丹参联合小剂量泼尼松龙治疗口腔粘膜下纤维化的临床疗效和蛋白质组学研究
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摘要
研究背景口腔粘膜下纤维化(oral submucous fiborsis, OSF)是一种慢性、隐匿性、具有癌变倾向的炎性疾病,主要病理变化包括上皮组织萎缩、粘膜固有层和粘膜下层胶原纤维堆积变性、血管闭塞减少。临床上患者表现为口腔粘膜逐渐变苍白、紧缩失去弹性、触摸有条索感、张口受限和吞咽困难等症状。WHO将OSF列为癌前状态,湖南省OSF癌变率高达1.7%。咀嚼槟榔是OSF主要的致病因素,其发病机制至今不明,可能与免疫、遗传、代谢障碍等有关。复杂的发病机制导致该病至今尚无满意的治疗方法。以往曾用的手术治疗常因手术次数多、创伤大、术后瘢痕挛缩而不易被患者接受；雷公藤多甙、糖皮质激素等药物治疗常由于容易引起胃肠道刺激、骨质疏松和皮质功能减退等副作用而不能长期服用。基于以上原因,寻找有效、安全的OSF治疗方法成为目前的研究热点和难点。
根据OSF的病理特征,从降低病变组织的免疫炎性反应、改善微循环障碍等方面着手寻找治疗OSF的有效方法成为可能。基于糖皮质激素因其良好的抗炎作用而仍是多种组织纤维化疾病的首选药物,同时丹参具有良好的活血化瘀功能且丹参水提物和丹参素能防治泼尼松所致的骨质疏松,本研究采用中西药结合治疗,观察丹参联合小剂量泼尼松龙局部注射治疗OSF的临床疗效,评价两者联合应用在降低病变组织的免疫炎性反应、改善其微循环障碍从而抗纤维化的作用,同时通过高通量、高效率的差异蛋白质组学技术从整体水平研究丹参联合小剂量泼尼松龙治疗OSF的潜在机制并加以验证。
研究目的建立完善的OSF临床和病理资料管理系统；观察并比较丹参联合小剂量泼尼松龙及单独使用泼尼松龙治疗OSF的临床疗效；寻找丹参联合小剂量泼尼松龙治疗OSF的相关蛋白；验证丹参联合小剂量泼尼松龙治疗OSF的相关蛋白。
研究方法(1)建立OSF组织标本库,运用Access 2003、Excel 2003等软件建立OSF临床资料数据库,对患者进行追踪观察。
(2)选取OSF初诊患者中、晚期各60例,各随机分为两组,分别采用丹参联合小剂量泼尼松龙及单独使用泼尼松龙治疗3个月,比较用药前、后患者病损面积、张口度和疼痛指数的变化,比较两治疗方案的临床疗效。
(3)利用固相pH梯度双向凝胶电泳技术分离OSF组和丹参联合小剂量泼尼松龙治疗组颊粘膜组织的总蛋白,建立双向凝胶电泳图谱,应用PDQuest凝胶分析软件分析识别两组间差异表达的蛋白质,应用MALDI-TOF-MS对差异表达的蛋白质进行鉴定。(4)采用Western blot免疫印迹方法对鉴定出的差异蛋白之一——14-3-3σ蛋白进行蛋白水平的验证；选取OSF患者颊粘膜组织48例,其中早期15例、中期18例、晚期15例,丹参联合小剂量泼尼松龙治疗OSF后的颊粘膜组织15例,正常颊粘膜组织10例,运用免疫组化技术检测14-3-3σ蛋白在各组织中的分布和表达。
研究结果(1)成功构建了OSF组织标本库,自行设计开发了OSF临床资料数据库,收集了300余例患者的临床资料,为后续研究提供了条件。
(2)丹参联合小剂量泼尼松龙治疗OSF3个月后,第1组口腔粘膜下纤维化中期和晚期患者的灰白色病损面积分别由10.37±3.40 cm2、19.60±-3.27 cm2减少为5.90±4.10cm2,16.33±4.02 cm2,中晚各期治疗前后比较,差异有统计学意义(P<0.05)；张口度分别由3.41±0.77 cm、1.98±0.39 cm增加为3.87±0.67 cm、2.26±0.46 cm,中晚各期治疗前后比较,差异有统计学意义(P<0.05)。第2组治疗后中期患者的灰白色病损面积由10.87±3.18 cm2减少为6.70±3.75 cm2,张口度分别由3.57±±0.75cm增加为3.97±0.69 cm,治疗前后比较,差异均有统计学意义(P<0.05)；而晚期治疗前后比较,其灰白色病损面积和张口度差异均无统计学意义(P>0.05)。两组方法治疗口腔粘膜下纤维化中期的有效率分别为86.66%、73.33%,两组比较无统计学差异(P>0.05)；而两组方法治疗口腔粘膜下纤维化晚期的有效率分别为70%、16.67%,两组比较有统计学差异(P<0.05)。丹参与泼尼松龙联合用药治疗口腔粘膜下纤维化,还可减少泼尼松龙引起的不良反应。
(3)获得了背景清晰、重复性好、高质量的双向凝胶电泳图谱,筛选出与丹参联合小剂量泼尼松龙治疗OSF相关的23个蛋白质分子,其中在丹参联合小剂量泼尼松龙治疗OSF后的颊粘膜组织中高表达的有4个,分别为14-3-3σ、K4、Serotransferrin、Hemoglobin subunit beta;在丹参联合小剂量泼尼松龙治疗OSF后的颊粘膜组织中低表达的有19个,分别为K6、α-SMA、肌球蛋白(5个亚型)、原肌球蛋白(3个亚型)、ANXA2、S100A7、GAPDH和HspB5等,这些蛋白可能与丹参和泼尼松龙的作用机制密切相关。
(4)14-3-3σ蛋白在正常颊粘膜组织和丹参联合小剂量泼尼松龙治疗OSF后的颊粘膜组织中的表达高于在OSF颊组织中的表达(P<0.05),与差异蛋白质组学结果一致。
