基于炎性疾病组织重建的食品营养学与疾病病理学机制研究
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摘要
在肥胖与静脉曲张等慢性炎性疾病的发病机制中,包含着血管化、脂肪沉积和蛋白水解等组织重建事件。基于这些组织重建事件,开展疾病病理学和食品营养学研究,有利于这些疾病的诊断与防治。本论文以此为出发点,针对农产品加工及贮藏工程领域的重要科学问题,深入研究了食品功能因子—木犀草素在肥胖与相关代谢疾病中的作用；此外,研究了半胱氨酰组织蛋白酶在与肥胖相关的静脉曲张发病机制中的作用。
第一部分：木犀草素改善小鼠肥胖与胰岛素抵抗的机制研究
肥大细胞(MCs)在饮食诱导的肥胖和糖尿病的发展中起着至关重要的作用,它可以通过增强血管化作用直接参与肥胖代谢的调控。一些合成的MCs稳定剂,色甘酸钠(DSCG)和酮替芬可以改善相关的小鼠代谢失调。作为一种天然黄酮类MCs稳定剂,木犀草素能够比DSCG和酮替芬更加有效地阻止MCs的脱颗粒和细胞因子释放。
本研究中,我们以正常饮食C57BL/6雄鼠作为对照,采用高脂饮食诱导的方式建立肥胖小鼠模型,并在高脂饮食中添加0.002%或0.01%的木犀草素,来考察两种低剂量木犀草素干预对饮食诱导的小鼠肥胖和胰岛素抵抗的影响。根据研究内容,主要采用组织化学、Real-time PCR、ELISA和Western Blot等技术,得到以下研究结果：1)饮食补充0.002%或0.01%木犀草素,显著抑制了高脂饮食诱导的小鼠体重增加、脂肪沉积和脂肪细胞肥大。2)木犀草素饮食干预,改善了小鼠的葡萄糖不耐受性和胰岛素敏感性。3)木犀草素饮食干预,减少了小鼠附睾脂肪组织的血管生成和相关的组织蛋白酶表达和活性,并且激活了细胞凋亡。4)木犀草素饮食干预,降低了小鼠附睾脂肪组织中巨噬细胞的浸润,以及组织和循环中的炎性细胞因子水平。5)进一步研究表明,木犀草素在小鼠体内,能够抑制MCs向附睾脂肪组织的浸润,以及其特异蛋白酶的表达。
总之,本论文研究结果证明,木犀草素作为一种食品源天然黄酮化合物,其低剂量饮食补充能显著改善小鼠饮食诱导的肥胖和胰岛素抵抗,提示这一方式可以作为一种新型的饮食营养干预和治疗方式而缓解上述常见的代谢疾病。
第二部分：溶酶体半胱氨酰组织蛋白酶在静脉曲张中的作用：一个组织学的研究
静脉曲张是一种主要的慢性炎性静脉疾病。原发性静脉曲张的形成是一个复杂的、多中心的病理过程,其病因和发病机制至今仍未能明确,而肥胖是其风险因子之一。病理研究显示,静脉曲张血管壁中存在着特征性的胞外基质重建和蛋白水解事件,其中基质金属蛋白酶家族成员己被认为参与了曲张静脉壁的组织重建。但是,对于其他家族蛋白酶成员,例如在动脉疾病组织重建中起重要作用的溶酶体半胱氨酰组织蛋白酶,是否也具有相应的作用却知之甚少。
在本研究中,我们收集了18位静脉曲张病人和9位创伤性截肢病人的大隐静脉分别作为静脉曲张组和正常静脉组,主要采用化学、免疫化学和免疫荧光组织学技术,系统地研究了几种主要的溶酶体半胱氨酸蛋白酶,组织蛋白酶B、L、K、S以及它们的内源性抑制剂胱蛋白酶抑制剂C在静脉中的分布和表达。主要研究结果如下：1)利用HE染色和Van Gieson-orcein染色,比较了正常静脉和曲张静脉的结构差异,显示曲张静脉在内膜、中膜和外膜均存在不同程度的组织重建和基质蛋白紊乱,提示着大量蛋白水解事件的发生。2)采用免疫组织化学技术,证明在曲张静脉壁中组织蛋白酶B、L、K和S含量增加,而胱蛋白酶抑制剂C的含量减少；从而,打破了正常静脉组织中组织蛋白酶与其内源性抑制剂间的平衡关系,并可能由此导致曲张静脉壁的组织重建。3)为了探讨这些蛋白酶表达的炎性机制,我们详细研究了曲张静脉壁组成细胞(内皮细胞、平滑肌细胞)和炎性细胞(巨噬细胞、MCs、T淋巴细胞)的组织蛋白酶表达模式。研究显示曲张静脉中升高表达的组织蛋白酶,来源于平滑肌细胞、内皮细胞、T淋巴细胞、巨噬细胞和肥大细胞。4)在静脉曲张脉壁中,淋巴脉管的显著增生加重了炎性细胞向组织的浸润。
总之,在静脉曲张壁中组织蛋白酶水平升高,并与血管壁炎性细胞共定位。这些特性提示了,溶酶体半胱氨酰组织蛋白酶可能响应炎性反应而参与了静脉曲张的胞外基质重建过程。
In the pathogenesis of chronic inflammatory diseases, such as obesity and varicose veins, extensive tissue remodeling events are involved. Based on these events, such as angiogenesis, adipogenesis and proteolysis, preforming pathological and food nutritional studies will help the development of new related diagnostic and therapeutic approaches. Aimed on the important scientific problems in the field of agricultural products processing and storage engineering, this paper study of the functional food factor-luteolin action on obesity and related metabolic diseases; in addition, research on cysteinyl cathepsin role in obesity-related varicose veins pathogenesis.
Part One:mechanism studies of luteolin on ameliorating diet-induced obesity and insulin resistance in mice
Mast cells play important roles in diet-induced obesity and diabetes, and some synthetic mast cell stabilizers such as DSCG and ketotifen can improve related metabolic disturbances in mice. As a potent natural mast cells stabilizer, luteolin possess multiple biological activities benefit for human healthy and more effective than DSCG and ketotifen in blocking mast cells degranulation and cytokine release.
