穿心莲内酯对牙周炎骨吸收的影响及其机理的实验研究
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摘要
背景
牙周炎是人类的常见病和多发病，本质上属于非特异性的炎症和特异性的免疫应答而导致牙周组织的破坏，其中牙槽骨吸收是牙周炎重要的病理过程，也是人类失牙的重要原因。现已明确T细胞过度活化可引发牙周炎，IFN-γ的增强抗原呈递作用和NF-κB通路活化与牙槽骨吸收关系密切，但牙周炎所致牙槽骨吸收机理尚不明确，因而一般抗炎治疗效果不佳。祖国医学在治疗多种复杂性疾病方面有明显的优势，在中药中具有独特作用机制的小分子天然药物如穿心莲内酯等受到关注。研究表明穿心莲内酯可以抑制NF-κB信号通路，发挥抗炎和免疫调节作用，但其是否能够抑制T细胞的过度活化，抑制牙周炎骨吸收还有待研究结果的验证，同时，穿心莲内酯抑制NF-κB信号通路的作用和牙周炎骨吸收的IFN-γ依赖途径之间的相互关系，都需要进一步深入研究。
目的
通过穿心莲内酯抑制实验性牙周炎骨吸收的效果观察，研究穿心莲内酯在牙周炎免疫调节治疗中的作用，分析穿心莲内酯抑制T细胞过度活化的作用机制，探讨IFN-γ依赖性牙周炎牙槽骨吸收和穿心莲内酯抑制NF-κB信号通路作用之间的关系，旨在为牙周炎牙槽骨吸收的免疫调节治疗提供新的思路和实验室证据。
方法
采用饱和水溶液法制备穿心莲内酯(andrographolide)-β-环糊精包合物，提高穿心莲内酯药物的溶解度；采用LPS局部注射的方式建立小鼠实验性牙周炎牙槽骨吸收模型，以模型动物为基础，根据分组情况，分别给予实验动物穿心莲内酯灌胃和腹腔注射IFN-γ-Ab进行干预，进行体内和体外实验研究。首先在体内，通过显微CT和组织病理学切片研究穿心莲内酯对于LPS诱导的实验性牙周炎骨吸收的影响，利用血清学免疫检测和免疫组化染色研究穿心莲内酯对牙周炎骨吸收相关因子IFN-γ和TNF-α等的调控作用；随后在体外，获取牙周炎状态下动物体内的T细胞和骨髓巨噬细胞进行原代培养并进行相关研究，应用流式细胞术、实时定量PCR和Westernblot观察穿心莲内酯对T细胞活化，IFN-γ、RANKL和TNF-α炎症细胞因子的表达和T细胞NF-κB通路活化的影响，观察穿心莲内酯对巨噬细胞增殖特性、抗原递呈功能调节和NF-κB通路活化的影响；利用破骨细胞诱导分化培养基体外培养小鼠单核巨噬细胞RAW264.7，诱导其向破骨细胞表型分化，观察穿心莲内酯对条件培养基诱导破骨细胞终末分化形成作用的影响和此过程中细胞内NF-κB通路活化情况。
结果
经过β-环糊精的物理包合作用，穿心莲内酯在37℃时的溶解度从0.072mg·ml~(-1)提高至0.956mg·ml~(-1)；显微CT显示：穿心莲内酯灌胃使得牙周炎骨吸收模型动物的骨小梁相关参数较之未处理组有显著改善（P<0.05）；穿心莲内酯灌胃使得牙周炎骨吸收模型动物血清中炎症因子IFN-γ和TNF-α的表达水平较之未处理组显著降低（P<0.05），但是和小鼠腹腔注射IFN-γ-Ab作用无差异（P>0.05）；穿心莲内酯灌胃使得牙周炎骨吸收模型动物牙周组织中的炎症分子表达较之未处理组显著减少（P <0.05）；穿心莲内酯处理组可以下调T细胞中IFN-γ、RANKL和TNF-α炎症因子的表达，抑制T细胞中NF-κB通路的活化，结果较之未处理组差异显著（P<0.05），但是和IFN-γ-Ab处理组作用无差异（P>0.05）；穿心莲内酯处理组可以抑制巨噬细胞的增殖生长，下调巨噬细胞中CIITA的表达，抑制巨噬细胞中NF-κB通路的活化，结果较之未处理组差异显著（P<0.05），但是和IFN-γ-Ab处理组作用无差异（P>0.05）；穿心莲内酯处理组可以抑制条件培养基诱导RAW264.7细胞形成破骨细胞终末分化的作用，抑制RAW264.7细胞中NF-κB通路的活化，结果较之未处理组差异显著（P<0.05），但是和IFN-γ-Ab处理组作用无差异（P>0.05）。
结论
穿心莲内酯可以抑制实验性牙周炎的牙槽骨吸收。本研究结果提示：穿心莲内酯可以抑制T细胞过度活化，对实验性牙周炎具有免疫调节作用，可以抑制IFN-γ依赖性的牙周炎牙槽骨吸收，这些作用的产生都和穿心莲内酯抑制NF-κB信号通路的活化作用有关。
Periodontitis is a common oral disease with high incidence in human body.Unspecific inflammatory reaction and specific immunological response play keyroles in its development. It’s reported that the over-activation of T cells can lead toperiodontitis. Besides, IFN-γ promotes the antigen presentation and the activation ofNF-κB signal resulting in alveolar bone resorption. However, the immunopathologicmechanism of periodontitis is complex and routine anti-inflammatory treatment isusually ineffective. Traditional Chinese medicine has unique advantage in treatingdiseases with complex mechanism and many natural drugs of small molecule thatshow unique effect have drawn attention. Andrographolide is reported to inhibit theover-activation of NF-κB signal playing roles in anti-inflammation andimmunoregulation, while whether it can inhibit the over-activation of T cells and thealveolar bone resorption still need verification. Further, it’s unclear whether there isrelation between the inhibitory effect of andrographolide on NF-κB signal and the effect of IFN-γ in periodontitis development.
