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肾脏对内毒素的协调细胞和分子反应定义了一个精确的脓毒症时间进程。

The orchestrated cellular and molecular responses of the kidney to endotoxin define a precise sepsis timeline.

机构信息

Department of Medicine, Indiana University School of Medicine, Indianapolis, United States.

Department of Pediatrics and the Herman B. Wells Center, Indiana University School of Medicine, Indianapolis, United States.

出版信息

Elife. 2021 Jan 15;10:e62270. doi: 10.7554/eLife.62270.

DOI:10.7554/eLife.62270
PMID:33448928
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7810465/
Abstract

Sepsis is a dynamic state that progresses at variable rates and has life-threatening consequences. Staging patients along the sepsis timeline requires a thorough knowledge of the evolution of cellular and molecular events at the tissue level. Here, we investigated the kidney, an organ central to the pathophysiology of sepsis. Single-cell RNA-sequencing in a murine endotoxemia model revealed the involvement of various cell populations to be temporally organized and highly orchestrated. Endothelial and stromal cells were the first responders. At later time points, epithelial cells upregulated immune-related pathways while concomitantly downregulating physiological functions such as solute homeostasis. Sixteen hours after endotoxin, there was global cell-cell communication failure and organ shutdown. Despite this apparent organ paralysis, upstream regulatory analysis showed significant activity in pathways involved in healing and recovery. This rigorous spatial and temporal definition of murine endotoxemia will uncover precise biomarkers and targets that can help stage and treat human sepsis.

摘要

脓毒症是一种动态状态，其进展速度不一，可导致危及生命的后果。要沿着脓毒症时间轴对患者进行分期，就需要深入了解组织水平上细胞和分子事件的演变。在这里，我们研究了肾脏，这是脓毒症病理生理学的核心器官。在小鼠内毒素血症模型中的单细胞 RNA 测序揭示了各种细胞群体的参与是具有时间组织性和高度协调性的。内皮细胞和基质细胞是最早的反应者。在稍后的时间点，上皮细胞上调了与免疫相关的途径，同时下调了溶质稳态等生理功能。在内毒素后 16 小时，出现了全局细胞间通讯故障和器官衰竭。尽管出现了这种明显的器官麻痹，但上游调控分析显示，参与愈合和恢复的途径仍有显著的活性。这种对内毒素血症的严格的时空定义将揭示有助于分期和治疗人类脓毒症的精确生物标志物和靶点。

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