中国病理生理杂志2025，Vol.41Issue(12)：2479-2488,10.DOI:10.3969/j.issn.1000-4718.2025.12.024
小鼠脓毒症急性肺损伤二次打击模型构建研究
A two-hit murine model of acute lung injury in sepsis:construction and pathophysiological validation
摘要
Abstract
AIM:This study aims to establish a two-hit murine model of sepsis-induced lung injury,providing a reliable foundation for investigating its pathogenic mechanisms and developing anti-inflammatory drugs.METHODS:Male C57BL/6J mice(n=10 per group)were randomly assigned to five groups:sham group,low-,medium-,and high-dose lipopolysaccharide(LPS-L,LPS-M,and LPS-H)groups,and a positive drug intervention dexamethasone(Dex)group(LPS-M+Dex group).A two-hit modeling approach was employed.First,systemic inflammation was induced by intraperitoneal injection of LPS at 2.5,5,or 10 mg/kg,followed 16 h later by intratracheal instillation of LPS(1.25,2.5,or 5 mg/kg)to elicit targeted lung injury.At 24 h post-second hit,blood samples,bronchoalveolar lavage fluid(BALF),and organ tissues were harvested.Model evaluation included assessment of the mouse sepsis score(MSS),body weight changes,peripheral blood inflammatory cell counts,chest X-ray imaging,gross lung morphology,pulmonary in-flammatory parameters,hematoxylin and eosin(HE)staining with histopathological scoring,and immunohistochemical quantification of lung barrier integrity markers—namely,intercellular adhesion molecule-1(ICAM-1),vascular cell adhe-sion molecule-1(VCAM-1),and zonula occludens-1(ZO-1).RESULTS:Compared to the sham-operated group,model mice exhibited typical symptoms of sepsis,including a significantly increased MSS and decreased body weight(P<0.01).The organ indices of the lung,heart,spleen,and kidney were significantly elevated(P<0.05),whereas platelet count and lymphocyte number were significantly reduced(P<0.05).Radiographic and gross observation revealed markedly in-creased pulmonary infiltration on X-ray and prominent pulmonary petechiae on gross observation(P<0.01).The lung wet-to-dry ratio,BALF protein content,and pathological score were significantly increased(P<0.05),accompanied by a sig-nificant upregulation of myeloperoxidase(MPO)expression in lung tissue(P<0.05).Furthermore,the expression levels of intercellular adhesion molecules(ICAM-1,VCAM-1)were significantly upregulated(P<0.05),while the expression of ZO-1 was markedly downregulated in lung tissue(P<0.05).Dexamethasone intervention effectively reversed the afore-mentioned pathological alterations.CONCLUSION:The LPS two-hit strategy successfully established a murine model of sepsis-induced lung injury that effectively replicates the key pathophysiological characteristics of the condition.Dexameth-asone demonstrated a significant protective effect against sepsis-induced lung injury.关键词
脓毒症/肺损伤/脂多糖Key words
sepsis/acute lung injury/lipopolysaccharide分类
医药卫生引用本文复制引用
王晨,吕海钢,许加安,单乐天,周莉,何煜舟,袁强..小鼠脓毒症急性肺损伤二次打击模型构建研究[J].中国病理生理杂志,2025,41(12):2479-2488,10.基金项目
浙江省尖兵领雁项目(No.2025C02188) （No.2025C02188）