研究结论(1)OSF组织标本库和临床资料数据库管理系统可作为OSF基础及临床研究很好的技术平台。
(2)丹参联合小剂量泼尼松龙局部注射治疗OSF中期、晚期具有良好疗效,可作为安全有效治疗OSF的方法进行推广。
(3) 14-3-3σ、K4、Serotransferrin、Hemoglobin subunit beta、K6、α-SMA、肌球蛋白、原肌球蛋白、ANXA2、S100A7、GAPDH和HspB5等蛋白可能与丹参和泼尼松龙治疗OSF的作用机制相关。
(4)14-3-36蛋白有望成为OSF疗效评价和新药研发的标志物。
Backgorund Oral submucous Fibrosis(OSF) is a kind of chronic insidious disease and it predisposes to cancer. Histologically, OSF is characterized by epithelial atrophy and progressive accumulation of collagen fibers in the lamina propria and submucous of the oral mucosa with a progressive loss of vasularity. The majority of patients present with rigidity of lip, tongue, and palate leading to varying degrees of limitation of opening the mouth and tongue movement. A number of studies provide overwhelming evidence the betel quid is the main aetiological factor for OSF, OSF was reguarded as a precancerous condition by WHO, the malignant transformation rate of OSF was 1.7% in Hunan Province. The pathogenesis of OSF is still unknown, It may be associated with immunity, heredity, dysmetabolism and microcirculation disturbance. The complex pathogenesis of OSF makes it have no satisfying therapies. Formerly, surgery on the fibrous bands is not easy to be accepted by trauma and postoperative scar. Glucosida tripterygii TOTA and glucocorticoids also can not be taked for long-term by the side effect of gastralgia, osteoporosis, and hypocorticalism. Therefore, a new therapy for the treatment of OSF is necessary. According to the pathogenesis of OSF, it is efficient therapy by lowering the inflammatory reaction lesion and improving the microcirculation disturbance. As glucocorticoids are still the choice drug on fibrosis, and Salvia miltiorrhiza is good at activating blood circulation to dissipate blood stasis, moreover, Salvia miltiorrhiza can also inhibit osteoporosismade by glucocorticoids, our study like to evaluate the role of the combination of Salvia miltiorrhiza and low dose prednisolone on patients with oral submucous fibrosis, and explore the latent mechanism involved in the role of the combination of Salvia miltiorrhiza and low dose prednisolone on patients with oral submucous fibrosis in general level with proteomics technology.