The male C57BL/6mice were fed low fat diet, high fat diet (HFD), HFD with0.002%and0.01%luteolin for12weeks, respectively. Dietary luteolin suppressed HFD-induced body weight gain, fat deposition and adipocyte hypertrophy. Meanwhile, glucose intolerance and insulin sensitivity was also improved. Interestingly, dietary luteolin ameliorated angiogenesis and associated cell apoptosis and cathepsin activity in epididymis adipose tissues (EAT), which is a critical mechanism that mast cells are involved in diet-induced obesity and diabetes. Further, we showed dietary luteolin reduced macrophage infiltrations in EAT and inflammatory cytokine levels in EAT and serum. Finally, luteolin inhibited mast cell infiltrations and mast cell specific protease expression in EAT.
As a natural flavonoid, low-dose diet supplement of luteolin ameliorates diet-induced obesity and insulin resistance in mice, suggesting a new therapeutic and nutrition interventional approach for these diseases.
Part Two:functions of lysosomal cysteinyl cathepsins in human varicose veins:a histology study
Varicose veins (VVs) are a major chronic venous disease characterized by extensive remodeling of the extracellular matrix (ECM) architecture and proteolytic events in the vascular wall, which may be important in VVs development—though direct evidence is still missing. Primary VVs formation is a complex and multicentric pathological process. Although the aetiology and pathogenesis of varicose vein remain unclear, obesity is one of the risk factors for varicose vein development. Among proteolysis events, matrix metalloproteinases and their tissue inhibitors have garnered the most attention and been linked with the pathological events of VVs, but little is known about the functional relevance of other protease family members. Whether a cysteinyl cathepsin expression regulatory profile similar to that in arteries occurs in veins, however, remains unknown.
Here, we studied the distribution of lysosomal cysteine proteases, cathepsin B, L, K, and S, and their endogenous inhibitor, cystatin C, in long saphenous vein specimens from9normal donors and18patients with Ws. Immunohistochemical analysis demonstrated increased levels of cathepsin L, K, B, and S and reduced levels of cystatin C in Ws. This imbalance between cathepsins and cystatin C may favor Ws remodeling. To investigate the inflammatory mechanism of their expression, we examined a detailed inflammatory cell profile in Ws, including macrophages, T lymphocytes, and mast cells. Increased numbers of CD3-positive T cells and tryptase-positive mast cells were found in Ws, and enhanced levels of cathepsins were detected from lesion T cells、 mast cells、 endothelial cells、 macrophage and smooth-muscle cells. In varicose vein wall, lymphatic vasa significantly hyperplasia aggravated inflammatory cell infiltration into vascular wall.
