FK506通过减少瘢痕形成促进周围神经再生的作用及机制研究
摘要
FK506是1984年从链霉菌中分离出的大环内酯类抗生素,英文名tacrolimus,广泛应用于器官移植术,近年来被发现具有强大的促神经再生作用。
目的
第一部分：通过建立大鼠坐骨神经横断伤修复模型,探讨FK506对神经吻合口瘢痕形成的影响及其与神经再生、神经功能恢复之间的关系。
第二部分：通过FK506对大鼠皮肤成纤维细胞的作用研究,探讨其减少神经吻合口瘢痕形成的机制。
方法
第一部分：
1.建立大鼠坐骨神经横断伤修复模型,FK506按手术后4mg/kg/d灌胃；动物分组(每组15只)如下：模型组：手术后生理盐水灌胃6周；灌胃2周组：手术后FK506灌胃2周+生理盐水灌胃4周；灌胃4周组：手术后FK506灌胃4周+生理盐水灌胃2周；灌胃6周组：手术后FK506灌胃6周；正常对照组：未手术生理盐水灌胃6周。
2.手术后6周取坐骨神经行MASSON染色观察胶原纤维增生情况及测量瘢痕面积(mm2)。
3.手术后6周取坐骨神经行HE(Hematoxylin eosin,苏木精伊红)染色观察有髓神经纤维密度及结缔组织情况并测量有髓神经纤维密度、平均轴突直径、髓鞘厚度。
4.手术后6周取坐骨神经行超薄切片、醋酸铀-硝酸铅双染后,透射电镜下观察再生神经纤维超微结构。
5.手术后6周,神经标本取材完毕后,切取两侧腓肠肌,测定腓肠肌湿重恢复率(术侧与各自对侧正常肌肉比较,%)。
6.手术后6周,采用de Medinaceli方法,测定坐骨神经功能指数(Sciatic Functional Index, SFI)。
7.手术后6周,测定复合肌肉动作电位(compound muscle active potential, CMAP)波幅、潜伏期。
8.有髓神经纤维密度及SFI与瘢痕面积进行相关性分析。
第二部分：
1.获取大鼠皮肤成纤维细胞并培养,5mg晶体颗粒状FK506溶解在DMSO(Dimethyl sulfoxide,二甲基亚砜)中,并保存于-20℃。含不同浓度FK506的培养基于每次实验前配制。实验分组如下：对照组：细胞以不含胎牛血清的DMEM(Dulbecco's modified Eagle's medium,达尔伯克(氏)改良伊格尔(氏)培养基)培育8小时；DMSO组：细胞以含DMSO的DMEM培育8小时；FK50612.5μM组：细胞以含12.5μM FK506的DMEM培育8小时；FK50625μM组：细胞以含25μM FK506的DMEM培育8小时；FK50650μM组：细胞以含50μM FK506的DMEM培育8小时；FK50675μM组：细胞以含75μM FK506的DMEM培育8小时；FK506100μM组：细胞以含100μM FK506的DMEM培育8小时；JNK(c-Jun N-terminal kinase, c-Jun氨基末端激酶)抑制剂预处理组：SP600125(40μM)预处理30分钟,继以不含胎牛血清的DMEM培育8小时；ERK(extracellular-signal regulated kinase,细胞外信号调节激酶)抑制剂预处理组：PD98059(60μM)预处理30分钟,继以不含胎牛血清的DMEM培育8小时；
JNK抑制剂预处理+FK50650μM组：SP600125(40μM)预处理30分钟,继以含50μM FK506的DMEM培育8小时;
ERK抑制剂预处理+FK50650μM组：PD98059(60μM)预处理30分钟,继以含50μM FK506的DMEM培育8小时。
2. CCK-8(Cell Counting Kit-8,细胞计数试剂盒-8)检测不同干预对成纤维细胞活性的影响。
3. Hoechst33342荧光染色观察细胞凋亡形态。
4.流式细胞分析技术检测细胞凋亡。
5. Western blot法检测蛋白水平的表达。
结果
第一部分：
1.FK506明显减少神经纵截面胶原纤维含量和神经横截面瘢痕面积。
2.FK506明显增加神经横截面有髓纤维密度、平均轴突直径、髓鞘厚度。
3.FK506明显增加有髓神经纤维的成熟度。
4.FK506显著增加腓肠肌湿重恢复率。
5.FK506显著改善坐骨神经功能指数,用药组较模型组恢复提前。
6.FK506显著缩短复合肌肉动作电位潜伏期、提高复合肌肉动作电位波幅。
7.相关性分析提示有髓神经纤维密度及坐骨神经功能都与瘢痕面积存在完全负相关关系。
第二部分：
1.FK506浓度依赖性的降低大鼠皮肤成纤维细胞存活率
2.FK506诱导大鼠皮肤成纤维细胞产生凋亡特征性的形态学变化。
3.FK506浓度依赖性的诱导大鼠皮肤成纤维细胞凋亡,并且凋亡能被JNK抑制剂SP600125或ERK抑制剂PD98059削弱。
4.FK506浓度依赖性的增高大鼠皮肤成纤维细胞p-JNK(phosphorylation of c-Jun N-terminal kinase,磷酸化c-Jun氨基末端激酶)、p-ERK(phosphorylation of extracellular-signal regulated kinase,磷酸化细胞外信号调节激酶)、胞浆细胞色素C及活化的caspase-3表达。
5.JNK抑制剂SP600125或ERK抑制剂PD98059预处理显著降低p-JNK或p-ERK、以及活化的caspase-3的表达。
结论
第一部分：
1.FK506能明显减少神经损伤修复后神经内胶原纤维的含量和瘢痕的面积。