Object To establish tissue specimen bank and clinical information da-tabase of OSF. To explore the therapeutic effects of the combination of Salv-ia miltiorrhiza and low dose prednisolone on patients with oral submucous fibrosis and find the associated protein.
Methods (1) To establish tissue specimen bank, and use Access 2003 and Excel 2003 to establish clinical information database of OSF.
(2) There are 60 medium-term OSF patients and 60 advanced stage OSF patients, and each were randomly divided into the first groups (treated with both salvia miltiorrhiza and prednisolone) and the second group (treated separately with prednisolone). The therapeutic effects were compared among each group after the three month treatment.
(3) Total proteins were extracted from OSF bucca tissues and the bucca tissues after treated by combination of Salvia miltiorrhiza and low dose prednisolone on patients with oral submucous fibrosis and were separated by immobilized PH gradient two-dimensional gel electrophoresis to establish the expression maps of proteomics. The differential expressed proteins between the two groups were analyzed with PDQuest image analysis software, and identified with MALDI-TOF-MS (matix-assisted laser desorption/ionization time of flight mass spectrometry).
(4) Differentially expression level of selected protein was validate by Western blot and Immunohistochemistry analysis.
Results (1) Tissue specimen bank and clinical information database of OSF were successfully constructed. More than 300 patient's clinical information was included in the information database which provides conveniences for subsequent research.
(2) Both significant differences were found in the lesion area of the medium-term cases and the advanced stage cases of the first groups between prior treatment (10.37±3.40 cm2,19.60±3.27 cm2) and post treatment (5.90±4.10 cm2,16.33±4.02 cm2) (P<0.05); and also both significant differences were found in the mouth opening between prior treatment (3.41±0.77 cm,1.98±0.39 cm) and post treatment (3.87±0.67 cm,2.26±0.46 cm) (P<0.05). There were significant differences in the lesion area and mouth opening of the medium-term cases of the second groups between prior treatment (10.87±3.18 cm2,3.57±0.75 cm) and post treatment (6.70±3.75 cm2,3.97±0.69 cm) (P<0.05); but there was no significant difference in the lesion area and mouth opening of the advanced stage cases of the second groups (P>0.05). There was significant difference in the therapeutic efficacy between the first group (70%) and the second group (16.67%) of the advanced stage cases (P<0.05); but there was no significant difference in the clinical effects between the two groups of the medium-term cases (P>0.05). The side effect of prednisolone could be reduced while applied with salvia miltiorrhiza together.
(3) Two-dimensional gel electrophoresis profiles with clear background, well reproducibility and high quality were obtained. Twenty-three specially expressed proteins were identified to be related to combination of Salvia miltiorrhiza and low dose prednisolone.4 spots (14-3-3σ、K4、Serotransferrin、Hemoglobin subunit beta) expressed highly and 19 spots (K6,α-SMA, MYL,TPM, ANXA2, S100A7, GAPDH, HspB5, et al) expressed lowly in therapy group specimens.
(4) By analysis and classification of those proteins,14-3-3σprotein was considered to be the therapy on combination of Salvia miltiorrhiza and low dose prednisolone-associated protein candidate. Western blot exhibited an increase expression of 14-3-3σprotein. Immunohistochemical analysis of tissues showed that expression of 14-3-3σprotein in normal tissues and treated tissues were higher than in OSF tissues.