Elevated cathepsins, and their co-localization to infiltrated inflammatory cells and to vascular cells, suggest that these proteases participate in ECM degradation in response to inflammation during W pathogenesis.
第一部分：木犀草素改善小鼠肥胖与胰岛素抵抗的机制研究
肥大细胞(MCs)在饮食诱导的肥胖和糖尿病的发展中起着至关重要的作用,它可以通过增强血管化作用直接参与肥胖代谢的调控。一些合成的MCs稳定剂,色甘酸钠(DSCG)和酮替芬可以改善相关的小鼠代谢失调。作为一种天然黄酮类MCs稳定剂,木犀草素能够比DSCG和酮替芬更加有效地阻止MCs的脱颗粒和细胞因子释放。
本研究中,我们以正常饮食C57BL/6雄鼠作为对照,采用高脂饮食诱导的方式建立肥胖小鼠模型,并在高脂饮食中添加0.002%或0.01%的木犀草素,来考察两种低剂量木犀草素干预对饮食诱导的小鼠肥胖和胰岛素抵抗的影响。根据研究内容,主要采用组织化学、Real-time PCR、ELISA和Western Blot等技术,得到以下研究结果：1)饮食补充0.002%或0.01%木犀草素,显著抑制了高脂饮食诱导的小鼠体重增加、脂肪沉积和脂肪细胞肥大。2)木犀草素饮食干预,改善了小鼠的葡萄糖不耐受性和胰岛素敏感性。3)木犀草素饮食干预,减少了小鼠附睾脂肪组织的血管生成和相关的组织蛋白酶表达和活性,并且激活了细胞凋亡。4)木犀草素饮食干预,降低了小鼠附睾脂肪组织中巨噬细胞的浸润,以及组织和循环中的炎性细胞因子水平。5)进一步研究表明,木犀草素在小鼠体内,能够抑制MCs向附睾脂肪组织的浸润,以及其特异蛋白酶的表达。
总之,本论文研究结果证明,木犀草素作为一种食品源天然黄酮化合物,其低剂量饮食补充能显著改善小鼠饮食诱导的肥胖和胰岛素抵抗,提示这一方式可以作为一种新型的饮食营养干预和治疗方式而缓解上述常见的代谢疾病。
第二部分：溶酶体半胱氨酰组织蛋白酶在静脉曲张中的作用：一个组织学的研究
静脉曲张是一种主要的慢性炎性静脉疾病。原发性静脉曲张的形成是一个复杂的、多中心的病理过程,其病因和发病机制至今仍未能明确,而肥胖是其风险因子之一。病理研究显示,静脉曲张血管壁中存在着特征性的胞外基质重建和蛋白水解事件,其中基质金属蛋白酶家族成员己被认为参与了曲张静脉壁的组织重建。但是,对于其他家族蛋白酶成员,例如在动脉疾病组织重建中起重要作用的溶酶体半胱氨酰组织蛋白酶,是否也具有相应的作用却知之甚少。
在本研究中,我们收集了18位静脉曲张病人和9位创伤性截肢病人的大隐静脉分别作为静脉曲张组和正常静脉组,主要采用化学、免疫化学和免疫荧光组织学技术,系统地研究了几种主要的溶酶体半胱氨酸蛋白酶,组织蛋白酶B、L、K、S以及它们的内源性抑制剂胱蛋白酶抑制剂C在静脉中的分布和表达。主要研究结果如下：1)利用HE染色和Van Gieson-orcein染色,比较了正常静脉和曲张静脉的结构差异,显示曲张静脉在内膜、中膜和外膜均存在不同程度的组织重建和基质蛋白紊乱,提示着大量蛋白水解事件的发生。2)采用免疫组织化学技术,证明在曲张静脉壁中组织蛋白酶B、L、K和S含量增加,而胱蛋白酶抑制剂C的含量减少；从而,打破了正常静脉组织中组织蛋白酶与其内源性抑制剂间的平衡关系,并可能由此导致曲张静脉壁的组织重建。3)为了探讨这些蛋白酶表达的炎性机制,我们详细研究了曲张静脉壁组成细胞(内皮细胞、平滑肌细胞)和炎性细胞(巨噬细胞、MCs、T淋巴细胞)的组织蛋白酶表达模式。研究显示曲张静脉中升高表达的组织蛋白酶,来源于平滑肌细胞、内皮细胞、T淋巴细胞、巨噬细胞和肥大细胞。4)在静脉曲张脉壁中,淋巴脉管的显著增生加重了炎性细胞向组织的浸润。
总之,在静脉曲张壁中组织蛋白酶水平升高,并与血管壁炎性细胞共定位。这些特性提示了,溶酶体半胱氨酰组织蛋白酶可能响应炎性反应而参与了静脉曲张的胞外基质重建过程。
In the pathogenesis of chronic inflammatory diseases, such as obesity and varicose veins, extensive tissue remodeling events are involved. Based on these events, such as angiogenesis, adipogenesis and proteolysis, preforming pathological and food nutritional studies will help the development of new related diagnostic and therapeutic approaches. Aimed on the important scientific problems in the field of agricultural products processing and storage engineering, this paper study of the functional food factor-luteolin action on obesity and related metabolic diseases; in addition, research on cysteinyl cathepsin role in obesity-related varicose veins pathogenesis.
