nx-CSF-CLP group.
In septic rats with concomitant CKD, SNA was significantly enhanced and organ dysfunction was increased. It has been suggested that the mechanism of exacerbated organ dysfunction in these models may involve abnormal systemic hemodynamics, possibly triggered by activation of the central sympathetic nervous system through activation of microglia in the PVN.
交感神经活动（SNA）在脓毒症和慢性肾脏病（CKD）等多种疾病的发病机制中起核心作用。下丘脑室旁核（PVN）中微胶质细胞的激活与SNA有关。脓毒症合并CKD时不良预后的相关机制仍有待确定。因此，我们旨在阐明微胶质细胞激活导致的SNA增加对脓毒症合并CKD时血流动力学和器官损伤的影响。
在方案1中，雄性Sprague-Dawley大鼠接受肾切除术（Nx）或假手术，随后进行盲肠结扎和穿刺（CLP）或假手术。CLP后，与Nx-假手术组大鼠相比，Nx-CLP组大鼠血压降低、心率增加、血清肌酐和胆红素水平升高，血小板计数降低。心率变异性分析显示，Nx-CLP组大鼠的低频与高频（LF/HF）比值增加，表明SNA增加。CLP后，Nx-CLP组大鼠的肌酐和胆红素水平也高于假手术-CLP组，血小板计数低于假手术-CLP组。在方案2中，Nx-CLP组大鼠分为两个亚组：一组接受米诺环素（一种微胶质细胞激活抑制剂），另一组通过渗透微型泵脑室内注射人工脑脊液（CSF）。与CSF治疗组（Nx-CSF-CLP）相比，米诺环素治疗组（Nx-mino-CLP）的低血压和心率增加反应减弱，LF/HF比值也降低。超声心动图显示，Nx-mino-CLP组左心室尺寸和下腔静脉更大。此外，与Nx-CSF-CLP组相比，Nx-mino-CLP组的肌酐和胆红素水平更低，血小板计数更高。
在合并CKD的脓毒症大鼠中，SNA显著增强，器官功能障碍增加。提示这些模型中器官功能障碍加重的机制可能涉及异常的全身血流动力学，可能是由PVN中微胶质细胞激活引发中枢交感神经系统激活所致。
