Kim Yoon Tae, Jeong Geunyeol, Kim Yihyo, Roh HyeonJu, Lim Susung, Jang Jinah, Choi Yun Hui, Park Kyoung Chul, Jin Mirim
Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon 21999, Republic of Korea.
College of Medicine, Gachon University, Incheon 21936, Republic of Korea.
Biomol Ther (Seoul). 2025 Sep 1;33(5):852-865. doi: 10.4062/biomolther.2025.071. Epub 2025 Aug 13.
Sepsis is a leading cause of mortality in hospitals with a lack of reliable biomarkers and specialized therapeutics. Recently, highly secreted tryptophanyl-tRNA synthetase 1 (WARS1), an endogenous ligand for Toll-like receptor (TLR) 2 and TLR4, was found to be a potential theranostic target for hypercytokinemic severe sepsis. In this study, using the minipig sepsis model inoculated with cecum slurry, we demonstrated that increases in WARS1 levels were associated with severity of sepsis and showed strong correlations with RBC count and the levels of HGB, HCT, EPO, lactate, and PLT count in the acute phase of sepsis. Further, administration of the WARS1 neutralizing antibody to the septic minipigs inhibited the increase in the overall SOFA score with a significantly lower P/F ratio, which was accompanied by the suppression of proinflammatory cytokine and chemokine expressions as well as EPO production, a decrease in AST and ALT levels, and inflammatory immune cell infiltration in the lung. Taken together, these findings provide a novel insight into the pathophysiology of acute phase of sepsis and suggest the clinical application of WARS1 neutralizing therapeutics in the treatment of sepsis.
脓毒症是医院内导致死亡的主要原因之一，目前缺乏可靠的生物标志物和专门的治疗方法。最近，人们发现高分泌型色氨酰 - tRNA合成酶1（WARS1）作为Toll样受体（TLR）2和TLR4的内源性配体，是高细胞因子血症性严重脓毒症的一个潜在诊疗靶点。在本研究中，我们使用接种盲肠匀浆的小型猪脓毒症模型，证明WARS1水平的升高与脓毒症的严重程度相关，并且在脓毒症急性期与红细胞计数以及血红蛋白、血细胞比容、促红细胞生成素、乳酸和血小板计数水平呈现出强相关性。此外，给脓毒症小型猪注射WARS1中和抗体可抑制总体序贯器官衰竭评估（SOFA）评分的升高，同时显著降低P/F比值，这伴随着促炎细胞因子和趋化因子表达的抑制以及促红细胞生成素的产生，天冬氨酸氨基转移酶（AST）和丙氨酸氨基转移酶（ALT）水平降低，以及肺部炎症免疫细胞浸润减少。综上所述，这些发现为脓毒症急性期的病理生理学提供了新的见解，并提示WARS1中和疗法在脓毒症治疗中的临床应用前景。