Conclusion (1) Tissue specimen bank and clinical information database of OSF which were successfully constructed can be used for the study of OSF.
(2) There is obvious advantage in treating OSF by the combination of Salvia miltiorrhiza and prednisolone.
(3) 14-3-3σ、K4、Serotransferrin、Hemoglobin subunit beta,K6, a-SMA, MYL, TPM, ANXA2, S100A7, GAPDH and HspB5 could be thinked associated to the treatment of combination of Salvia miltiorrhiza and prednisolone on OSF.
(4) 14-3-3σcould be used as indicator to predict the mechanism of combination of Salvia miltiorrhiza and prednisolone on OSF.
根据OSF的病理特征,从降低病变组织的免疫炎性反应、改善微循环障碍等方面着手寻找治疗OSF的有效方法成为可能。基于糖皮质激素因其良好的抗炎作用而仍是多种组织纤维化疾病的首选药物,同时丹参具有良好的活血化瘀功能且丹参水提物和丹参素能防治泼尼松所致的骨质疏松,本研究采用中西药结合治疗,观察丹参联合小剂量泼尼松龙局部注射治疗OSF的临床疗效,评价两者联合应用在降低病变组织的免疫炎性反应、改善其微循环障碍从而抗纤维化的作用,同时通过高通量、高效率的差异蛋白质组学技术从整体水平研究丹参联合小剂量泼尼松龙治疗OSF的潜在机制并加以验证。
研究目的建立完善的OSF临床和病理资料管理系统；观察并比较丹参联合小剂量泼尼松龙及单独使用泼尼松龙治疗OSF的临床疗效；寻找丹参联合小剂量泼尼松龙治疗OSF的相关蛋白；验证丹参联合小剂量泼尼松龙治疗OSF的相关蛋白。
研究方法(1)建立OSF组织标本库,运用Access 2003、Excel 2003等软件建立OSF临床资料数据库,对患者进行追踪观察。
(2)选取OSF初诊患者中、晚期各60例,各随机分为两组,分别采用丹参联合小剂量泼尼松龙及单独使用泼尼松龙治疗3个月,比较用药前、后患者病损面积、张口度和疼痛指数的变化,比较两治疗方案的临床疗效。
(3)利用固相pH梯度双向凝胶电泳技术分离OSF组和丹参联合小剂量泼尼松龙治疗组颊粘膜组织的总蛋白,建立双向凝胶电泳图谱,应用PDQuest凝胶分析软件分析识别两组间差异表达的蛋白质,应用MALDI-TOF-MS对差异表达的蛋白质进行鉴定。(4)采用Western blot免疫印迹方法对鉴定出的差异蛋白之一——14-3-3σ蛋白进行蛋白水平的验证；选取OSF患者颊粘膜组织48例,其中早期15例、中期18例、晚期15例,丹参联合小剂量泼尼松龙治疗OSF后的颊粘膜组织15例,正常颊粘膜组织10例,运用免疫组化技术检测14-3-3σ蛋白在各组织中的分布和表达。
研究结果(1)成功构建了OSF组织标本库,自行设计开发了OSF临床资料数据库,收集了300余例患者的临床资料,为后续研究提供了条件。
(2)丹参联合小剂量泼尼松龙治疗OSF3个月后,第1组口腔粘膜下纤维化中期和晚期患者的灰白色病损面积分别由10.37±3.40 cm2、19.60±-3.27 cm2减少为5.90±4.10cm2,16.33±4.02 cm2,中晚各期治疗前后比较,差异有统计学意义(P<0.05)；张口度分别由3.41±0.77 cm、1.98±0.39 cm增加为3.87±0.67 cm、2.26±0.46 cm,中晚各期治疗前后比较,差异有统计学意义(P<0.05)。第2组治疗后中期患者的灰白色病损面积由10.87±3.18 cm2减少为6.70±3.75 cm2,张口度分别由3.57±±0.75cm增加为3.97±0.69 cm,治疗前后比较,差异均有统计学意义(P<0.05)；而晚期治疗前后比较,其灰白色病损面积和张口度差异均无统计学意义(P>0.05)。两组方法治疗口腔粘膜下纤维化中期的有效率分别为86.66%、73.33%,两组比较无统计学差异(P>0.05)；而两组方法治疗口腔粘膜下纤维化晚期的有效率分别为70%、16.67%,两组比较有统计学差异(P<0.05)。丹参与泼尼松龙联合用药治疗口腔粘膜下纤维化,还可减少泼尼松龙引起的不良反应。
(3)获得了背景清晰、重复性好、高质量的双向凝胶电泳图谱,筛选出与丹参联合小剂量泼尼松龙治疗OSF相关的23个蛋白质分子,其中在丹参联合小剂量泼尼松龙治疗OSF后的颊粘膜组织中高表达的有4个,分别为14-3-3σ、K4、Serotransferrin、Hemoglobin subunit beta;在丹参联合小剂量泼尼松龙治疗OSF后的颊粘膜组织中低表达的有19个,分别为K6、α-SMA、肌球蛋白(5个亚型)、原肌球蛋白(3个亚型)、ANXA2、S100A7、GAPDH和HspB5等,这些蛋白可能与丹参和泼尼松龙的作用机制密切相关。
