超微益气软皮汤治疗系统性硬皮病的临床与实验研究
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摘要
第一部分益气软皮丸治疗236例SSc患者的临床回顾性研究
目的：对236例SSc患者病案进行临床回顾性研究,以探讨SSc发病规律、临床特征及影响SSc疗效的相关因素,评价益气软皮丸治疗SSc的临床疗效及安全性。
方法：回顾性调查经益气软皮丸治疗的236例SSc患者门诊病历资料,对患者性别、发病年龄、病程、疗程、首发症状、家族史、临床表现、实验室检查、不良反应及疗效等进行统计分析,并得出相关结论。
结果：1.236例患者中,男81例(占34.3%),女155例(占65.7%),男女比为1：1.91；平均发病年龄41.08±11.73岁,其中男性44.91±10.87岁,女性39.08±12.22岁(P<0.01)；平均病程3.71±4.11年,其中男性3.15±4.05年,女性4.01±4.13年(P<0.01)；168例患者以雷诺氏现象为首发症状(占71.2%)；4例患者有家族病史。
2.益气软皮丸治疗SSc的总有效率为95.3%。治疗后患者各主要症状体征及部分实验室指标较治疗前有显著改善。益气软皮丸治疗SSc以浮肿期疗效最优,硬化期次之,萎缩期较差(P<0.01)；益气软皮丸治疗SSc疗程长短对其疗效有明显影响(P<0.01),其疗程以不少于9个月为宜。
3.益气软皮丸治疗SSc具有较高的安全性。
结论：益气软皮丸治疗SSc具有较好的疗效和安全性。
第二部分超微益气软皮汤治疗SSc的临床观察
目的：评价超微益气软皮汤治疗SSc的临床疗效,观察其对CEC、ET-1的影响。
方法：采用随机对照的研究方法,选取32例SSc患者分成传统组和超微组,分别给予益气软皮汤和1/3剂量超微益气软皮汤,治疗3个月,观察治疗前后患者皮肤硬化积分、指距、齿距以及外周血CEC、血浆ET-1水平的变化,评价其疗效。
结果：1.传统组总有效率为87.5%,超微组总有效率为93.8%,两组间疗效差异无显著性(p>0.05)。
2.与治疗前比较,传统组和超微组均能显著减少SSc患者皮肤硬化积分,缩小指距,增大齿距(P<0.01)；两组间比较,差异无统计学意义(p>0.05)。3.与治疗前比较,传统组和超微组均能显著降低SSc患者外周血CEC数量,下调血浆ET-1水平(P<0.01)；两组间比较,差异无统计学意义(p>0.05)。
结论：1.益气软皮汤对SSc具有较好疗效,能明显减少SSc患者皮肤硬化积分,缩小指距,增大齿距,1/3超微组和传统组比较疗效相当。
2.益气软皮汤能显著降低SSc患者外周血CEC数量,下调血浆ET-1水平,1/3超微组和传统组具有同等效应。
第三部分超微益气软皮汤对硬皮病的抗纤维化作用及其机制的实验研究目的：探讨超微益气软皮汤对BLM诱导的硬皮病小鼠的抗纤维化作用及其分子机制。
方法：72只BALB/c小鼠随机分为正常对照组(A)、模型组(B)、青霉胺组(C)、益气软皮汤组(D)、超微益气软皮汤全量组(E)、超微益气软皮汤1/3量组(F)等6组,每组各12只。A组小鼠背部皮下注射0.1ml生理盐水,B、C、D、E、F组小鼠皮下注射300μg/mlBLM溶液0.1ml；同时C、D、E、F组分别以125mg/kg青霉胺、16.6g/kg益气软皮汤浸膏、16.6g/kg超微益气软皮汤浸膏、5.5 g/kg超微益气软皮汤浸膏灌胃,A组和B组给予等容量蒸馏水灌胃,以上均为每日1次,连续4周。末次给药24小时后取背部注射部位皮肤分别行组织病理学观察,真皮厚度测量,比色法测定羟脯氨酸含量,原位杂交法进行CTGFmRNA表达测定,免疫组化法行皮肤COL-Ⅰ、Ⅲ, TGF-β1表达检测。同时取右肺组织行组织病理学检查。
结果：1.与正常对照组比较,模型组小鼠皮肤及肺组织切片表现出典型的硬皮病组织病理学改变,各治疗组病变较模型组轻。
2.模型组小鼠真皮厚度及皮肤羟脯氨酸含量较正常对照组明显增加,差异具有显著性意义(P<0.01)；各治疗组真皮厚度及皮肤羟脯氨酸含量均较模型组明显降低(P<0.01)；超微组和1/3超微组与传统组比较,差异无显著性(P>0.05)
3.模型组小鼠皮肤CTGFmR NA积分光密度较正常对照组明显增加,差异具有显著意义(P<0.01)；各治疗组CTGFmRNA积分光密度较模型组明显降低,差异具有显著意义(P<0.01)；超微组和1/3超微组与传统组比较,差异无显著性(P>0.05)
4.模型组小鼠皮肤COL-Ⅰ、Ⅲ, TGF-β1积分光密度较正常对照组明显增加,差异具有显著意义(P<0.01)；各治疗组较模型组明显降低,差异具有显著意义(P<0.01)；超微组和1/3超微组与传统组比较,差异无显著性(P>0.05)。
5. COL-Ⅰ、Ⅲ表达量与CTGFmRNA和TGF-β1表达量之间存在正相关性,经益气软皮汤治疗后,COL-Ⅰ、Ⅲ的表达随CTGFmRNA和TGF-β1表达的下调而下调。
结论:1.300μg/ml BLM背部皮下注射可成功诱导BALB/c小鼠产生硬皮病样改变。
