Centre for Chinese Herbal Medicine Drug Development, Hong Kong Baptist University, Hong Kong SAR, China.
Centre for Chinese Herbal Medicine Drug Development, Hong Kong Baptist University, Hong Kong SAR, China; School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.
Phytomedicine. 2024 Jul;129:155694. doi: 10.1016/j.phymed.2024.155694. Epub 2024 May 1.
Ulcerative colitis (UC) is associated with intestinal macrophage infiltration due to disruption of the mucosal barrier and bacterial invasion. Therefore, it is crucial to identify therapeutic agents capable of attenuating the macrophage-induced inflammatory response to preserve mucosal homeostasis and immune tolerance. The modified Zhenwu decoction (CDD-2103) is a novel herbal formulation developed based on the principles of Traditional Chinese medicine. To date, there are no clinically approved herbal formulations for UC with a well-known mechanism of action on macrophages.
The objective of this study was to systematically investigate the inhibitory effect of the active fraction of CDD-2103 in a mouse model of chronic colitis and delineate the mechanisms underlying its inhibitory action.
CDD-2103 was extracted into four fractions using organic solvents with increasing polarity. A chronic 49-day dextran sulfate sodium (DSS)-induced colitis mice model, closely resembling human clinical conditions, was used to examine the effect of CDD-2103 on chronic colitis. To confirm the effect of CDD-2103 on macrophages in this chronic colitis model, adoptive macrophage transfer and CCL2 supplementation were conducted. The mechanisms of action of CDD-2103 were further elucidated utilizing bone marrow-derived macrophages (BMDMs). Transcriptome analysis was conducted to gain insights into the underlying mechanism of action of CDD-2103 in BMDMs.
Our in vitro and in vivo findings demonstrated that the ethanol-enriched fraction of CDD-2103 exhibited significant anti-inflammatory effects, leading to the suppression of colitis severity. This effect was associated with diminished accumulation of colonic macrophages in the lamina propria of CDD-2103-intervened colitis mice. Specifically, CDD-2103 inhibited CCR2/L2-mediated proinflammatory macrophage infiltration into the colon without affecting macrophage proliferation. Mechanistically, CDD-2103 inhibited Fyn expression-mediated p38 MAPK activation and subsequently suppressed CCR2 expression in BMDMs.
Collectively, our study supports the potential use of CDD-2103 to limit macrophage infiltration, thereby reducing inflammation during UC treatment. CDD-2103 and the components in the ethanolic fraction are promising candidates for the development of novel drugs for UC management. Additionally, our study underscores Fyn-mediated CCR2 expression as a potential therapeutic target for the management of UC.
溃疡性结肠炎（UC）与肠道巨噬细胞浸润有关，这是由于黏膜屏障破坏和细菌入侵所致。因此，识别能够减轻巨噬细胞诱导的炎症反应的治疗剂以维持黏膜稳态和免疫耐受至关重要。改良真武汤（CDD-2103）是一种基于中药原理开发的新型草药配方。迄今为止，尚无具有明确作用机制的用于 UC 的临床批准的草药配方。
本研究的目的是系统研究 CDD-2103 活性部分在慢性结肠炎小鼠模型中的抑制作用，并阐明其抑制作用的机制。
使用有机溶剂对 CDD-2103 进行了四次提取，有机溶剂的极性逐渐增加。使用慢性 49 天葡聚糖硫酸钠（DSS）诱导的结肠炎小鼠模型，该模型非常类似于人类临床情况，来研究 CDD-2103 对慢性结肠炎的影响。为了确认 CDD-2103 在这种慢性结肠炎模型中对巨噬细胞的作用，进行了巨噬细胞过继转移和 CCL2 补充。利用骨髓来源的巨噬细胞（BMDM）进一步阐明 CDD-2103 的作用机制。通过转录组分析，深入了解 CDD-2103 在 BMDM 中的作用机制。
我们的体外和体内研究结果表明，CDD-2103 的乙醇富集部分具有显著的抗炎作用，从而抑制结肠炎的严重程度。这种作用与 CDD-2103 干预结肠炎小鼠结肠固有层中结肠巨噬细胞的积累减少有关。具体而言，CDD-2103 抑制 CCR2/L2 介导的促炎巨噬细胞浸润结肠，而不影响巨噬细胞增殖。在机制上，CDD-2103 抑制 Fyn 表达介导的 p38 MAPK 激活，从而抑制 BMDM 中的 CCR2 表达。
综上所述，我们的研究支持使用 CDD-2103 来限制巨噬细胞浸润，从而减少 UC 治疗过程中的炎症。CDD-2103 和乙醇部分的成分是开发用于 UC 管理的新型药物的有前途的候选药物。此外，我们的研究强调了 Fyn 介导的 CCR2 表达作为 UC 管理的潜在治疗靶点。