Aim: To observe the therapeutic effect of andrographolide on experimentalperiodontitis model, analyze the mechanism for andrographolide to inhibit T cellover-activation, and explore the potential relation between the inhibitory effect ofandrographolide on NF-κB signal and the role of IFN-γ in periodontitis development,in order to provide new approach and evidence for treating periodontitis throughimmunoregulation.
Materials and methods: The inclusion compound of andrographolide-β-cyclodextrin was fabricated by a saturated solution method to improve the solubilityof andrographolide. Experimental murine periodontitis model was established byLPS local administration. The animals were treated by andrographolide intragastricadministration or IFN-γ-Ab intraperitoneal injection respectively, and in vivo andin vitro experiments were conducted. Firstly, in vivo studies were performed toobserve the effect of andrographolide on experimental periodontitis model inducedby LPS. Micro CT and histological section were conducted to observe the effect ofandrographolide on bone resorption in experimental periodontitis. Blood serumimmunological assays and immunohistochemical staining were performed to studythe regulating effect of andrographolide on the bone resorption related factors inperiodontitis. Then in vitro studies were performed to obtain T cells and bonemarrow macrophages from the experimental periodontitis model, which werecultured in vitro. Flow cytometry, Real time PCR and Western blot were done toobserve the effect of andrographolide on T cell activation, the expression ofinflammatory factors such as IFN-γ, RANKL and TNF-α and the activation ofNF-κB signal in T cells. Mouse mononuclear macrophage cell line RAW264.7wascultured in macrophage inductive conditioned medium. The influence ofandrographolide in late differentiation of macrophages and the activation of the NF-κB signal in this process were observed.
Results: After inclusion by β-cyclodextrin, the solubility of andrographolideincreased from0.072to0.956mg·ml-1.The micro CT results showed that theintragastric administration of andrographolide significantly improved the bonetrabeculae related parameters in the periodontitis model (p <0.05); The intragastricadministration of andrographolide significantly decreased the levels of IFN-γ andTNF-α in the blood serum of the periodontitis animal model (p <0.05), which wassimilar to the effect of IFN-γ-Ab intraperitoneal injection (p>0.05); The intragastricadministration of andrographolide obviously decreased the expressions ofinflammatory factors in the blood serum and the periodontal tissue of theperiodontitis animal (p <0.05); Andrographolide down-regulated the expressions ofIFN-γ, RANKL and TNF-α in T cells, and inhibited the activation of NF-κB signal(p <0.05), and this effect was similar to the effect of IFN-γ-Ab (p>0.05);Andrographolide inhibited the growth of macrophages, down-regulated theexpression of CIITA and inhibited the activation of NF-κB signal in macrophages(p <0.05), while this effect was also similar to the effect of IFN-γ-Ab (p>0.05);Andrographolide inhibited the inductive effect of conditioned medium on RAW264.7late phenotype differentiation from macrophages to osteoclasts, down-regulated theactivation of NF-κB signal in it (p <0.05), while this effect was also at the same levelto the effect of IFN-γ-Ab (p>0.05).Conclusion: Andrographolide inhibits the bone resorption in the experimentalperiodontitis model as well as the over-activation of T cells, showing significantimmunoregulating effect on experimental periodontitis. In addition, it inhibits theIFN-γ dependent alveolar bone resorption in periodontitis. These effects forandrographolide are related to its inhibitory effect on the NF-κB signal.