2.FK506能显著提高神经损伤修复后神经再生的速度和再生神经的质量。
3.FK506能明显加快神经功能的恢复。
4.FK506通过减少瘢痕形成促进周围神经再生和加快神经功能恢复。
第二部分：
1.FK506显著降低大鼠皮肤成纤维细胞存活率；
2.FK506显著增高大鼠皮肤成纤维细胞凋亡率；
3.FK506诱导大鼠皮肤成纤维细胞凋亡的机制可能与FK506激活JNK.ERK信号通路,使JNK和ERK磷酸化水平升高有关,而这两条信号通路激活后,经过或不经过线粒体途径,最终都引起caspase-3的活化从而导致细胞凋亡。
FK506(tacrolimus) is a macrolide antibiotic isolated from streptomycete in1984and has extensive application in the area of organ transplantation. Recent years, it has been demonstrated that FK506has powerful effect of promoting nerve regeneration.
Objective
Part Ⅰ
Sciatic nerve injury in rat model was established, in order to investigate whether FK506intensively promotes peripheral nerve regeneration and functional recovery by directly inhibiting scar formation of nerval anastomotic stoma.
Part II
To investigate whether FK506reduces scar formation of nerval anastomotic stoma through inducing fibroblast apoptosis.
Methods
Part Ⅰ
1. establishing the model of rat sciatic nerve injury, then the rats received intragastric administration of FK506according to the dose of4mg/kg/d. The rats were divided into5groups (n=15):
model group:intragastric administration with physiologic saline for6weeks after operation;
2weeks group:intragastric administration with FK506for2weeks and then with physiologic saline for4weeks after operation;
4weeks group:intragastric administration with FK506for4weeks and then with physiologic saline for2weeks after operation;
6weeks group:intragastric administration with FK506for6weeks after operation;
control group:intragastric administration with physiologic saline for6weeks without operation.
2. At6weeks after operation, MASSON staining of rat sciatic nerve was performed to observe collagen fibrils and scar formation. Scar areas was measured by Image-pro plus5.0analysis software.
3. At6weeks after operation, HE staining of rat sciatic nerve was performed to observe the density of medullated nerve fibers and connective tissue formation. The density of medullated nerve fibers, average axonal diameter and thickness of medullary sheath were measured.
4. At6weeks after operation, ultrathin section of rat sciatic nerve was performed to observe the ultramicrostructure of regenerated axon.
5. At6weeks after operation, the recovery rate of gastrocnemius wet weight was calculated (operation side/normal side,%).
