Lipopolysaccharide induces acute lung injury and alveolar haemorrhage in association with the cytokine storm, coagulopathy and AT1R/JAK/STAT augmentation in a rat model that mimics moderate and severe Covid-19 pathology
Lipopolysaccharide induces acute lung injury and alveolar haemorrhage in association with the cytokine storm, coagulopathy and AT1R/JAK/STAT augmentation in a rat model that mimics moderate and severe Covid-19 pathology
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DOI：
10.1111/1440-1681.13620
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发表时间：
2022-02-09
影响因子：
2.9
通讯作者：
Maarouf, Amro
中科院分区：
文献类型：
--
作者：
Al-Ani, Bahjat;ShamsEldeen, Asmaa M.;Maarouf, Amro
啮齿类动物中新冠肺炎研究的进展受到了血管紧张素转换酶2（ACE 2;病毒进入靶细胞的途径）对跨物种病毒刺突蛋白亲和力缺乏的阻碍。因此，我们试图确定脂多糖（LPS）诱导的大鼠急性呼吸窘迫综合征的改良方案是否可以模拟细胞信号通路以及Covid-19疾病的严重疾病表型。腹腔注射LPS 15 mg/kg（模型组）或生理盐水（对照组），3d后处死大鼠。在模型组中观察到严重急性呼吸综合征（SARS）样效应，如通过“细胞因子风暴”（IL-6、IL-17 A、GM-CSF和TNF-α的血液水平增加>2.7倍）、高血铁蛋白、可证实的凝血病（包括升高的D-二聚体（约10倍增加）、派-1、PT和APTT（p < 0.0001））的发展所证明的。此外，LPS增加肺血管紧张素II I型受体（AT 1 R）-JAK-STAT轴的表达（增加>4倍）。胸部影像学检查显示双肺小斑片状阴影。重度肺损伤表现为肺泡萎陷和出血、气道腔上皮细胞脱落、炎性细胞（CD 45+白细胞）浸润、肺泡间隔广泛增厚以及与Covid-19相似的超微结构改变。因此，这些发现表明，向大鼠IT注射15 mg/kg LPS诱导了AT 1 R/JAK/STAT介导的细胞因子风暴，导致肺炎和凝血病，与人类中观察到的中度和重度Covid-19疾病相当。
Progress in the study of Covid-19 disease in rodents has been hampered by the lack of angiotensin-converting enzyme 2 (ACE2; virus entry route to the target cell) affinities for the virus spike proteins across species. Therefore, we sought to determine whether a modified protocol of lipopolysaccharide (LPS)-induced acute respiratory distress syndrome in rats can mimic both cell signalling pathways as well as severe disease phenotypes of Covid-19 disease. Rats were injected via intratracheal (IT) instillation with either 15 mg/kg of LPS (model group) or saline (control group) before being killed after 3 days. A severe acute respiratory syndrome (SARS)-like effect was observed in the model group as demonstrated by the development of a "cytokine storm" (>2.7 fold increase in blood levels of IL-6, IL-17A, GM-CSF, and TNF-alpha), high blood ferritin, demonstrable coagulopathy, including elevated D-dimer (approximately 10-fold increase), PAI-1, PT, and APTT (p < 0.0001). In addition, LPS increased the expression of lung angiotensin II type I receptor (AT1R)-JAK-STAT axis (>4 fold increase). Chest imaging revealed bilateral small patchy opacities of the lungs. Severe lung injury was noted by the presence of both, alveolar collapse and haemorrhage, desquamation of epithelial cells in the airway lumen, infiltration of inflammatory cells (CD45+ leukocytes), widespread thickening of the interalveolar septa, and ultrastructural alterations similar to Covid-19. Thus, these findings demonstrate that IT injection of 15 mg/kg LPS into rats, induced an AT1R/JAK/STAT-mediated cytokine storm with resultant pneumonia and coagulopathy that was commensurate with moderate and severe Covid-19 disease noted in humans.