Affiliated Foshan Maternity & Child Healthcare Hospital, Southern Medical University (Foshan Maternity & Child Healthcare Hospital), Foshan 528000, China; School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
Clinical Pharmacy Center, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
Phytomedicine. 2023 Mar;111:154662. doi: 10.1016/j.phymed.2023.154662. Epub 2023 Jan 11.
BACKGROUND: Postoperative abdominal adhesion (PAA) is the most common complication after abdominal surgeries, which can lead to intestinal obstruction, chronic abdominal pain or female infertility. Jiawei Xiaochengqi decoction (JWXCQ) is a hospital preparation widely used for PAA treatment in Nanfang Hospital of Southern Medical University for more than twenty years. PURPOSE: This study aimed to investigate the therapeutic effects and potential mechanism of JWXCQ against PAA and provide beneficial information for its clinical application. METHODS: The main active components of JWXCQ were identified using ultra high performance liquid chromatography (UHPLC) combined with standard substance comparison. The efficacy and underlying mechanism of JWXCQ were evaluated through in vivo experiments with a postsurgical-induced peritoneal adhesion rat model, and in vitro studies with LPS-stimulated Raw 264.7 macrophages and primary fibroblasts. H&E and Masson staining were performed to assess histopathological changes. The levels of cytokines/proteins-associated with inflammation and degradation of extracellular matrix as well as CXCL2-CXCR2 pathway-related proteins were determined by ELISA, qRT-PCR, western blot assays or immunohistochemistry, respectively. Furthermore, siCXCR2 transfection was used to validate the mechanism of action of JWXCQ. RESULTS: JWXCQ treatment significantly reduced the formation of PAA, inhibited the inflammation and collagen deposition, and facilitated the secretion of MMP9, decreased the levels of IL-1β, IL-6, TIMP1, COL-1, and suppressed the CXCL2-CXCR2 pathway in PAA rats. Furthermore, JWXCQ inhibited its downstream pathways, the JAK2-STAT3 and PI3K-AKT signaling, as indicated by the suppression of the phosphorylation levels of STAT3 and AKT. In vitro cell experiments revealed that JWXCQ reduced IL-1β and IL-6 secretion in Raw 264.7 macrophages and COL-1 in primary fibroblasts. The CXCL2-CXCR2, JAK2-STAT3 and PI3K-AKT pathways were also inhibited after JWXCQ treatment, which were consistent with the in vivo results. More importantly, silence of CXCR2 eliminated the regulatory effects of JWXCQ. CONCLUSION: JWXCQ could effectively prevent the PAA formation by alleviating inflammation and collagen deposition, which was associated with the inhibition of CXCL2-CXCR2 pathway. This study investigated the relevant pharmacological mechanisms of JWXCQ, providing further evidence for the application of JWXCQ in clinical PAA treatment.
背景：术后腹腔粘连（PAA）是腹部手术后最常见的并发症，可导致肠梗阻、慢性腹痛或女性不孕。加味小承气汤（JWXCQ）是南方医科大学南方医院 20 多年来广泛用于治疗 PAA 的医院制剂。
目的：本研究旨在探讨 JWXCQ 治疗 PAA 的疗效及其潜在机制，为其临床应用提供有益信息。
方法：采用超高效液相色谱（UHPLC）结合标准物质比较法鉴定 JWXCQ 的主要活性成分。通过术后诱导的大鼠腹膜粘连模型的体内实验和 LPS 刺激的 Raw 264.7 巨噬细胞和原代成纤维细胞的体外研究，评估 JWXCQ 的疗效和潜在机制。H&E 和 Masson 染色评估组织病理学变化。通过 ELISA、qRT-PCR、western blot 检测或免疫组化分别测定与炎症和细胞外基质降解相关的细胞因子/蛋白以及 CXCL2-CXCR2 通路相关蛋白的水平。此外，采用 siCXCR2 转染验证 JWXCQ 的作用机制。
结果：JWXCQ 治疗显著减少了 PAA 的形成，抑制了炎症和胶原沉积，并促进了 MMP9 的分泌，降低了 IL-1β、IL-6、TIMP1、COL-1 的水平，并抑制了 PAA 大鼠的 CXCL2-CXCR2 通路。此外，JWXCQ 抑制了其下游途径 JAK2-STAT3 和 PI3K-AKT 信号通路，表现为 STAT3 和 AKT 磷酸化水平的抑制。体外细胞实验显示，JWXCQ 减少了 Raw 264.7 巨噬细胞中 IL-1β 和 IL-6 的分泌以及原代成纤维细胞中 COL-1 的分泌。CXCL2-CXCR2、JAK2-STAT3 和 PI3K-AKT 通路在 JWXCQ 治疗后也被抑制，与体内结果一致。更重要的是，沉默 CXCR2 消除了 JWXCQ 的调节作用。
结论：JWXCQ 通过减轻炎症和胶原沉积有效预防 PAA 的形成，这与抑制 CXCL2-CXCR2 通路有关。本研究探讨了 JWXCQ 的相关药理机制，为 JWXCQ 在临床 PAA 治疗中的应用提供了进一步的证据。
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