6. At6weeks after operation, Sciatic Functional Index (SFI) was determined by de Medinaceli process.
7. At6weeks after operation, the latency and wave amplitude of CMAP (compound muscle active potential) were detected.
8. Dependablity between medullated nerve fibers or SFI and scar areas was analyzed.
Part II
1. Primary cultures of rat skin fibroblasts were obtained from male Sprague-Dawley newborn rats1-2days after birth and then subcultured. Supplied as a crystalline solid, FK506was dissolved in DMSO (Dimethyl sulfoxide) and stored at-20℃. The culture media containing different concentrations of FK506were freshly prepared for each experiment. Fibroblasts were treated with different stimulus:
control group:fibroblasts were cultured with DMEM (Dulbecco's modified Eagle's medium) free of FBS (fetal bovine serum) for8hours;
DMSO group:fibroblasts were cultured with DMEM containing DMSO for8hours;
12.5μM FK506group:fibroblasts were cultured with DMEM containing12.5μM FK506for8hours;
25μM FK506group:fibroblasts were cultured with DMEM containing25μM FK506for8hours;
50μM FK506group:fibroblasts were cultured with DMEM containing50μM FK506for8hours;
75μM FK506group:fibroblasts were cultured with DMEM containing75μM FK506for8hours;
100μM FK506group:fibroblasts were cultured with DMEM containing100μM FK506for8hours;
JNK (c-Jun N-terminal kinase) inhibitor pretreatment group: fibroblasts were pretreated with SP600125(40μM) for30min, then cultured with DMEM free of FBS for8hours;
ERK (extracellular-signal regulated kinase) inhibitor pretreatment group:fibroblasts were pretreated with PD98059(60μM) for30min, then cultured with DMEM free of FBS for8hours;
JNK inhibitor pretreatment and50μM FK506group:fibroblasts were pretreated with SP600125(40μM) for30min, then cultured with DMEM containing50μM FK506for8hours;
ERK inhibitor pretreatment and50μM FK506group:fibroblasts were pretreated with PD98059(60μM) for30min, then cultured with DMEM containing50μM FK506for8hours.
2. CCK-8(Cell Counting Kit-8) assay was used to evaluate the inhibitory activity of FK506on cultured fibroblasts.
3. Hoechst33342staining was used to observe apoptotic fibroblasts.
4. Flow cytometry was used to detect apoptosis percentage of cultured fibroblasts.
5. Western blotting was used to detect expression level of apoptosis associated proteins.
Results
Part Ⅰ
1. FK506significantly reduced the formation of collagen fibrils and the scar areas of nerval anastomotic stoma.
2. FK506significantly increased the density of medullated nerve fibers, average axonal diameter and thickness of medullary sheath.
3. FK506significantly increased degree of maturity of medullated nerve fibers.
4. FK506significantly increased the recovery rate of gastrocnemius wet weight.
5. FK506significantly improved SFI.
6. FK506significantly shortened the latency and elevated the wave amplitude of CMAP.
7. Complete negative correlations existed between medullated nerve fibers or SFI and scar areas.
Part II
1. FK506reduced rat skin fibroblasts viability in a dose-dependent manner.
2. FK506induced characteristic morphological changes of apoptosis in rat skin fibroblasts.
3. FK506induced significant apoptosis of rat skin fibroblasts in a dose-dependent manner, and the apoptosis could be weakened by JNK inhibitor SP600125or ERK inhibitor PD98059.
4. FK506increased the expressions of p-JNK (phosphorylation of c-Jun N-terminal kinase), p-ERK (phosphorylation of extracellular-signal regulated kinase), cytosolic cytochrome c and cleaved-caspase-3in a dose-dependent manner.
5. Pretreatment with JNK inhibitor SP600125or ERK inhibitor PD98059significantly reduced the expressions of p-JNK or p-ERK and cleaved-caspase-3.
Conclusions
Part Ⅰ
1. FK506could significantly decrease the formation of collagen fibrils and the scar areas of nerval anastomotic stoma following repair of peripheral nerve injury.
2. FK506could significantly increase the speed of nerve regeneration and the quality of regenerated nerve fibers following repair of peripheral nerve injury.
3. FK506could significantly accelerate the neurofunctional recovery.
4. FK506intensively promotes peripheral nerve regeneration and functional recovery by directly inhibiting scar formation of nerval anastomotic stoma.
Part II
1. FK506significantly decreased the viability of rat skin fibroblasts.
2. FK506significantly increased apoptotic percentage of rat skin fibroblasts.
3. FK506activated both JNK and ERK with or without mitochondrial cytochrome c release, followed by the cleavage of caspase-3, subsequently leading to the apoptosis of rat skin fibroblasts.
