Impact of sympathetic hyperactivity induced by brain microglial activation on organ damage in sepsis with chronic kidney disease.

IF 3.8 2区医学 Q1 CRITICAL CARE MEDICINE

Journal of Intensive Care Pub Date : 2024-09-02 DOI:10.1186/s40560-024-00742-2

Masaaki Nishihara, Keisuke Shinohara, Shota Ikeda, Tomohiko Akahoshi, Hiroyuki Tsutsui

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Abstract

Background: 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.

Methods and results: 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.

Conclusions: 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.

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脑小胶质细胞激活引起的交感神经亢进对慢性肾脏病败血症器官损伤的影响

背景：交感神经活动（SNA）在败血症和慢性肾脏病（CKD）等多种疾病的发病机制中起着核心作用。下丘脑室旁核（PVN）中小胶质细胞的激活与交感神经活动有关。脓毒症合并慢性肾脏病导致不良预后的机制仍有待确定。因此，我们旨在阐明小胶质细胞活化导致的 SNA 增加对与 CKD 相关的败血症的血液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，然后接受盲肠结扎和穿刺（CLP）或假手术。与 Nx-Sham 大鼠相比，Nx-CLP 大鼠术后血压下降，心率加快，血清肌酐和胆红素水平升高，血小板计数减少。心率变异性分析表明，Nx-CLP 大鼠的低频与高频（LF/HF）比率增加，表明 SNA 增加。此外，Nx-CLP 大鼠的肌酐和胆红素水平较高，血小板计数也低于 CLP 后的假大鼠。在方案 2 中，Nx-CLP 大鼠被分为两个亚组：一组接受米诺环素（一种小神经胶质细胞活化抑制剂）治疗，另一组通过渗透微型泵在脑室内接受人工脑脊液（CSF）治疗。与CSF治疗组（Nx-CSF-CLP）相比，米诺环素治疗组（Nx-mino-CLP）的低血压和心率增快反应减弱，低频/高频比值也有所下降。超声心动图显示，Nx-mino-CLP 组的左心室尺寸和下腔静脉较大。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：脓毒症大鼠合并 CKD 时，SNA 明显升高，器官功能障碍加重。有人认为，这些模型中器官功能障碍加剧的机制可能涉及系统血流动力学异常，这可能是中枢交感神经系统通过激活 PVN 中的小胶质细胞引发的。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Intensive Care Medicine-Critical Care and Intensive Care Medicine

CiteScore

11.90

自引率

1.40%

发文量

审稿时长

15 weeks

期刊介绍： "Journal of Intensive Care" is an open access journal dedicated to the comprehensive coverage of intensive care medicine, providing a platform for the latest research and clinical insights in this critical field. The journal covers a wide range of topics, including intensive and critical care, trauma and surgical intensive care, pediatric intensive care, acute and emergency medicine, perioperative medicine, resuscitation, infection control, and organ dysfunction. Recognizing the importance of cultural diversity in healthcare practices, "Journal of Intensive Care" also encourages submissions that explore and discuss the cultural aspects of intensive care, aiming to promote a more inclusive and culturally sensitive approach to patient care. By fostering a global exchange of knowledge and expertise, the journal contributes to the continuous improvement of intensive care practices worldwide.