(4)14-3-3σ蛋白在正常颊粘膜组织和丹参联合小剂量泼尼松龙治疗OSF后的颊粘膜组织中的表达高于在OSF颊组织中的表达(P<0.05),与差异蛋白质组学结果一致。
研究结论(1)OSF组织标本库和临床资料数据库管理系统可作为OSF基础及临床研究很好的技术平台。
(2)丹参联合小剂量泼尼松龙局部注射治疗OSF中期、晚期具有良好疗效,可作为安全有效治疗OSF的方法进行推广。
(3) 14-3-3σ、K4、Serotransferrin、Hemoglobin subunit beta、K6、α-SMA、肌球蛋白、原肌球蛋白、ANXA2、S100A7、GAPDH和HspB5等蛋白可能与丹参和泼尼松龙治疗OSF的作用机制相关。
(4)14-3-36蛋白有望成为OSF疗效评价和新药研发的标志物。
Backgorund Oral submucous Fibrosis(OSF) is a kind of chronic insidious disease and it predisposes to cancer. Histologically, OSF is characterized by epithelial atrophy and progressive accumulation of collagen fibers in the lamina propria and submucous of the oral mucosa with a progressive loss of vasularity. The majority of patients present with rigidity of lip, tongue, and palate leading to varying degrees of limitation of opening the mouth and tongue movement. A number of studies provide overwhelming evidence the betel quid is the main aetiological factor for OSF, OSF was reguarded as a precancerous condition by WHO, the malignant transformation rate of OSF was 1.7% in Hunan Province. The pathogenesis of OSF is still unknown, It may be associated with immunity, heredity, dysmetabolism and microcirculation disturbance. The complex pathogenesis of OSF makes it have no satisfying therapies. Formerly, surgery on the fibrous bands is not easy to be accepted by trauma and postoperative scar. Glucosida tripterygii TOTA and glucocorticoids also can not be taked for long-term by the side effect of gastralgia, osteoporosis, and hypocorticalism. Therefore, a new therapy for the treatment of OSF is necessary. According to the pathogenesis of OSF, it is efficient therapy by lowering the inflammatory reaction lesion and improving the microcirculation disturbance. As glucocorticoids are still the choice drug on fibrosis, and Salvia miltiorrhiza is good at activating blood circulation to dissipate blood stasis, moreover, Salvia miltiorrhiza can also inhibit osteoporosismade by glucocorticoids, our study like to evaluate the role of the combination of Salvia miltiorrhiza and low dose prednisolone on patients with oral submucous fibrosis, and explore the latent mechanism involved in the role of the combination of Salvia miltiorrhiza and low dose prednisolone on patients with oral submucous fibrosis in general level with proteomics technology.