2.益气软皮汤能显著对抗BLM的致纤维化作用。
3.益气软皮汤能下调硬皮病模型小鼠皮肤CTGF mRNA、TGF-β1的表达并可能由此导致COL-Ⅰ、Ⅲ的表达的降低。
CHAPTER I:A retrospective study on 236 cases of systemic sclerosis treated with Yiqiruanpi Pill
Objective:To explore the pathogenic factors, clinical features, and the correlative factors influencing the effectiveness of SSc,and to evaluate the clinical effectiveness and safety of Yiqiruanpi Pill on treating systemic sclerosis(SSc).
Method:Clinical data of 236 cases of SSc treated with Yiqiruanpi Pill were retrospectively analyzed, including sex, age, course of disease and treatment,initial symptoms,family history, clinical manifestations, laboratory examinations, untoward effect and therapeutic effect.All available data were dealt with statistical analysis and correlative conclusions were made.
Results:1. Of the 236 patients 81 were males(34.3%)and 155 were females(65.7%), the ratio of males to females was 1 to 1.91.The mean age of onset was 41.08±11.73 years old and the male's was 44.91±10.87 years old and the female's was 39.08±12.22 years old (P<0.01). The mean course of disease was 3.71±4.11 years and the male's was 3.15±4.05 years and the female's was 4.01±4.13 years (P<0.01).168 cases had Raynaud's phenomenon as their initial symptom (71.2%) and 4 cases had family history.
2. The total effective rate was 95.3%.The principal symptoms and physical signs and partial laboratory examinations were significantly improved.The effectiveness of Yiqiruanpi Pill was optimal to swollen phase and secondary to scleritic phase and inferior to atrophy phase. The course of treatment had distinct effect to the effectiveness of Yiqiruanpi Pill and over 9 months' treatment had better effectiveness.
3. There's a higher safety of Yiqiruanpi Pill on treating SSc.
Conclusion:Yiqiruanpi Pill is effective for SSc and has a higher safety.
CHAPTERⅡ:Clinical research on 32 cases of SSc treated with Yiqiruanpi Decoction ultramicro-drug.
Objective:To evaluate the clinical effectiveness of Yiqiruanpi Decoction ultramicro-drug(YDUD) on treating SSc,and to explore its effect on circulating endothelial cell(CEC) and endothelin-1(ET-1).
