Mouse Bone Marrow Mesenchymal Stem Cells Inhibit Sepsis- Induced Lung Injury in Mice via Exosomal SAA1
Mouse Bone Marrow Mesenchymal Stem Cells Inhibit Sepsis- Induced Lung Injury in Mice via Exosomal SAA1
复制标题
小鼠骨髓间充质干细胞通过外泌体 SAA1 抑制小鼠脓毒症引起的肺损伤
DOI：
10.1021/acs.molpharmaceut.2c00542
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发表时间：
2022-09-29
影响因子：
4.9
通讯作者：
Jiang, Lai
中科院分区：
文献类型：
--
作者：
Lv, Zhou;Duan, Shuxian;Jiang, Lai
脓毒症是一种全球性疾病负担，约40%的病例发生急性肺损伤（ALI）。骨髓间充质干细胞（BMSCs）及其外泌体被广泛用于治疗包括脓毒症在内的多种疾病。血清淀粉样蛋白A1（SAA 1）作为一种急性时相蛋白，调节炎症和免疫。然而，SAA 1在BMSC-外泌体中在脓毒性肺损伤中的作用仍有待阐明。通过超离心分离源自血清和BMSC的外泌体。使用慢病毒质粒在小鼠BMSC中沉默或过表达SAA 1，所述慢病毒质粒含有SAA 1靶向短干扰RNA或SAA 1 cDNA。通过盲肠结扎穿孔（CLP）诱导脓毒症。LPS诱导小鼠急性肺损伤。用流式细胞仪分离小鼠肺泡巨噬细胞。使用商业试剂盒测量SAA 1、内毒素、TNF-α和IL-6的水平。通过免疫染色监测LPS内化。进行RT-qPCR或免疫印迹来测试基因和蛋白质表达。脓毒症诱导的肺损伤患者的血清外泌体具有显著更高的SAA 1、内毒素、TNF-α和IL-6水平。SAA 1在BMSCs中的过表达抑制CLP或LPS诱导的肺损伤，并降低CLP或LPS诱导的内毒素、TNF-α和IL-6水平。给药的SAA 1封闭肽被发现部分抑制SAA 1诱导的LPS内化的小鼠肺泡巨噬细胞和逆转SAA 1的保护作用。总之，BMSCs通过外泌体SAA 1抑制脓毒症诱导的肺损伤。这些结果突出了BMSCs、外泌体和SAA 1的重要性，这可能为脓毒性肺损伤的治疗提供新的方向。
Sepsis is a global disease burden, and approximately 40% of cases develop acute lung injury (ALI). Bone marrow mesenchymal stromal cells (BMSCs) and their exosomes are widely used in treating a variety of diseases including sepsis. As an acute phase protein, serum amyloid A1 (SAA1) regulates inflammation and immunity. However, the role of SAA1 in BMSCs-exosomes in septic lung injury remains to be elucidated. Exosomes derived from serum and BMSCs were isolated by ultracentrifugation. SAA1 was silenced or overexpressed in mouse BMSCs using lentiviral plasmids, containing either SAA1-targeting short interfering RNAs or SAA1 cDNA. Sepsis was induced by cecal ligation and puncture (CLP). LPS was used to induce ALI in mice. Mouse alveolar macrophages were isolated by flow cytometry. Levels of SAA1, endotoxin, TNF-alpha , and IL-6 were measured using commercial kits. LPS internalization was monitored by immunostaining. RT-qPCR or immunoblots were performed to test gene and protein expressions. Serum exosomes of patients with sepsis-induced lung injury had significantly higher levels of SAA1, endotoxin, TNF-alpha , and IL-6. Overexpression of SAA1 in BMSCs inhibited CLP-or LPS-induced lung injury and decreased CLP-or LPS-induced endotoxin, TNF-alpha , and IL-6 levels. Administration of the SAA1 blocking peptide was found to partially inhibit SAA1-induced LPS internalization by mouse alveolar macrophages and reverse the protective effect of SAA1. In conclusion, BMSCs inhibit sepsis-induced lung injury through exosomal SAA1. These results highlight the importance of BMSCs, exosomes, and SAA1, which may provide novel directions for the treatment of septic lung injury.