Part One:mechanism studies of luteolin on ameliorating diet-induced obesity and insulin resistance in mice
Mast cells play important roles in diet-induced obesity and diabetes, and some synthetic mast cell stabilizers such as DSCG and ketotifen can improve related metabolic disturbances in mice. As a potent natural mast cells stabilizer, luteolin possess multiple biological activities benefit for human healthy and more effective than DSCG and ketotifen in blocking mast cells degranulation and cytokine release.
The male C57BL/6mice were fed low fat diet, high fat diet (HFD), HFD with0.002%and0.01%luteolin for12weeks, respectively. Dietary luteolin suppressed HFD-induced body weight gain, fat deposition and adipocyte hypertrophy. Meanwhile, glucose intolerance and insulin sensitivity was also improved. Interestingly, dietary luteolin ameliorated angiogenesis and associated cell apoptosis and cathepsin activity in epididymis adipose tissues (EAT), which is a critical mechanism that mast cells are involved in diet-induced obesity and diabetes. Further, we showed dietary luteolin reduced macrophage infiltrations in EAT and inflammatory cytokine levels in EAT and serum. Finally, luteolin inhibited mast cell infiltrations and mast cell specific protease expression in EAT.
As a natural flavonoid, low-dose diet supplement of luteolin ameliorates diet-induced obesity and insulin resistance in mice, suggesting a new therapeutic and nutrition interventional approach for these diseases.
Part Two:functions of lysosomal cysteinyl cathepsins in human varicose veins:a histology study
Varicose veins (VVs) are a major chronic venous disease characterized by extensive remodeling of the extracellular matrix (ECM) architecture and proteolytic events in the vascular wall, which may be important in VVs development—though direct evidence is still missing. Primary VVs formation is a complex and multicentric pathological process. Although the aetiology and pathogenesis of varicose vein remain unclear, obesity is one of the risk factors for varicose vein development. Among proteolysis events, matrix metalloproteinases and their tissue inhibitors have garnered the most attention and been linked with the pathological events of VVs, but little is known about the functional relevance of other protease family members. Whether a cysteinyl cathepsin expression regulatory profile similar to that in arteries occurs in veins, however, remains unknown.
Here, we studied the distribution of lysosomal cysteine proteases, cathepsin B, L, K, and S, and their endogenous inhibitor, cystatin C, in long saphenous vein specimens from9normal donors and18patients with Ws. Immunohistochemical analysis demonstrated increased levels of cathepsin L, K, B, and S and reduced levels of cystatin C in Ws. This imbalance between cathepsins and cystatin C may favor Ws remodeling. To investigate the inflammatory mechanism of their expression, we examined a detailed inflammatory cell profile in Ws, including macrophages, T lymphocytes, and mast cells. Increased numbers of CD3-positive T cells and tryptase-positive mast cells were found in Ws, and enhanced levels of cathepsins were detected from lesion T cells、 mast cells、 endothelial cells、 macrophage and smooth-muscle cells. In varicose vein wall, lymphatic vasa significantly hyperplasia aggravated inflammatory cell infiltration into vascular wall.
Elevated cathepsins, and their co-localization to infiltrated inflammatory cells and to vascular cells, suggest that these proteases participate in ECM degradation in response to inflammation during W pathogenesis.
引文
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