Method:32 patients with SSc were divided randomly into two groups, treated with traditional Yiqiruanpi Decoction(YD) and 1/3-dose YDUD Piece respectively in 3 months.The changes of skin sclerosis scores, minimal middle finger-to-palm distance,maximal upper-to-lower teeth distance, the numbers of CEC and the plasma levels of ET-1 were measured respectively before and after treatment,and the therapeutic effects were evaluated.
Results:1. The total effect rate of YD group was 87.5% and the 1/3YDUD group was 93.8%. The clinical effectiveness of the two groups were equal (p>0.05)
2. Comparison of pre-treatment, YD group and 1/3YDUD group could both remarkably reduce skin sclerosis scores and minimal middle finger-to-palm distance and improve maximal upper-to-lower teeth distance (P<0.01). And there were no significant difference between them (p>0.05)
3. Comparison of pre-treatment, YD group and 1/3YDUD group could both significantly reduce the number of CEC and down-regulate the plasma level of ET-1 (P<0.01). And there were no significant difference between them (p>0.05)
Conclusions:1. YD can remarkably reduce skin sclerosis scores and minimal middle finger-to-palm distance and improve maximal upper-to-lower teeth distance, the efficiency between YD group and 1/3YDUD group are equal.
2. YD can significantly reduce the number of CEC and down-regulate the plasma level of ET-1, and there were no significant difference between YD group and 1/3YDUD group.
CHAPTERⅢ:Investigation of anti-fibrotic effect and its mechanisms of Yiqiruanpi Decoction ultramicro-drug on murine model of BLM- induced scleroderma.
Objective:To investigate the anti-fibrotic effect of YDUD on murine model of BLM-induced scleroderma, and to explore the molecular mechanisms of this effect.
Method:1.72 SPF female BALB/c mice were randomly divided into 6 groups (12 in each group):normal control group(A), model group (B), D-Penicillamine (D-Pen) group (C), YD group(D), YDUD group (E) and 1/3-dose YDUD group (F). Group B, C, D,E and F received daily subcutaneous injection of 0.1 ml of BLM (300μg/ml, diluted in saline), and group A received 0.1ml of saline;Meanwhile,group C, D, E and F were treated with 125mg/kg D-Pen,16.6g /kg YD,16.6g/kg YDUD,5.5 g/kg YDUD, and group A and B were treated with the same volume of saline, respectively,all by daily i.g. for 4 weeks.
2.On the next day after the final treatment the back skin pieces of all these mice were removed for histological examination, measurement of dermal thickness,determination of hydroxyproline contents by colorimetric method, determination of CTGF mRNA expression by in situ hybridization (ISH) and COL-Ⅰ、Ⅲ, TGF-β1 by immunohistochemistry. The right-side lungs were also excised for histological examination.
Results:1.The model mice skin and lungs showed significant sclerosis histologically compared with normal control group,and all treatment groups had less sclerosis than the model group.
2.The dermis of model group was significantly thicker than that of normal control group and all treatment groups (P<0.01).The skin hydroxyproline contents of model group were significantly higher than those of normal control group and all treatment groups (P<0.01).There were no marked differences in group E and group F compared with group D(P>0.05).
3. The integral optical density(IOD) of the skin CTGFmRNA of model group was significantly higher than that of normal control group and all treatment groups (P<0.01). There were no marked differences of IOD in group E and group F compared with group D(P>0.05).
4. The integral optical density(IOD) of the skin TGF-β1 and COL-Ⅰ、Ⅲof model group was significantly higher than that of normal control group and all treatment groups (P<0.01). There were no marked differences of IOD in group E and group F compared with group D(P>0.05).
5. The abundance of COL-Ⅰ、Ⅲof group D、E and F correlated closely with CTGFmRNA and TGF-β1.After treatment with Yiqiruanpi Decoction, the abundance of COL-Ⅰ、Ⅲwas reduced with the down- regulation of CTGFmRNA and TGF-β1.
Conclusions:1.BLM can successfully induce scleroderma in BALB/c mice at a daily dose of 0.1ml (300μg/ml) by subcutaneous injection into the back for 4 weeks.
2. YD can significantly prevent the development of dermal fibrosis induced by BLM.
3. YD can down-regulate the expression of CTGF mRNA and TGF-β1, which may result in the down-regulation of the expression of COL-Ⅰand COL-Ⅲ.
