Wang Qian, Yu Zhicai, Song Zhixin, Lu Xue, Li Zhu, Pi Dandan, Li Jing, Xu Feng
Department of Critical Care Medicine, Children's Hospital of Chongqing Medical University, Chongqing, China.
National Clinical Research Center for Child Health and Disorders, Chongqing, China.
J Inflamm (Lond). 2025 Jan 24;22(1):4. doi: 10.1186/s12950-025-00430-4.
Sepsis is a severe condition causing organ failure due to an abnormal immune reaction to infection, characterized by ongoing excessive inflammation and immune system issues. Osteopontin (OPN) is secreted by various cells and plays a crucial role in inflammatory responses and immune regulation. Nonetheless, the precise function of OPN in sepsis remains to be elucidated.
In the present study, we evaluated the levels of OPN in paediatric patients with sepsis and healthy individuals. We examined the impact of OPN on survival rates, systemic inflammation, and lung injury within an experimental sepsis model using cecal ligation and puncture (CLP). Furthermore, the pro-inflammatory effects and potential mechanisms of OPN in sepsis were investigated through Mouse Hemophagocytic Synuclein (MH-S) cells.
The OPN level was found to be elevated in patients with sepsis (368.5 ± 249.4 ng/ml) compared to children with infections (73.78 ± 40.46 ng/ml) (p < 0.0001) and healthy individuals (44.03 ± 20.76 ng/ml) (p < 0.0001). The serum concentration of OPN was elevated in pediatric patients with septic shock compared to those with sepsis (504 ± 266.3 ng/ml vs. 238.6 ± 143.8 ng/ml, p < 0.001). Intravenous administration of OPN inhibitor into the tail vein decreased the mortality rate (HR = 0.2695, p = 0.0015), suppressed systemic inflammatory responses and mitigated lung tissue damage. The concentration of tumour necrosis factor (TNF)-α, IL-6 and IL-1β in serum of CLP mice treated with OPN inhibitor decreased compared with CLP mice. Within the sepsis mouse model, there was a marked increase in OPN expression in the lung's tissues compared to the sham group mice. This surge was accompanied by a significant accumulation of alveolar macrophages and an upregulation of inflammasome expression. Mechanistic investigations in MH-s cells revealed that OPN-siRNA suppressed the LPS-induced macrophage inflammatory response by inhibiting caspase1-dependent classical pyroptosis signaling pathway. However, recombinant OPN was supplemented after OPN silencing, the protective effects in MH-s cells treated with LPS were reversed.
This study reveals that OPN has an adverse impact on the host's immune response to sepsis. Suppressing OPN expression holds potential therapeutic value for the treatment of sepsis.
Study on the diagnostic value of osteopontin in children with sepsis. MR5024001771. Registered 22 January 2024. https//www.medicalresearch.org.cn.
脓毒症是一种严重病症，由于对感染的异常免疫反应导致器官衰竭，其特征为持续的过度炎症反应和免疫系统问题。骨桥蛋白（OPN）由多种细胞分泌，在炎症反应和免疫调节中起关键作用。然而，OPN在脓毒症中的具体功能仍有待阐明。
在本研究中，我们评估了脓毒症患儿和健康个体的OPN水平。我们在采用盲肠结扎和穿刺（CLP）的实验性脓毒症模型中，研究了OPN对生存率、全身炎症反应和肺损伤的影响。此外，通过小鼠噬血细胞性突触核蛋白（MH-S）细胞研究了OPN在脓毒症中的促炎作用及其潜在机制。
发现脓毒症患者的OPN水平（368.5±249.4 ng/ml）高于感染患儿（73.78±40.46 ng/ml）（p<0.0001）和健康个体（44.03±20.76 ng/ml）（p<0.0001）。与脓毒症患儿相比，感染性休克患儿的血清OPN浓度升高（504±266.3 ng/ml对238.6±143.8 ng/ml，p<0.001）。经尾静脉注射OPN抑制剂可降低死亡率（HR=0.2695，p=0.0015），抑制全身炎症反应并减轻肺组织损伤。与CLP小鼠相比，用OPN抑制剂处理的CLP小鼠血清中肿瘤坏死因子（TNF）-α、IL-6和IL-1β的浓度降低。在脓毒症小鼠模型中，与假手术组小鼠相比，肺组织中OPN表达显著增加。这种增加伴随着肺泡巨噬细胞的大量积聚和炎性小体表达的上调。在MH-s细胞中的机制研究表明，OPN-siRNA通过抑制半胱天冬酶1依赖性经典细胞焦亡信号通路，抑制LPS诱导的巨噬细胞炎症反应。然而，在OPN沉默后补充重组OPN，LPS处理的MH-s细胞中的保护作用被逆转。
本研究表明，OPN对宿主对脓毒症的免疫反应有不利影响。抑制OPN表达对脓毒症治疗具有潜在的治疗价值。
骨桥蛋白对脓毒症患儿的诊断价值研究。MR5024001771。2024年1月22日注册。https//www.medicalresearch.org.cn。
