Department of Critical Care Medicine, First Affiliated Hospital of Xinjiang Medical University, Urumqi, No. 137, Liyushan Road, Xinshi District, Urumqi, Xinjiang Uygur Autonomous Region, 830054, People's Republic of China.
Inflammation. 2022 Dec;45(6):2339-2351. doi: 10.1007/s10753-022-01696-z. Epub 2022 Jun 10.
This study aims to confirm the protective effect of Pentraxin 3 (PTX3) on intestinal mucosal barrier damage in sepsis in animal and cell models and explore its mechanism. Analysis of the GSE147775 gene set revealed that the level of PTX3 was upregulated in the lipopolysaccharide (LPS)-induced rat sepsis model. The mice sepsis model was established by cecal ligation perforation (CLP), and the cell inflammation model was induced by LPS. Cell apoptosis and the expression of apoptosis-related protein were detected by flow cytometry and Western blotting. The PTX3 level was significantly upregulated in the mice sepsis model. Intestinal mucosal barrier damage was aggravated and inflammatory factor expression was upregulated after PTX3 downregulation in sepsis mice. After upregulation of PTX3, intestinal mucosal barrier damage was alleviated and inflammatory factor expression was decreased in sepsis mice. Further data mining suggested that the anti-inflammatory effect of PTX3 might be realized through inhibition of the toll-like receptor (TLR) signaling pathway. Moreover, compared with the LPS group, downregulation of PTX3 increased cell apoptosis and the levels of BCL2-associated X (Bax), myeloperoxidase (MPO), tumor necrosis factor-alfa (TNF-α), interleukin 1 beta (IL-1β), and interferon-gamma (IFN-γ), and decreased the levels of B-cell lymphoma-2 (Bcl-2), zona occludens (ZO)-1, and occludin. On the contrary, overexpression of PTX3 reduced cell apoptosis and the levels of Bax, MPO, TNF-α, IL-1β, and IFN-γ. Moreover, downregulation of PTX3 reversed the inhibitive effects on cell apoptosis and inflammation and promotive effects on the levels of Zo-1 and occludin induced by CLI-095 (a TLR signaling pathway inhibitor). In the CLP-induced mice sepsis model and LPS-induced cell inflammation model, PTX3 inhibits inflammatory response and reduces intestinal mucosal barrier damage through the TLR signaling pathway.
本研究旨在确认 Pentraxin 3（PTX3）在动物和细胞模型中对脓毒症肠黏膜屏障损伤的保护作用，并探讨其机制。通过对 GSE147775 基因集进行分析，发现 LPS 诱导的大鼠脓毒症模型中 PTX3 水平上调。通过盲肠结扎穿孔（CLP）建立小鼠脓毒症模型，用 LPS 诱导细胞炎症模型。通过流式细胞术和 Western blot 检测细胞凋亡和凋亡相关蛋白的表达。小鼠脓毒症模型中 PTX3 水平显著上调。下调 PTX3 后，脓毒症小鼠的肠黏膜屏障损伤加重，炎症因子表达上调。上调 PTX3 后，脓毒症小鼠的肠黏膜屏障损伤减轻，炎症因子表达下调。进一步的数据挖掘表明，PTX3 的抗炎作用可能是通过抑制 Toll 样受体（TLR）信号通路实现的。此外，与 LPS 组相比，下调 PTX3 增加了细胞凋亡以及 BCL2 相关 X（Bax）、髓过氧化物酶（MPO）、肿瘤坏死因子-α（TNF-α）、白细胞介素 1β（IL-1β）和干扰素-γ（IFN-γ）的水平，降低了 B 细胞淋巴瘤-2（Bcl-2）、闭合蛋白（ZO）-1 和紧密连接蛋白（occludin）的水平。相反，过表达 PTX3 降低了细胞凋亡以及 Bax、MPO、TNF-α、IL-1β和 IFN-γ的水平。此外，下调 PTX3 逆转了 CLI-095（TLR 信号通路抑制剂）诱导的细胞凋亡和炎症抑制作用以及对 Zo-1 和 occludin 水平的促进作用。在 CLP 诱导的小鼠脓毒症模型和 LPS 诱导的细胞炎症模型中，PTX3 通过 TLR 信号通路抑制炎症反应，减少肠黏膜屏障损伤。