目的：对236例SSc患者病案进行临床回顾性研究,以探讨SSc发病规律、临床特征及影响SSc疗效的相关因素,评价益气软皮丸治疗SSc的临床疗效及安全性。
方法：回顾性调查经益气软皮丸治疗的236例SSc患者门诊病历资料,对患者性别、发病年龄、病程、疗程、首发症状、家族史、临床表现、实验室检查、不良反应及疗效等进行统计分析,并得出相关结论。
结果：1.236例患者中,男81例(占34.3%),女155例(占65.7%),男女比为1：1.91；平均发病年龄41.08±11.73岁,其中男性44.91±10.87岁,女性39.08±12.22岁(P<0.01)；平均病程3.71±4.11年,其中男性3.15±4.05年,女性4.01±4.13年(P<0.01)；168例患者以雷诺氏现象为首发症状(占71.2%)；4例患者有家族病史。
2.益气软皮丸治疗SSc的总有效率为95.3%。治疗后患者各主要症状体征及部分实验室指标较治疗前有显著改善。益气软皮丸治疗SSc以浮肿期疗效最优,硬化期次之,萎缩期较差(P<0.01)；益气软皮丸治疗SSc疗程长短对其疗效有明显影响(P<0.01),其疗程以不少于9个月为宜。
3.益气软皮丸治疗SSc具有较高的安全性。
结论：益气软皮丸治疗SSc具有较好的疗效和安全性。
第二部分超微益气软皮汤治疗SSc的临床观察
目的：评价超微益气软皮汤治疗SSc的临床疗效,观察其对CEC、ET-1的影响。
方法：采用随机对照的研究方法,选取32例SSc患者分成传统组和超微组,分别给予益气软皮汤和1/3剂量超微益气软皮汤,治疗3个月,观察治疗前后患者皮肤硬化积分、指距、齿距以及外周血CEC、血浆ET-1水平的变化,评价其疗效。
结果：1.传统组总有效率为87.5%,超微组总有效率为93.8%,两组间疗效差异无显著性(p>0.05)。
2.与治疗前比较,传统组和超微组均能显著减少SSc患者皮肤硬化积分,缩小指距,增大齿距(P<0.01)；两组间比较,差异无统计学意义(p>0.05)。3.与治疗前比较,传统组和超微组均能显著降低SSc患者外周血CEC数量,下调血浆ET-1水平(P<0.01)；两组间比较,差异无统计学意义(p>0.05)。
结论：1.益气软皮汤对SSc具有较好疗效,能明显减少SSc患者皮肤硬化积分,缩小指距,增大齿距,1/3超微组和传统组比较疗效相当。
2.益气软皮汤能显著降低SSc患者外周血CEC数量,下调血浆ET-1水平,1/3超微组和传统组具有同等效应。
第三部分超微益气软皮汤对硬皮病的抗纤维化作用及其机制的实验研究目的：探讨超微益气软皮汤对BLM诱导的硬皮病小鼠的抗纤维化作用及其分子机制。
方法：72只BALB/c小鼠随机分为正常对照组(A)、模型组(B)、青霉胺组(C)、益气软皮汤组(D)、超微益气软皮汤全量组(E)、超微益气软皮汤1/3量组(F)等6组,每组各12只。A组小鼠背部皮下注射0.1ml生理盐水,B、C、D、E、F组小鼠皮下注射300μg/mlBLM溶液0.1ml；同时C、D、E、F组分别以125mg/kg青霉胺、16.6g/kg益气软皮汤浸膏、16.6g/kg超微益气软皮汤浸膏、5.5 g/kg超微益气软皮汤浸膏灌胃,A组和B组给予等容量蒸馏水灌胃,以上均为每日1次,连续4周。末次给药24小时后取背部注射部位皮肤分别行组织病理学观察,真皮厚度测量,比色法测定羟脯氨酸含量,原位杂交法进行CTGFmRNA表达测定,免疫组化法行皮肤COL-Ⅰ、Ⅲ, TGF-β1表达检测。同时取右肺组织行组织病理学检查。
结果：1.与正常对照组比较,模型组小鼠皮肤及肺组织切片表现出典型的硬皮病组织病理学改变,各治疗组病变较模型组轻。
2.模型组小鼠真皮厚度及皮肤羟脯氨酸含量较正常对照组明显增加,差异具有显著性意义(P<0.01)；各治疗组真皮厚度及皮肤羟脯氨酸含量均较模型组明显降低(P<0.01)；超微组和1/3超微组与传统组比较,差异无显著性(P>0.05)
3.模型组小鼠皮肤CTGFmR NA积分光密度较正常对照组明显增加,差异具有显著意义(P<0.01)；各治疗组CTGFmRNA积分光密度较模型组明显降低,差异具有显著意义(P<0.01)；超微组和1/3超微组与传统组比较,差异无显著性(P>0.05)
4.模型组小鼠皮肤COL-Ⅰ、Ⅲ, TGF-β1积分光密度较正常对照组明显增加,差异具有显著意义(P<0.01)；各治疗组较模型组明显降低,差异具有显著意义(P<0.01)；超微组和1/3超微组与传统组比较,差异无显著性(P>0.05)。
5. COL-Ⅰ、Ⅲ表达量与CTGFmRNA和TGF-β1表达量之间存在正相关性,经益气软皮汤治疗后,COL-Ⅰ、Ⅲ的表达随CTGFmRNA和TGF-β1表达的下调而下调。
结论:1.300μg/ml BLM背部皮下注射可成功诱导BALB/c小鼠产生硬皮病样改变。
2.益气软皮汤能显著对抗BLM的致纤维化作用。
3.益气软皮汤能下调硬皮病模型小鼠皮肤CTGF mRNA、TGF-β1的表达并可能由此导致COL-Ⅰ、Ⅲ的表达的降低。
CHAPTER I:A retrospective study on 236 cases of systemic sclerosis treated with Yiqiruanpi Pill
