【作者】 吴琪；

【导师】 吴金虎；

【作者基本信息】 武汉大学 ， 临床药学， 2023， 硕士

【摘要】 背景:脓毒症的主要特征是宿主对感染的反应失调,细胞因子引起的炎症风暴是脓毒症的主要致病机制之一。白细胞介素-3(IL-3)是一种促炎症因子,在炎症性疾病中具有多方面的作用。目前,IL-3在脓毒症的发病机制中的作用是未知的。方法:对重症监护室(ICU)中脓毒症患者、ICU非脓毒症患者和健康志愿者血液中IL-3水平进行了测量和分析。使用2种小鼠模型:盲肠穿刺和结扎(CLP)诱导的和内毒素(LPS)诱导的脓毒症小鼠评估IL-3对生存、器官损伤、细菌清除率、炎症反应和MAPK通路的影响。结果:脓毒症患者的血液IL-3水平显著高于ICU非脓毒症患者和健康志愿者。脓毒症休克患者的血浆IL-3水平比非休克患者明显升高。此外,血浆IL-3水平与序贯器官衰竭评估(SOFA)评分相关。CLP诱导的和LPS诱导的两个脓毒症小鼠模型中,血清IL-3水平升高。抗IL-3抗体延长脓毒症小鼠生存时间,减轻肺、肝和肾组织损伤,提高细菌清除率,减少血清和脾组织中IL-3、白细胞介素-6(IL-6)、白细胞介素1-β(IL-1β)和肿瘤坏死因子-α(TNF-α)炎症因子水平,下调肺、肝和肾组织MAPK通路中磷酸化p38、ERK和JNK蛋白含量。应用重组IL-3蛋白,缩短脓毒症小鼠生存时间,加重肺、肝和肾器官损伤,减轻细菌清除率,升高血清和脾组织中IL-3、IL-6、IL-1β和TNF-α炎症因子水平,上调肺、肝和肾组织MAPK通路中磷酸化p38、ERK、JNK蛋白含量。结论:脓毒症患者血液IL-3水平升高,可能与疾病的严重程度有关。在实验性脓毒症中,抑制IL-3延长脓毒症小鼠生存时间,而IL-3则起相反作用。抗IL-3可能是治疗脓毒症的一个靶点。更多还原

【Abstract】 Background Sepsis is mainly characterized by a dysregulated host response to infection,and cytokine storm syndrome is one of the main pathogenic mechanisms of sepsis.Interleukin-3(IL-3),a pro-inflammatory factor,is a multifaceted role in inflammatory diseases.However,its role in the pathogenesis of sepsis remains unknown.Methods Blood levels of IL-3 were measured and analyzed in Intensive Care Unit(ICU)patients with sepsis,non-septic patients in the ICU,and healthy volunteers.The effects of IL-3 on survival,organ damage,bacterial clearance,inflammation response,and the MAPK pathway were evaluated using two female mouse models:cecal ligation and puncture(CLP)-induced and lipopolysaccharide(LPS)-induced sepsis.Results The blood IL-3 levels of septic patients were significantly higher than those of non-septic ICU patients and healthy volunteers.In patients with septic shock,the plasma IL-3levels were significantly higher than those in non-shock patients.Additionally,plasma IL-3levels correlated with sequential organ failure assessment(SOFA)scores.In two CLP-induced and LPS-induced mouse models of sepsis,the serum levels of IL-3 were increased.Treatment with anti-IL-3 antibodies prolonged the survival of septic mice,reduced lung,liver,and kidney tissues injury,increased bacterial clearance,decreased serum and spleen levels of IL-3,interleukin-6(IL-6),interleukin-1-beta(IL-1β)and tumor necrosis factor-α(TNF-α)inflammatory factors,and down-regulated the levels of phosphorylated p38,ERK and JNK proteins in the MAPK pathway in lung,liver and kidney tissues.Application of recombinant IL-3 protein shortened survival time in septic mice,aggravated organ damage in the lung,liver,and kidney,reduced bacterial clearance,elevated serum and spleen levels of IL-3,IL-6,IL-1β,and TNF-αinflammatory factors,and up-regulated the phosphorylated p38,ERK,and JNK proteins in the MAPK pathway of lung,liver,and kidney tissues.Conclusions Plasma IL-3 levels elevated in patients with sepsis,which may correlate with the severity of the disease.In experimental sepsis,inhibition of IL-3 prolonged survival time in septic mice,whereas IL-3 played the opposite role.Therefore,anti-IL-3 may be a new target for the treatment of sepsis.更多还原