目的
第一部分：通过建立大鼠坐骨神经横断伤修复模型,探讨FK506对神经吻合口瘢痕形成的影响及其与神经再生、神经功能恢复之间的关系。
第二部分：通过FK506对大鼠皮肤成纤维细胞的作用研究,探讨其减少神经吻合口瘢痕形成的机制。
方法
第一部分：
1.建立大鼠坐骨神经横断伤修复模型,FK506按手术后4mg/kg/d灌胃；动物分组(每组15只)如下：模型组：手术后生理盐水灌胃6周；灌胃2周组：手术后FK506灌胃2周+生理盐水灌胃4周；灌胃4周组：手术后FK506灌胃4周+生理盐水灌胃2周；灌胃6周组：手术后FK506灌胃6周；正常对照组：未手术生理盐水灌胃6周。
2.手术后6周取坐骨神经行MASSON染色观察胶原纤维增生情况及测量瘢痕面积(mm2)。
3.手术后6周取坐骨神经行HE(Hematoxylin eosin,苏木精伊红)染色观察有髓神经纤维密度及结缔组织情况并测量有髓神经纤维密度、平均轴突直径、髓鞘厚度。
4.手术后6周取坐骨神经行超薄切片、醋酸铀-硝酸铅双染后,透射电镜下观察再生神经纤维超微结构。
5.手术后6周,神经标本取材完毕后,切取两侧腓肠肌,测定腓肠肌湿重恢复率(术侧与各自对侧正常肌肉比较,%)。
6.手术后6周,采用de Medinaceli方法,测定坐骨神经功能指数(Sciatic Functional Index, SFI)。
7.手术后6周,测定复合肌肉动作电位(compound muscle active potential, CMAP)波幅、潜伏期。
8.有髓神经纤维密度及SFI与瘢痕面积进行相关性分析。
第二部分：
1.获取大鼠皮肤成纤维细胞并培养,5mg晶体颗粒状FK506溶解在DMSO(Dimethyl sulfoxide,二甲基亚砜)中,并保存于-20℃。含不同浓度FK506的培养基于每次实验前配制。实验分组如下：对照组：细胞以不含胎牛血清的DMEM(Dulbecco's modified Eagle's medium,达尔伯克(氏)改良伊格尔(氏)培养基)培育8小时；DMSO组：细胞以含DMSO的DMEM培育8小时；FK50612.5μM组：细胞以含12.5μM FK506的DMEM培育8小时；FK50625μM组：细胞以含25μM FK506的DMEM培育8小时；FK50650μM组：细胞以含50μM FK506的DMEM培育8小时；FK50675μM组：细胞以含75μM FK506的DMEM培育8小时；FK506100μM组：细胞以含100μM FK506的DMEM培育8小时；JNK(c-Jun N-terminal kinase, c-Jun氨基末端激酶)抑制剂预处理组：SP600125(40μM)预处理30分钟,继以不含胎牛血清的DMEM培育8小时；ERK(extracellular-signal regulated kinase,细胞外信号调节激酶)抑制剂预处理组：PD98059(60μM)预处理30分钟,继以不含胎牛血清的DMEM培育8小时；
JNK抑制剂预处理+FK50650μM组：SP600125(40μM)预处理30分钟,继以含50μM FK506的DMEM培育8小时;
ERK抑制剂预处理+FK50650μM组：PD98059(60μM)预处理30分钟,继以含50μM FK506的DMEM培育8小时。
2. CCK-8(Cell Counting Kit-8,细胞计数试剂盒-8)检测不同干预对成纤维细胞活性的影响。
3. Hoechst33342荧光染色观察细胞凋亡形态。
4.流式细胞分析技术检测细胞凋亡。
5. Western blot法检测蛋白水平的表达。
结果
第一部分：
1.FK506明显减少神经纵截面胶原纤维含量和神经横截面瘢痕面积。
2.FK506明显增加神经横截面有髓纤维密度、平均轴突直径、髓鞘厚度。
3.FK506明显增加有髓神经纤维的成熟度。
4.FK506显著增加腓肠肌湿重恢复率。
5.FK506显著改善坐骨神经功能指数,用药组较模型组恢复提前。
6.FK506显著缩短复合肌肉动作电位潜伏期、提高复合肌肉动作电位波幅。
7.相关性分析提示有髓神经纤维密度及坐骨神经功能都与瘢痕面积存在完全负相关关系。
第二部分：
1.FK506浓度依赖性的降低大鼠皮肤成纤维细胞存活率
2.FK506诱导大鼠皮肤成纤维细胞产生凋亡特征性的形态学变化。
3.FK506浓度依赖性的诱导大鼠皮肤成纤维细胞凋亡,并且凋亡能被JNK抑制剂SP600125或ERK抑制剂PD98059削弱。
4.FK506浓度依赖性的增高大鼠皮肤成纤维细胞p-JNK(phosphorylation of c-Jun N-terminal kinase,磷酸化c-Jun氨基末端激酶)、p-ERK(phosphorylation of extracellular-signal regulated kinase,磷酸化细胞外信号调节激酶)、胞浆细胞色素C及活化的caspase-3表达。
5.JNK抑制剂SP600125或ERK抑制剂PD98059预处理显著降低p-JNK或p-ERK、以及活化的caspase-3的表达。
结论
第一部分：
1.FK506能明显减少神经损伤修复后神经内胶原纤维的含量和瘢痕的面积。
2.FK506能显著提高神经损伤修复后神经再生的速度和再生神经的质量。
3.FK506能明显加快神经功能的恢复。