Objective:To explore the pathogenic factors, clinical features, and the correlative factors influencing the effectiveness of SSc,and to evaluate the clinical effectiveness and safety of Yiqiruanpi Pill on treating systemic sclerosis(SSc).
Method:Clinical data of 236 cases of SSc treated with Yiqiruanpi Pill were retrospectively analyzed, including sex, age, course of disease and treatment,initial symptoms,family history, clinical manifestations, laboratory examinations, untoward effect and therapeutic effect.All available data were dealt with statistical analysis and correlative conclusions were made.
Results:1. Of the 236 patients 81 were males(34.3%)and 155 were females(65.7%), the ratio of males to females was 1 to 1.91.The mean age of onset was 41.08±11.73 years old and the male's was 44.91±10.87 years old and the female's was 39.08±12.22 years old (P<0.01). The mean course of disease was 3.71±4.11 years and the male's was 3.15±4.05 years and the female's was 4.01±4.13 years (P<0.01).168 cases had Raynaud's phenomenon as their initial symptom (71.2%) and 4 cases had family history.
2. The total effective rate was 95.3%.The principal symptoms and physical signs and partial laboratory examinations were significantly improved.The effectiveness of Yiqiruanpi Pill was optimal to swollen phase and secondary to scleritic phase and inferior to atrophy phase. The course of treatment had distinct effect to the effectiveness of Yiqiruanpi Pill and over 9 months' treatment had better effectiveness.
3. There's a higher safety of Yiqiruanpi Pill on treating SSc.
Conclusion:Yiqiruanpi Pill is effective for SSc and has a higher safety.
CHAPTERⅡ:Clinical research on 32 cases of SSc treated with Yiqiruanpi Decoction ultramicro-drug.
Objective:To evaluate the clinical effectiveness of Yiqiruanpi Decoction ultramicro-drug(YDUD) on treating SSc,and to explore its effect on circulating endothelial cell(CEC) and endothelin-1(ET-1).
Method:32 patients with SSc were divided randomly into two groups, treated with traditional Yiqiruanpi Decoction(YD) and 1/3-dose YDUD Piece respectively in 3 months.The changes of skin sclerosis scores, minimal middle finger-to-palm distance,maximal upper-to-lower teeth distance, the numbers of CEC and the plasma levels of ET-1 were measured respectively before and after treatment,and the therapeutic effects were evaluated.
