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目的揭示细菌脂多糖(LPS)诱发小鼠肿瘤样增殖中血管新生及组织增殖的病理机制及青蒿素和桦木酸阻断肿瘤样增殖的药理机制。方法利用脂多糖或含脂多糖的完全弗氏佐剂(CFA)建立小鼠皮下组织及关节滑膜肿瘤样增殖模型,在形态学特征(炎症分级)描述及组织化学指标(血管及组织增殖、炎性细胞浸润)鉴定的基础上,采用生化法、生理法和免疫法定量测定一氧化氮(NO)、血氧饱和度(Sp O2)和3-硝基酪氨酸(3NT)的血清浓度,并对诱导型一氧化氮合酶(i NOS)、缺氧诱导因子1α(HIF-1α)和血管内皮细胞生长因子(VEGF)的表达水平进行免疫组化分析。结果脂多糖与完全弗氏佐剂可导致炎症表型及组织异常增殖相关显微结构变化,使一氧化氮升高、血氧饱和度下降、3-硝基酪氨酸增加(蛋白质硝化),诱导型一氧化氮合酶、缺氧诱导因子1α和血管内皮细胞生长因子表达显著上调,并伴随血管新生及组织增殖。一氧化氮供体化合物可重现此过程,而一氧化氮合成抑制剂则有拮抗作用。青蒿琥酯和桦木酸可下调诱导型一氧化氮合酶、缺氧诱导因子1α和血管内皮细胞生长因子表达,降低一氧化氮并提高血氧饱和度,缓解或中止炎症性异常血管新生和组织增殖现象。结论脂多糖激发的诱导型一氧化氮合酶过表达和一氧化氮大量释放可能是血管新生及组织增殖的直接驱动力,青蒿琥酯和桦木酸能阻断肿瘤样增殖的病理过程,因而具有潜在的预防及治疗作用。
Objective To reveal the pathological mechanism of bacterial lipopolysaccharide (LPS) -induced tumor angiogenesis and tissue proliferation in mice and the pharmacological mechanism of artemisinin and betulinic acid blocking tumor-like proliferation. Methods Tumor-like hyperplasia models of subcutaneous and synovial joints were established by lipopolysaccharide (LPS) or complete Freund’s adjuvant (CFA) containing lipopolysaccharide. The morphological characteristics (inflammation grade) and histochemical markers (vascular and tissue proliferation, Inflammatory cell infiltration), the serum concentrations of nitric oxide (NO), oxygen saturation (Sp O2) and 3-nitrotyrosine (3NT) were quantitatively determined by biochemical, physiological and immunoassay methods The expressions of iNOS, HIF-1α and VEGF were detected by immunohistochemistry. Results Lipopolysaccharide and complete Freund’s adjuvant could lead to changes in the microstructure of inflammatory phenotypes and abnormal tissue proliferation, resulting in increased nitric oxide, decreased oxygen saturation, increased nitrotyrosine (protein nitration) Inducible nitric oxide synthase, hypoxia-inducible factor 1 alpha and vascular endothelial growth factor expression were significantly up-regulated, accompanied by angiogenesis and tissue proliferation. Nitric oxide donor compounds reproduce this process, whereas nitric oxide synthase inhibitors have antagonistic effects. Artesunate and betulinic acid can down-regulate the expression of inducible nitric oxide synthase, hypoxia inducible factor 1 alpha and vascular endothelial cell growth factor, decrease nitric oxide and increase oxygen saturation, relieve or abolish inflammatory angiogenesis and Tissue proliferation phenomenon. Conclusion Lipopolysaccharide-induced inducible nitric oxide synthase overexpression and nitrous oxide release may be the direct driving force of angiogenesis and tissue proliferation. Artesunate and betulinic acid can block the pathological process of tumor-like proliferation, thus Potential for prevention and treatment.