4.FK506通过减少瘢痕形成促进周围神经再生和加快神经功能恢复。
第二部分：
1.FK506显著降低大鼠皮肤成纤维细胞存活率；
2.FK506显著增高大鼠皮肤成纤维细胞凋亡率；
3.FK506诱导大鼠皮肤成纤维细胞凋亡的机制可能与FK506激活JNK.ERK信号通路,使JNK和ERK磷酸化水平升高有关,而这两条信号通路激活后,经过或不经过线粒体途径,最终都引起caspase-3的活化从而导致细胞凋亡。
FK506(tacrolimus) is a macrolide antibiotic isolated from streptomycete in1984and has extensive application in the area of organ transplantation. Recent years, it has been demonstrated that FK506has powerful effect of promoting nerve regeneration.
Objective
Part Ⅰ
Sciatic nerve injury in rat model was established, in order to investigate whether FK506intensively promotes peripheral nerve regeneration and functional recovery by directly inhibiting scar formation of nerval anastomotic stoma.
Part II
To investigate whether FK506reduces scar formation of nerval anastomotic stoma through inducing fibroblast apoptosis.
Methods
Part Ⅰ
1. establishing the model of rat sciatic nerve injury, then the rats received intragastric administration of FK506according to the dose of4mg/kg/d. The rats were divided into5groups (n=15):
model group:intragastric administration with physiologic saline for6weeks after operation;
2weeks group:intragastric administration with FK506for2weeks and then with physiologic saline for4weeks after operation;
4weeks group:intragastric administration with FK506for4weeks and then with physiologic saline for2weeks after operation;
6weeks group:intragastric administration with FK506for6weeks after operation;
control group:intragastric administration with physiologic saline for6weeks without operation.
2. At6weeks after operation, MASSON staining of rat sciatic nerve was performed to observe collagen fibrils and scar formation. Scar areas was measured by Image-pro plus5.0analysis software.
3. At6weeks after operation, HE staining of rat sciatic nerve was performed to observe the density of medullated nerve fibers and connective tissue formation. The density of medullated nerve fibers, average axonal diameter and thickness of medullary sheath were measured.
4. At6weeks after operation, ultrathin section of rat sciatic nerve was performed to observe the ultramicrostructure of regenerated axon.
5. At6weeks after operation, the recovery rate of gastrocnemius wet weight was calculated (operation side/normal side,%).
