The orchestrated cellular and molecular responses of the kidney to endotoxin define a precise sepsis timeline.
The orchestrated cellular and molecular responses of the kidney to endotoxin define a precise sepsis timeline.
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DOI：
10.7554/elife.62270
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发表时间：
2021-01-15
期刊：
影响因子：
7.7
通讯作者：
Dagher PC
中科院分区：
文献类型：
--
作者：
Janosevic D;Myslinski J;McCarthy TW;Zollman A;Syed F;Xuei X;Gao H;Liu YL;Collins KS;Cheng YH;Winfree S;El-Achkar TM;Maier B;Melo Ferreira R;Eadon MT;Hato T;Dagher PC
脓毒症是一种动态状态，以可变的速率进展，并具有危及生命的后果。沿着脓毒症时间轴对患者进行分期需要对组织水平上的细胞和分子事件的演变有透彻的了解。在这里，我们研究了肾脏，脓毒症的病理生理学的中心器官。在鼠内毒素血症模型中的单细胞RNA测序揭示了各种细胞群的参与是暂时组织和高度协调的。内皮细胞和基质细胞是第一反应者。在随后的时间点，上皮细胞上调免疫相关途径，同时伴随下调生理功能，如溶质稳态。内毒素注射后16小时，出现全身细胞间通讯障碍和器官关闭。尽管这种明显的器官瘫痪，上游调控分析表明，在愈合和恢复的途径参与显着的活动。这种严格的鼠内毒素血症的空间和时间定义将揭示精确的生物标志物和目标，可以帮助分期和治疗人类脓毒症。
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.