Results:1. The total effect rate of YD group was 87.5% and the 1/3YDUD group was 93.8%. The clinical effectiveness of the two groups were equal (p>0.05)
2. Comparison of pre-treatment, YD group and 1/3YDUD group could both remarkably reduce skin sclerosis scores and minimal middle finger-to-palm distance and improve maximal upper-to-lower teeth distance (P<0.01). And there were no significant difference between them (p>0.05)
3. Comparison of pre-treatment, YD group and 1/3YDUD group could both significantly reduce the number of CEC and down-regulate the plasma level of ET-1 (P<0.01). And there were no significant difference between them (p>0.05)
Conclusions:1. YD can remarkably reduce skin sclerosis scores and minimal middle finger-to-palm distance and improve maximal upper-to-lower teeth distance, the efficiency between YD group and 1/3YDUD group are equal.
2. YD can significantly reduce the number of CEC and down-regulate the plasma level of ET-1, and there were no significant difference between YD group and 1/3YDUD group.
CHAPTERⅢ:Investigation of anti-fibrotic effect and its mechanisms of Yiqiruanpi Decoction ultramicro-drug on murine model of BLM- induced scleroderma.
Objective:To investigate the anti-fibrotic effect of YDUD on murine model of BLM-induced scleroderma, and to explore the molecular mechanisms of this effect.
Method:1.72 SPF female BALB/c mice were randomly divided into 6 groups (12 in each group):normal control group(A), model group (B), D-Penicillamine (D-Pen) group (C), YD group(D), YDUD group (E) and 1/3-dose YDUD group (F). Group B, C, D,E and F received daily subcutaneous injection of 0.1 ml of BLM (300μg/ml, diluted in saline), and group A received 0.1ml of saline;Meanwhile,group C, D, E and F were treated with 125mg/kg D-Pen,16.6g /kg YD,16.6g/kg YDUD,5.5 g/kg YDUD, and group A and B were treated with the same volume of saline, respectively,all by daily i.g. for 4 weeks.
2.On the next day after the final treatment the back skin pieces of all these mice were removed for histological examination, measurement of dermal thickness,determination of hydroxyproline contents by colorimetric method, determination of CTGF mRNA expression by in situ hybridization (ISH) and COL-Ⅰ、Ⅲ, TGF-β1 by immunohistochemistry. The right-side lungs were also excised for histological examination.
Results:1.The model mice skin and lungs showed significant sclerosis histologically compared with normal control group,and all treatment groups had less sclerosis than the model group.
2.The dermis of model group was significantly thicker than that of normal control group and all treatment groups (P<0.01).The skin hydroxyproline contents of model group were significantly higher than those of normal control group and all treatment groups (P<0.01).There were no marked differences in group E and group F compared with group D(P>0.05).
3. The integral optical density(IOD) of the skin CTGFmRNA of model group was significantly higher than that of normal control group and all treatment groups (P<0.01). There were no marked differences of IOD in group E and group F compared with group D(P>0.05).
4. The integral optical density(IOD) of the skin TGF-β1 and COL-Ⅰ、Ⅲof model group was significantly higher than that of normal control group and all treatment groups (P<0.01). There were no marked differences of IOD in group E and group F compared with group D(P>0.05).
5. The abundance of COL-Ⅰ、Ⅲof group D、E and F correlated closely with CTGFmRNA and TGF-β1.After treatment with Yiqiruanpi Decoction, the abundance of COL-Ⅰ、Ⅲwas reduced with the down- regulation of CTGFmRNA and TGF-β1.
Conclusions:1.BLM can successfully induce scleroderma in BALB/c mice at a daily dose of 0.1ml (300μg/ml) by subcutaneous injection into the back for 4 weeks.
2. YD can significantly prevent the development of dermal fibrosis induced by BLM.
3. YD can down-regulate the expression of CTGF mRNA and TGF-β1, which may result in the down-regulation of the expression of COL-Ⅰand COL-Ⅲ.
引文
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