牙周炎是人类的常见病和多发病，本质上属于非特异性的炎症和特异性的免疫应答而导致牙周组织的破坏，其中牙槽骨吸收是牙周炎重要的病理过程，也是人类失牙的重要原因。现已明确T细胞过度活化可引发牙周炎，IFN-γ的增强抗原呈递作用和NF-κB通路活化与牙槽骨吸收关系密切，但牙周炎所致牙槽骨吸收机理尚不明确，因而一般抗炎治疗效果不佳。祖国医学在治疗多种复杂性疾病方面有明显的优势，在中药中具有独特作用机制的小分子天然药物如穿心莲内酯等受到关注。研究表明穿心莲内酯可以抑制NF-κB信号通路，发挥抗炎和免疫调节作用，但其是否能够抑制T细胞的过度活化，抑制牙周炎骨吸收还有待研究结果的验证，同时，穿心莲内酯抑制NF-κB信号通路的作用和牙周炎骨吸收的IFN-γ依赖途径之间的相互关系，都需要进一步深入研究。
目的
通过穿心莲内酯抑制实验性牙周炎骨吸收的效果观察，研究穿心莲内酯在牙周炎免疫调节治疗中的作用，分析穿心莲内酯抑制T细胞过度活化的作用机制，探讨IFN-γ依赖性牙周炎牙槽骨吸收和穿心莲内酯抑制NF-κB信号通路作用之间的关系，旨在为牙周炎牙槽骨吸收的免疫调节治疗提供新的思路和实验室证据。
方法
采用饱和水溶液法制备穿心莲内酯(andrographolide)-β-环糊精包合物，提高穿心莲内酯药物的溶解度；采用LPS局部注射的方式建立小鼠实验性牙周炎牙槽骨吸收模型，以模型动物为基础，根据分组情况，分别给予实验动物穿心莲内酯灌胃和腹腔注射IFN-γ-Ab进行干预，进行体内和体外实验研究。首先在体内，通过显微CT和组织病理学切片研究穿心莲内酯对于LPS诱导的实验性牙周炎骨吸收的影响，利用血清学免疫检测和免疫组化染色研究穿心莲内酯对牙周炎骨吸收相关因子IFN-γ和TNF-α等的调控作用；随后在体外，获取牙周炎状态下动物体内的T细胞和骨髓巨噬细胞进行原代培养并进行相关研究，应用流式细胞术、实时定量PCR和Westernblot观察穿心莲内酯对T细胞活化，IFN-γ、RANKL和TNF-α炎症细胞因子的表达和T细胞NF-κB通路活化的影响，观察穿心莲内酯对巨噬细胞增殖特性、抗原递呈功能调节和NF-κB通路活化的影响；利用破骨细胞诱导分化培养基体外培养小鼠单核巨噬细胞RAW264.7，诱导其向破骨细胞表型分化，观察穿心莲内酯对条件培养基诱导破骨细胞终末分化形成作用的影响和此过程中细胞内NF-κB通路活化情况。
结果
经过β-环糊精的物理包合作用，穿心莲内酯在37℃时的溶解度从0.072mg·ml~(-1)提高至0.956mg·ml~(-1)；显微CT显示：穿心莲内酯灌胃使得牙周炎骨吸收模型动物的骨小梁相关参数较之未处理组有显著改善（P<0.05）；穿心莲内酯灌胃使得牙周炎骨吸收模型动物血清中炎症因子IFN-γ和TNF-α的表达水平较之未处理组显著降低（P<0.05），但是和小鼠腹腔注射IFN-γ-Ab作用无差异（P>0.05）；穿心莲内酯灌胃使得牙周炎骨吸收模型动物牙周组织中的炎症分子表达较之未处理组显著减少（P <0.05）；穿心莲内酯处理组可以下调T细胞中IFN-γ、RANKL和TNF-α炎症因子的表达，抑制T细胞中NF-κB通路的活化，结果较之未处理组差异显著（P<0.05），但是和IFN-γ-Ab处理组作用无差异（P>0.05）；穿心莲内酯处理组可以抑制巨噬细胞的增殖生长，下调巨噬细胞中CIITA的表达，抑制巨噬细胞中NF-κB通路的活化，结果较之未处理组差异显著（P<0.05），但是和IFN-γ-Ab处理组作用无差异（P>0.05）；穿心莲内酯处理组可以抑制条件培养基诱导RAW264.7细胞形成破骨细胞终末分化的作用，抑制RAW264.7细胞中NF-κB通路的活化，结果较之未处理组差异显著（P<0.05），但是和IFN-γ-Ab处理组作用无差异（P>0.05）。
结论
穿心莲内酯可以抑制实验性牙周炎的牙槽骨吸收。本研究结果提示：穿心莲内酯可以抑制T细胞过度活化，对实验性牙周炎具有免疫调节作用，可以抑制IFN-γ依赖性的牙周炎牙槽骨吸收，这些作用的产生都和穿心莲内酯抑制NF-κB信号通路的活化作用有关。
Periodontitis is a common oral disease with high incidence in human body.Unspecific inflammatory reaction and specific immunological response play keyroles in its development. It’s reported that the over-activation of T cells can lead toperiodontitis. Besides, IFN-γ promotes the antigen presentation and the activation ofNF-κB signal resulting in alveolar bone resorption. However, the immunopathologicmechanism of periodontitis is complex and routine anti-inflammatory treatment isusually ineffective. Traditional Chinese medicine has unique advantage in treatingdiseases with complex mechanism and many natural drugs of small molecule thatshow unique effect have drawn attention. Andrographolide is reported to inhibit theover-activation of NF-κB signal playing roles in anti-inflammation andimmunoregulation, while whether it can inhibit the over-activation of T cells and thealveolar bone resorption still need verification. Further, it’s unclear whether there isrelation between the inhibitory effect of andrographolide on NF-κB signal and the effect of IFN-γ in periodontitis development.
