WEHI研究所成果：有望克服“细胞因子风暴” 

资讯作者：Emily Henderson

编辑翻译：菁菁

一个国际研究团队发现了一种类似药物的化合物，该化合物可以阻断关键的炎症信号途径，抑制过度的炎症反应，避免“细胞因子风暴”，从而有助于治疗包括COVID-19在内的多种疾病。

Seth Masters是WEHI（Walter and Eliza Hall Institute of Medical Research）研究所的副教授。他和他的研究团队发现，一种化合物可以抑制关键炎症蛋白CD14的上调。这一发现发表在EBioMedicine上。

具体而言，研究人员发现了一种类似药物的化合物。这种化合物可阻断关键的炎症途径，该途径与免疫细胞蛋白CD14相关。

在实验室中，这一化合物降低了CD14的表达水平，从而起到抑制炎症反应的作用。研究团队希望他们发现的化合物可以推动炎症相关疾病的新药开发。

Seth副教授说，炎症是人体应对感染的自然反应。他说：“起初，炎症可以帮助人体对抗感染。但是，如果炎症反应过度，就会引起一系列慢性、急性疾病。”

“在COVID-19等病毒性疾病中，一些患者会出现过度的炎症反应，如‘细胞因子风暴’。这可能导致住院或死亡。通过阻断CD14通路，我们可以降低许多疾病的炎症反应，从而减轻症状，并有可能挽救更多生命。”

“本次研究的重点是CD14蛋白质。这种蛋白质在巨噬细胞中被发现。CD14的主要功能是检测感染，促使炎症发生，从而通过炎症清除病原体。然而，随着炎症的发展，巨噬细胞中CD14的数量会增加，并可能失控。这可能导致感染，或导致一些疾病恶化。

我们团队使用CRISPR技术探索CD14水平升高的驱动因素。我们发现了许多非常重要的基因——当这些基因被关闭，则可以避免CD14过度驱动炎症。

令人兴奋的是，类药物抑制剂会阻断其中一个基因产生的蛋白质。在实验室阶段，我们发现这种化合物可以阻止CD14的升高，从而避免引发炎症。这一发现具有难以置信的巨大前景。如果将该化合物开发成为安全有效的药物，它可能会有助于治疗许多炎性疾病。”Seth教授说。他认为，潜在抗炎化合物的发现有助于探索新的抗炎疗法。

但是，Seth副教授还认为，如果成功将这一化合物开发为安全有效的药物，将仅对遏制严重炎症有益。

Seth副教授说：“炎症是抵抗许多传染病的关键过程，因此，我们只需要使用抗炎药来治疗最严重和威胁生命的炎症。”

“这项研究的下一步将是在临床前试验中查看该候选药物是否对特定疾病有效。非常有希望将这一研究转化为一种有效的治疗炎症性疾病的方法。”

英文原文：

Aninternational team of researchers have uncovered a drug-like compound that blocks a crucial inflammatory pathway, potentially paving the way for a new treatment for a host of diseases - including COVID-19.

WEHI's Associate Professor Seth Masters and his research team discovered the compound could prevent up-regulation of CD14, a key inflammatory protein. The discovery was recently published in EBioMedicine.

Researchers have uncovered a drug-like compound that blocks a key inflammatory pathway, involving the immune cell protein CD14.

In the laboratory, the compound reduced CD14 levels, limiting inflammation and preventing it from overwhelming the body.

The team hope the compound could lead to the development of new medicines for inflammatory diseases, including COVID-19.

Inflammation is our body's natural reaction to infection, said Associate Professor Masters. "In the beginning, it helps you fight the infection - but too much inflammation is linked to a range of chronic and acute diseases," he said.

"In a viral disease such as COVID-19, some patients experience excessive inflammation - called a 'cytokine storm' - which can lead to hospitalization or death. Blocking the CD14 pathway can reduce the severity of many diseases, and potentially save lives.

The team focussed their research on a protein called CD14, that is found on certain inflammatory immune cells called macrophages.

CD14's job is to detect infection, helping to drive inflammation to clear a pathogen. But we know that the amount of CD14 increases on macrophages as inflammation progresses, potentially getting out of control, which could lead to worse outcomes for infections or other diseases.

Our team used CRISPR technology to search for genes that help CD14 levels to rise.

We found many really interesting genes that were critical - and when we turned these genes off, they could prevent CD14-driven inflammation from overwhelming the body.

Excitingly, a drug-like inhibitor blocks the protein produced by one of these genes. We found this compound could block the rise in CD14 and consequent inflammation in the laboratory, which is incredibly promising."

Seth Masters, WEHI's Associate Professor

"If this compound could be developed into a safe and effective drug, it could potentially assist in the treatment of many inflammatory diseases,

However, once available, the drug would only be beneficial for curbing severe inflammation.

"Inflammation is a critical process for fighting many infectious, so we only need to use an anti-inflammatory drug for the most severe and life-threatening forms of inflammation," Associate Professor Masters said.

"The next step in this research would be to see if this drug candidate worked against particular diseases in pre-clinical trials. There is great hope this research will one day be translated into an effective treatment for inflammatory illnesses."

参考文献：

Jimenez-Duran, G., Jimenez-Duran, G., et al. (2020) Pharmacological validation of targets regulating CD14 during macrophage differentiation. EBioMedicine. 

doi.org/10.1016/j.ebiom.2020.103039.

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