The critical role of neutrophil-endothelial cell interactions in sepsis: new synergistic approaches employing organ-on-chip, omics, immune cell phenotyping and in silico modeling to identify new therapeutics.
The critical role of neutrophil-endothelial cell interactions in sepsis: new synergistic approaches employing organ-on-chip, omics, immune cell phenotyping and in silico modeling to identify new therapeutics.
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DOI：
10.3389/fcimb.2023.1274842
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发表时间：
2023
影响因子：
5.7
通讯作者：
中科院分区：
文献类型：
--
作者：
败血症是一个全球性的健康问题，占全世界死亡人数的五分之一以上。败血症现在被定义为由宿主对感染反应失调引起的危及生命的器官功能障碍。败血症可由细菌（革兰氏阴性或革兰氏阳性）、真菌或病毒（如COVID）感染引起。然而，在动物模型和传统的体外脓毒症模型中开发的治疗方法在临床试验中几乎没有成功，因为这些模型未能完全复制疾病的潜在病理生理和异质性。目前的理解是，宿主对脓毒症的反应在患者中是高度不同的，这种异质性影响免疫功能和对感染的反应。需要对免疫功能进行表型分析并将败血症患者分类为特定的内型，以开发个性化的治疗方法。中性粒细胞-内皮相互作用在脓毒症的进展中起关键作用，中性粒细胞内流增加和内皮屏障破坏在器官损伤的早期过程中起重要作用。了解中性粒细胞-内皮细胞相互作用的机制以及免疫功能如何影响这种相互作用，可以帮助我们更好地控制疾病，并发现新的诊断和预后工具，以进行有效的治疗。在这篇综述中，我们将讨论最新的研究，探索如何在硅片上建立新的器官模型的协同组合，将人类细胞/组织、组学分析和脓毒症患者的临床数据结合起来，使我们能够识别相关的信号通路并表征患者的特定免疫表型。然后可以利用机器学习等新兴技术来识别可药物治疗靶点，并将其与免疫表型和潜在感染因子联系起来。这种协同方法可以导致新疗法的开发和FDA批准的药物的鉴定，这些药物可以重新用于治疗败血症。
Sepsis is a global health concern accounting for more than 1 in 5 deaths worldwide. Sepsis is now defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Sepsis can develop from bacterial (gram negative or gram positive), fungal or viral (such as COVID) infections. However, therapeutics developed in animal models and traditional in vitro sepsis models have had little success in clinical trials, as these models have failed to fully replicate the underlying pathophysiology and heterogeneity of the disease. The current understanding is that the host response to sepsis is highly diverse among patients, and this heterogeneity impacts immune function and response to infection. Phenotyping immune function and classifying sepsis patients into specific endotypes is needed to develop a personalized treatment approach. Neutrophil-endothelium interactions play a critical role in sepsis progression, and increased neutrophil influx and endothelial barrier disruption have important roles in the early course of organ damage. Understanding the mechanism of neutrophil-endothelium interactions and how immune function impacts this interaction can help us better manage the disease and lead to the discovery of new diagnostic and prognosis tools for effective treatments. In this review, we will discuss the latest research exploring how in silico modeling of a synergistic combination of new organ-on-chip models incorporating human cells/tissue, omics analysis and clinical data from sepsis patients will allow us to identify relevant signaling pathways and characterize specific immune phenotypes in patients. Emerging technologies such as machine learning can then be leveraged to identify druggable therapeutic targets and relate them to immune phenotypes and underlying infectious agents. This synergistic approach can lead to the development of new therapeutics and the identification of FDA approved drugs that can be repurposed for the treatment of sepsis.
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影响因子：
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作者：
通讯作者：
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DOI：
10.1016/s1473-3099(17)30117-2
发表时间：
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影响因子：
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