Aim: To observe the therapeutic effect of andrographolide on experimentalperiodontitis model, analyze the mechanism for andrographolide to inhibit T cellover-activation, and explore the potential relation between the inhibitory effect ofandrographolide on NF-κB signal and the role of IFN-γ in periodontitis development,in order to provide new approach and evidence for treating periodontitis throughimmunoregulation.
Materials and methods: The inclusion compound of andrographolide-β-cyclodextrin was fabricated by a saturated solution method to improve the solubilityof andrographolide. Experimental murine periodontitis model was established byLPS local administration. The animals were treated by andrographolide intragastricadministration or IFN-γ-Ab intraperitoneal injection respectively, and in vivo andin vitro experiments were conducted. Firstly, in vivo studies were performed toobserve the effect of andrographolide on experimental periodontitis model inducedby LPS. Micro CT and histological section were conducted to observe the effect ofandrographolide on bone resorption in experimental periodontitis. Blood serumimmunological assays and immunohistochemical staining were performed to studythe regulating effect of andrographolide on the bone resorption related factors inperiodontitis. Then in vitro studies were performed to obtain T cells and bonemarrow macrophages from the experimental periodontitis model, which werecultured in vitro. Flow cytometry, Real time PCR and Western blot were done toobserve the effect of andrographolide on T cell activation, the expression ofinflammatory factors such as IFN-γ, RANKL and TNF-α and the activation ofNF-κB signal in T cells. Mouse mononuclear macrophage cell line RAW264.7wascultured in macrophage inductive conditioned medium. The influence ofandrographolide in late differentiation of macrophages and the activation of the NF-κB signal in this process were observed.
Results: After inclusion by β-cyclodextrin, the solubility of andrographolideincreased from0.072to0.956mg·ml-1.The micro CT results showed that theintragastric administration of andrographolide significantly improved the bonetrabeculae related parameters in the periodontitis model (p <0.05); The intragastricadministration of andrographolide significantly decreased the levels of IFN-γ andTNF-α in the blood serum of the periodontitis animal model (p <0.05), which wassimilar to the effect of IFN-γ-Ab intraperitoneal injection (p>0.05); The intragastricadministration of andrographolide obviously decreased the expressions ofinflammatory factors in the blood serum and the periodontal tissue of theperiodontitis animal (p <0.05); Andrographolide down-regulated the expressions ofIFN-γ, RANKL and TNF-α in T cells, and inhibited the activation of NF-κB signal(p <0.05), and this effect was similar to the effect of IFN-γ-Ab (p>0.05);Andrographolide inhibited the growth of macrophages, down-regulated theexpression of CIITA and inhibited the activation of NF-κB signal in macrophages(p <0.05), while this effect was also similar to the effect of IFN-γ-Ab (p>0.05);Andrographolide inhibited the inductive effect of conditioned medium on RAW264.7late phenotype differentiation from macrophages to osteoclasts, down-regulated theactivation of NF-κB signal in it (p <0.05), while this effect was also at the same levelto the effect of IFN-γ-Ab (p>0.05).Conclusion: Andrographolide inhibits the bone resorption in the experimentalperiodontitis model as well as the over-activation of T cells, showing significantimmunoregulating effect on experimental periodontitis. In addition, it inhibits theIFN-γ dependent alveolar bone resorption in periodontitis. These effects forandrographolide are related to its inhibitory effect on the NF-κB signal.
引文
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