Increase in soluble protein oligomers triggers the innate immune system promoting inflammation and vascular dysfunction in the pathogenesis of sepsis.
Increase in soluble protein oligomers triggers the innate immune system promoting inflammation and vascular dysfunction in the pathogenesis of sepsis.
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DOI：
10.1042/cs20180368
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发表时间：
2018-07-18
期刊：
影响因子：
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通讯作者：
Wenceslau CF
中科院分区：
文献类型：
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作者：
Komic A;Martinez-Quinones P;McCarthy CG;Webb RC;Wenceslau CF
脓毒症是一种严重病态且危及生命的疾病，也是现代医疗经济体日益令人担忧的负担。尽管需要药物血管收缩剂进行充分的容量复苏，感染性休克患者仍表现出持续性低血压，但这种现象的分子机制仍不清楚。错误折叠蛋白的积累与许多疾病有关，并且已观察到可溶性寡聚蛋白中间体是这些条件下的主要细胞毒性物质。寡聚蛋白组装体已被证明可以结合并激活多种模式识别受体 (PRR)，包括甲酰肽受体 (FPR)。虽然抑制内质网应激和稳定蛋白质稳态一直是脓毒症治疗的有希望的研究方向，但很少有人关注错误折叠蛋白质的积累在驱动脓毒症发病机制中可能产生的潜在影响。在这里，我们提出，在脓毒症中，有毒错误折叠蛋白以可溶性蛋白寡聚体（SPO）的形式积累，通过激活一种或多种PRR（包括FPR），导致脓毒症中观察到的炎症和血管功能障碍。我们的实验室发现脓毒症小鼠的心脏和肾内动脉中的 SPO 水平有所增加。我们还观察到，阻力动脉和血管平滑肌细胞暴露于 SPO 与包括 p-ERK 和 p-P38 通路在内的 MAPK 信号传导增加有关，并且这种反应随着 FPR 的敲除而消失。这一假设具有广阔的临床意义，因为它提出了一种可用作脓毒症治疗靶点的新机制。
Sepsis is a profoundly morbid and life-threatening condition, and an increasingly alarming burden on modern healthcare economies. Patients with septic shock exhibit persistent hypotension despite adequate volume resuscitation requiring pharmacological vasoconstrictors, but the molecular mechanisms of this phenomenon remain unclear. The accumulation of misfolded proteins is linked to numerous diseases, and it has been observed that soluble oligomeric protein intermediates are the primary cytotoxic species in these conditions. Oligomeric protein assemblies have been shown to bind and activate a variety of pattern recognition receptors (PRRs) including formyl peptide receptor (FPR). While inhibition of ER stress and stabilization of protein homeostasis have been promising lines of inquiry regarding sepsis therapy, little attention has been given to the potential effects that the accumulation of misfolded proteins may have in driving sepsis pathogenesis. Here we propose that in sepsis there is an accumulation of toxic misfolded proteins in the form of soluble protein oligomers (SPOs) that contribute to the inflammation and vascular dysfunction observed in sepsis via the activation of one or more PRRs including FPR. Our laboratory has shown increased levels of SPOs in the heart and intrarenal arteries of septic mice. We have also observed that exposure of resistance arteries and vascular smooth muscle cells to SPOs is associated with increased MAPK signaling including p-ERK and p-P38 pathways, and that this response is abolished with the knockout of FPR. This hypothesis has promising clinical implications as it proposes a novel mechanism that can be exploited as a therapeutic target in sepsis.