Wang Jiangmei, Wu Weiliang, Wen Tingting, Zheng Guoping, Qiu Guanguan, Qian Huifeng, Zhang Ruoyang, Xia Jie, Hu Yaoqin, Huang Ruoqiong, Zang Ruoxi, Le Zhenkai, Shu Qiang, Xu Jianguo
The Children's Hospital of Zhejiang University School of Medicine and National Clinical Research Center for Child Health, 3333 Binsheng Road, Hangzhou, 310052, Zhejiang, China.
The First Affiliated Hospital of Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310006, Zhejiang, China.
Respir Res. 2025 Mar 18;26(1):107. doi: 10.1186/s12931-025-03181-1.
Sepsis is a common indirect insult leading to acute respiratory distress syndrome (ARDS). Circulating extracellular vesicles (EVs) have been reported to participate in the pathogenesis of sepsis. However, the alteration of EV-bound S100A8/A9 during septic shock, along with the role of S100A8/A9 in driving acute lung injury, remains unexplored.
EVs were isolated from the plasma of patients upon admission with sepsis or septic shock, as well as from healthy controls. Levels of EV S100A8/A9 were assayed via ELISA. To examine the effects and underlying mechanisms of septic shock EVs in acute lung injury, these EVs were administered intratracheally into wild-type C57BL/6 mice or mice with a deficiency of advanced glycation end-products (RAGE). In addition, a mouse model of polymicrobial sepsis was introduced using cecal ligation and puncture (CLP).
Levels of EV S100A8/A9 were significantly elevated in patients with sepsis or septic shock compared to healthy controls. Receiver operating characteristic (ROC) analysis demonstrated that EV S100A8/A9 effectively distinguished between septic shock and sepsis and had predictive potential for the development of ARDS. Notably, the levels of S100A8/A9 in EVs and alveolar macrophages from CLP mice were significantly higher than those in sham mice. Intratracheal administration of septic shock EVs directly induced acute lung injury and M1 macrophage polarization in a lipopolysaccharide-independent manner. Septic shock EVs were efficiently taken up by alveolar macrophages in vivo, leading to a significant increase in S100A8/A9 levels, which was inhibited by preincubating the EVs with an S100A8/A9 neutralizing antibody. Additionally, mice with deficiency in RAGE, a receptor for S100A8/A9, were partially protected from acute lung injury induced by septic shock EVs. In vitro, septic shock EVs prompted a proinflammatory response in bone marrow-derived macrophages. This response was blocked by preincubating the EVs with the S100A8/A9 neutralizing antibody.
Our results suggested that EV S100A8/A9 has potential value in distinguishing septic shock from sepsis and predicting the development of ARDS. Septic shock EVs-induced lung injury is at least partially mediated through S100A8/A9-RAGE pathway, involving the activation of alveolar macrophages.
脓毒症是导致急性呼吸窘迫综合征（ARDS）的常见间接损伤因素。据报道，循环细胞外囊泡（EVs）参与脓毒症的发病机制。然而，脓毒性休克期间EV结合的S100A8/A9的变化以及S100A8/A9在引发急性肺损伤中的作用仍未得到探索。
从脓毒症或脓毒性休克患者入院时的血浆以及健康对照者的血浆中分离出EVs。通过酶联免疫吸附测定法（ELISA）检测EV S100A8/A9的水平。为了研究脓毒性休克EVs在急性肺损伤中的作用及其潜在机制，将这些EVs经气管内给予野生型C57BL/6小鼠或晚期糖基化终产物受体（RAGE）缺陷小鼠。此外，采用盲肠结扎穿刺术（CLP）建立多微生物脓毒症小鼠模型。
与健康对照相比，脓毒症或脓毒性休克患者的EV S100A8/A9水平显著升高。受试者工作特征（ROC）分析表明，EV S100A8/A9能有效区分脓毒性休克和脓毒症，并且对ARDS的发生具有预测潜力。值得注意的是，CLP小鼠的EVs和肺泡巨噬细胞中S100A8/A9的水平显著高于假手术小鼠。经气管内给予脓毒性休克EVs以脂多糖非依赖的方式直接诱导急性肺损伤和M1巨噬细胞极化。脓毒性休克EVs在体内被肺泡巨噬细胞有效摄取，导致S100A8/A9水平显著升高，用S100A8/A9中和抗体预孵育EVs可抑制这一升高。此外，RAGE（S100A8/A9的一种受体）缺陷的小鼠对脓毒性休克EVs诱导的急性肺损伤有部分保护作用。在体外，脓毒性休克EVs促使骨髓来源的巨噬细胞发生促炎反应。用S100A8/A9中和抗体预孵育EVs可阻断这一反应。
我们 的结果表明，EV S100A8/A9在区分脓毒性休克和脓毒症以及预测ARDS的发生方面具有潜在价值。脓毒性休克EVs诱导的肺损伤至少部分是通过S100A8/A9-RAGE途径介导的，涉及肺泡巨噬细胞的激活。
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