【摘要】 目的：探究高海拔暴露导致的小鼠肺损伤的类型及其机制。方法：8周龄的雄性C57BL/6小鼠随机分为常氧组和低压低氧暴露组，每组10只，将低压低氧暴露组小鼠持续暴露于6 000 m海拔的低压低氧环境中3d以建立小鼠急性肺损伤模型。取小鼠肺组织；HE和Masson染色观察肺脏病理情况；DESeq2和ClusterProfiler分析转录物组差异表达基因和通路；STRING筛选枢纽基因。结果：与常氧对照组相比，低压低氧暴露组小鼠的肺组织中：肺泡间隔厚度、透明膜数、肺泡腔和肺间质内中性粒细胞浸润以及肺损伤评分显著增加（P<0.01），然而未发生显著纤维化；Alas2、Slc4a1、Rhag、Car1、Car2、Hbb、Agtr1b、Bmp2、Bmper、Vegfc、Foxm1、Fgf18、Igf1、Cxcl12和Mmp14基因的mRNA水平显著升高（P<0.01），而Notch1、Notch4和Cxcr4基因的mRNA水平显著下降（P<0.01）；诱导型一氧化氮合酶（iNOS）、cleaved caspase-3、cleaved PARP、纤连蛋白（fibronectin）、弹性蛋白（elastin）、腱生蛋白C(tenascin C)、基质金属蛋白酶抑制剂1(TIMP1)、WNT3a和β-连环蛋白（β-catenin）的蛋白水平显著升高（P<0.05）。结论：短期高海拔低压低氧暴露通过诱导参与细胞凋亡、血管通透性调控、细胞外基质重塑和Ⅱ型肺泡上皮细胞增殖等过程的基因表达发生显著变化从而诱导小鼠发生急性肺损伤。更多还原

【Abstract】 AIM: To investigate the types and mechanisms of lung injury induced by high-altitude exposure in mice. METHODS: Eight-week-old male C57BL/6 mice were randomly assigned to a normoxia group and a hypobaric hypoxia exposure group, with 10 mice in each group. The hypobaric hypoxia group was continuously exposed to a hypobaric hypoxia environment simulating an altitude of 6 000 m for 3 d to establish an acute lung injury model. Lung tissues were collected. Lung pathological changes were evaluated using HE and Masson staining. Transcriptome analysis was conducted using DESeq2 and ClusterProfiler to identify differentially expressed genes and pathways, and hub genes were screened using the STRING database. RESULTS: Compared with the normoxia group, the hypobaric hypoxia group exhibited significant increases in alveolar septal thickness, hyaline membrane formation, and neutrophil infiltration both in the alveolar space and the interstitial space, along with elevated lung injury scores(P<0. 01), with no significant fibrosis observed. The mRNA levels of Alas2, Slc4a1, Rhag, Car1, Car2, Hbb, Agtr1b, Bmp2, Bmper, Vegfc, Foxm1, Fgf18, Igf1, Cxcl12 and Mmp14 genes were significantly elevated(P<0. 01), while Notch1, Notch4 and Cxcr4 mRNA levels were significantly decreased(P<0. 01). Protein levels of inducible nitric oxide synthase(iNOS), cleaved caspase-3, cleaved PARP, fibronectin, elastin, tenascin C, tissue inhibitor of metalloproteinase-1(TIMP1), WNT3a, and β-catenin were significantly increased(P<0. 05). CONCLUSION: Short-term high-altitude hypobaric hypoxia exposure induced acute lung injury in mice by significantly altering the expression of genes involved in apoptosis, vascular permeability regulation, extracellular matrix remodeling, and type Ⅱ alveolar epithelial cell proliferation.更多还原