Object To establish tissue specimen bank and clinical information da-tabase of OSF. To explore the therapeutic effects of the combination of Salv-ia miltiorrhiza and low dose prednisolone on patients with oral submucous fibrosis and find the associated protein.
Methods (1) To establish tissue specimen bank, and use Access 2003 and Excel 2003 to establish clinical information database of OSF.
(2) There are 60 medium-term OSF patients and 60 advanced stage OSF patients, and each were randomly divided into the first groups (treated with both salvia miltiorrhiza and prednisolone) and the second group (treated separately with prednisolone). The therapeutic effects were compared among each group after the three month treatment.
(3) Total proteins were extracted from OSF bucca tissues and the bucca tissues after treated by combination of Salvia miltiorrhiza and low dose prednisolone on patients with oral submucous fibrosis and were separated by immobilized PH gradient two-dimensional gel electrophoresis to establish the expression maps of proteomics. The differential expressed proteins between the two groups were analyzed with PDQuest image analysis software, and identified with MALDI-TOF-MS (matix-assisted laser desorption/ionization time of flight mass spectrometry).
(4) Differentially expression level of selected protein was validate by Western blot and Immunohistochemistry analysis.
Results (1) Tissue specimen bank and clinical information database of OSF were successfully constructed. More than 300 patient's clinical information was included in the information database which provides conveniences for subsequent research.
(2) Both significant differences were found in the lesion area of the medium-term cases and the advanced stage cases of the first groups between prior treatment (10.37±3.40 cm2,19.60±3.27 cm2) and post treatment (5.90±4.10 cm2,16.33±4.02 cm2) (P<0.05); and also both significant differences were found in the mouth opening between prior treatment (3.41±0.77 cm,1.98±0.39 cm) and post treatment (3.87±0.67 cm,2.26±0.46 cm) (P<0.05). There were significant differences in the lesion area and mouth opening of the medium-term cases of the second groups between prior treatment (10.87±3.18 cm2,3.57±0.75 cm) and post treatment (6.70±3.75 cm2,3.97±0.69 cm) (P<0.05); but there was no significant difference in the lesion area and mouth opening of the advanced stage cases of the second groups (P>0.05). There was significant difference in the therapeutic efficacy between the first group (70%) and the second group (16.67%) of the advanced stage cases (P<0.05); but there was no significant difference in the clinical effects between the two groups of the medium-term cases (P>0.05). The side effect of prednisolone could be reduced while applied with salvia miltiorrhiza together.
(3) Two-dimensional gel electrophoresis profiles with clear background, well reproducibility and high quality were obtained. Twenty-three specially expressed proteins were identified to be related to combination of Salvia miltiorrhiza and low dose prednisolone.4 spots (14-3-3σ、K4、Serotransferrin、Hemoglobin subunit beta) expressed highly and 19 spots (K6,α-SMA, MYL,TPM, ANXA2, S100A7, GAPDH, HspB5, et al) expressed lowly in therapy group specimens.
(4) By analysis and classification of those proteins,14-3-3σprotein was considered to be the therapy on combination of Salvia miltiorrhiza and low dose prednisolone-associated protein candidate. Western blot exhibited an increase expression of 14-3-3σprotein. Immunohistochemical analysis of tissues showed that expression of 14-3-3σprotein in normal tissues and treated tissues were higher than in OSF tissues.
Conclusion (1) Tissue specimen bank and clinical information database of OSF which were successfully constructed can be used for the study of OSF.
(2) There is obvious advantage in treating OSF by the combination of Salvia miltiorrhiza and prednisolone.
(3) 14-3-3σ、K4、Serotransferrin、Hemoglobin subunit beta,K6, a-SMA, MYL, TPM, ANXA2, S100A7, GAPDH and HspB5 could be thinked associated to the treatment of combination of Salvia miltiorrhiza and prednisolone on OSF.
(4) 14-3-3σcould be used as indicator to predict the mechanism of combination of Salvia miltiorrhiza and prednisolone on OSF.
引文
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