6. At6weeks after operation, Sciatic Functional Index (SFI) was determined by de Medinaceli process.
7. At6weeks after operation, the latency and wave amplitude of CMAP (compound muscle active potential) were detected.
8. Dependablity between medullated nerve fibers or SFI and scar areas was analyzed.
Part II
1. Primary cultures of rat skin fibroblasts were obtained from male Sprague-Dawley newborn rats1-2days after birth and then subcultured. Supplied as a crystalline solid, FK506was dissolved in DMSO (Dimethyl sulfoxide) and stored at-20℃. The culture media containing different concentrations of FK506were freshly prepared for each experiment. Fibroblasts were treated with different stimulus:
control group:fibroblasts were cultured with DMEM (Dulbecco's modified Eagle's medium) free of FBS (fetal bovine serum) for8hours;
DMSO group:fibroblasts were cultured with DMEM containing DMSO for8hours;
12.5μM FK506group:fibroblasts were cultured with DMEM containing12.5μM FK506for8hours;
25μM FK506group:fibroblasts were cultured with DMEM containing25μM FK506for8hours;
50μM FK506group:fibroblasts were cultured with DMEM containing50μM FK506for8hours;
75μM FK506group:fibroblasts were cultured with DMEM containing75μM FK506for8hours;
100μM FK506group:fibroblasts were cultured with DMEM containing100μM FK506for8hours;
JNK (c-Jun N-terminal kinase) inhibitor pretreatment group: fibroblasts were pretreated with SP600125(40μM) for30min, then cultured with DMEM free of FBS for8hours;
ERK (extracellular-signal regulated kinase) inhibitor pretreatment group:fibroblasts were pretreated with PD98059(60μM) for30min, then cultured with DMEM free of FBS for8hours;
JNK inhibitor pretreatment and50μM FK506group:fibroblasts were pretreated with SP600125(40μM) for30min, then cultured with DMEM containing50μM FK506for8hours;
ERK inhibitor pretreatment and50μM FK506group:fibroblasts were pretreated with PD98059(60μM) for30min, then cultured with DMEM containing50μM FK506for8hours.
2. CCK-8(Cell Counting Kit-8) assay was used to evaluate the inhibitory activity of FK506on cultured fibroblasts.
3. Hoechst33342staining was used to observe apoptotic fibroblasts.
4. Flow cytometry was used to detect apoptosis percentage of cultured fibroblasts.
5. Western blotting was used to detect expression level of apoptosis associated proteins.
Results
Part Ⅰ
1. FK506significantly reduced the formation of collagen fibrils and the scar areas of nerval anastomotic stoma.
2. FK506significantly increased the density of medullated nerve fibers, average axonal diameter and thickness of medullary sheath.
3. FK506significantly increased degree of maturity of medullated nerve fibers.
4. FK506significantly increased the recovery rate of gastrocnemius wet weight.
5. FK506significantly improved SFI.
6. FK506significantly shortened the latency and elevated the wave amplitude of CMAP.
7. Complete negative correlations existed between medullated nerve fibers or SFI and scar areas.
Part II
1. FK506reduced rat skin fibroblasts viability in a dose-dependent manner.
2. FK506induced characteristic morphological changes of apoptosis in rat skin fibroblasts.
3. FK506induced significant apoptosis of rat skin fibroblasts in a dose-dependent manner, and the apoptosis could be weakened by JNK inhibitor SP600125or ERK inhibitor PD98059.
4. FK506increased the expressions of p-JNK (phosphorylation of c-Jun N-terminal kinase), p-ERK (phosphorylation of extracellular-signal regulated kinase), cytosolic cytochrome c and cleaved-caspase-3in a dose-dependent manner.
5. Pretreatment with JNK inhibitor SP600125or ERK inhibitor PD98059significantly reduced the expressions of p-JNK or p-ERK and cleaved-caspase-3.
Conclusions
Part Ⅰ
1. FK506could significantly decrease the formation of collagen fibrils and the scar areas of nerval anastomotic stoma following repair of peripheral nerve injury.
2. FK506could significantly increase the speed of nerve regeneration and the quality of regenerated nerve fibers following repair of peripheral nerve injury.
3. FK506could significantly accelerate the neurofunctional recovery.
4. FK506intensively promotes peripheral nerve regeneration and functional recovery by directly inhibiting scar formation of nerval anastomotic stoma.
Part II
1. FK506significantly decreased the viability of rat skin fibroblasts.
2. FK506significantly increased apoptotic percentage of rat skin fibroblasts.
3. FK506activated both JNK and ERK with or without mitochondrial cytochrome c release, followed by the cleavage of caspase-3, subsequently leading to the apoptosis of rat skin fibroblasts.
引文
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