Schmoch Thomas, Gallenstein Nadia, Peters Verena, Bartosova Maria, Uhle Florian, Kummer Laura, Mair Anian, Krauser Ute, Feisst Manuel, Nawroth Peter P, Weigand Markus A, Schmitt Claus Peter, Brenner Thorsten
Department of Anesthesiology and Intensive Care Medicine, University Hospital Essen, University Duisburg-Essen, Essen, Germany; Medical Faculty Heidelberg, Department of Anesthesiology, Heidelberg University, Heidelberg, Germany; Department of Anesthesiology and Intensive Care Medicine, Hôpitaux Robert Schuman - Hôpital Kirchberg, Luxembourg City, Luxembourg.
Medical Faculty Heidelberg, Department of Anesthesiology, Heidelberg University, Heidelberg, Germany.
EBioMedicine. 2025 Apr;114:105644. doi: 10.1016/j.ebiom.2025.105644. Epub 2025 Mar 18.
We previously identified methylglyoxal as a biomarker for early identification and outcome prediction in human sepsis. We hypothesised that methylglyoxal causally impacts disease severity, and the methylglyoxal-scavenging dipeptide anserine can attenuate the detrimental effects of methylglyoxal.
Using a translational approach, secondary analyses of two observational trials were performed to test the initial hypotheses. Afterwards, these results were re-evaluated in different murine models of experimental sepsis in vivo. The detrimental effects of methylglyoxal as well as the underlying mechanisms were further assessed in vitro using transendothelial electrical resistance measurements, fluorescence-activated cell sorting analyses, cytokine assays, gene expression analyses, and enzyme activity assays, as well as immunofluorescence and immunohistochemistry staining.
The secondary analyses confirmed methylglyoxal as an independent marker associated with increased mortality within the first 48 h after sepsis onset and high catecholamine and fluid requirements in the first 24 h after sepsis onset. In the sepsis models, methylglyoxal-derived carbonyl stress significantly contributed to the development of capillary leakage by disrupting endothelial barrier-forming proteins. Mechanistically, a pathway involving the receptor of advanced glycation end products and mitogen-activated protein kinase was identified. The methylglyoxal-scavenging dipeptide anserine (β-alanyl-N-methylhistidine) reduced methylglyoxal-induced advanced glycation end-product formation and disruptions of junctional complexes in vitro. Moreover, anserine reduced capillary leakage and mortality in vivo.
Methylglyoxal causally contributes to capillary leak formation and mortality in experimental sepsis, which can be mitigated by anserine. Therefore, anserine represents an innovative therapeutic option for the treatment of septic shock.
German Research Foundation (grant number BR 4144/2-1).
我们之前已确定甲基乙二醛是人类脓毒症早期识别和预后预测的生物标志物。我们推测甲基乙二醛对疾病严重程度有因果影响，而清除甲基乙二醛的二肽肌肽可减轻甲基乙二醛的有害作用。
采用转化研究方法，对两项观察性试验进行二次分析以检验初始假设。之后，在不同的实验性脓毒症小鼠体内模型中对这些结果进行重新评估。使用跨内皮电阻测量、荧光激活细胞分选分析、细胞因子检测、基因表达分析、酶活性检测以及免疫荧光和免疫组织化学染色，在体外进一步评估甲基乙二醛的有害作用及其潜在机制。
二次分析证实甲基乙二醛是一个独立标志物，与脓毒症发作后48小时内死亡率增加以及脓毒症发作后24小时内高儿茶酚胺和液体需求量相关。在脓毒症模型中，甲基乙二醛衍生的羰基应激通过破坏内皮屏障形成蛋白，显著促成了毛细血管渗漏的发生。从机制上看，确定了一条涉及晚期糖基化终产物受体和丝裂原活化蛋白激酶的途径。清除甲基乙二醛的二肽肌肽（β-丙氨酰-N-甲基组氨酸）在体外减少了甲基乙二醛诱导的晚期糖基化终产物形成以及连接复合体的破坏。此外，肌肽在体内降低了毛细血管渗漏和死亡率。
甲基乙二醛在实验性脓毒症中对毛细血管渗漏形成和死亡率有因果作用，而肌肽可减轻这种作用。因此，肌肽是治疗感染性休克的一种创新治疗选择。
德国研究基金会（资助编号BR 4144/2 - 1）
