体外冲击波抑制兔耳增生性瘢痕的实验研究
发布时间：2018-08-24 13:04
【摘要】：尽管在过去数年间诊疗技术方面取得了突飞猛进的发展，增生性瘢痕(HS)的预防和治疗仍是临床医生亟待解决的难题之一。HS不仅严重影响机体功能和美观，还可因疼痛（或触痛）和感觉异常（瘙痒、烧灼感）导致患者睡眠障碍、焦虑、抑郁，显著降低患者的生活质量。随着社会经济水平和人们对自我形象的注重，HS的防治受到越来越多的关注。研究HS的预防和治疗对提高患者的生活质量具有重要意义。 目前关于HS形成的机制主要包括：细胞因素、细胞因子因素、微循环因素、免疫因素、基因表达因素、创面因素等。HS的治疗目标是恢复功能，缓解症状，改善外观和预防复发。目前已有多种方法用于增生性瘢痕的治疗，如外用或局部注射药物、手术治疗、物理治疗（如激光疗法、加压疗法、按摩等）、放射治疗、冷冻疗法、基因治疗等。虽然可选择的方法多样，然而上述各种疗法却存在不同程度的不足之处，如手术的创伤性，脉冲染料激光可引起局部色素改变和对较厚的HS效果不理想。瘢痕内药物注射除可引起疼痛和色素改变外，还可引起注射部位的水疱、溃疡和坏死。加压疗法可因高压力引起的不适感、限制活动和影响外观而使患者依从性下降。而冰冻疗法治疗瘢痕可引起色素缺失，放射疗法则存在放射性皮炎和潜在的致癌可能。因此，寻求一种无创、安全、有效和经济的方法治疗增生性瘢痕具有重要意义。 体外冲击波疗法(ESWT)具有无创、安全、操作简便等优势，目前已广泛应用于泌尿系和消化系结石、骨折不愈合或延迟愈合、肩周炎、肱骨外上髁炎慢性软组织疾病。此外，ESWT还广泛用于改善组织缺血、治疗烧伤和糖尿病足、提高皮肤/皮瓣移植成活率等方面。ESWT的作用机制包括：促进创面血管生成，增加组织血流供应，抑制早期的炎症反应，促进间充质干细胞和内皮祖细胞趋至创面，刺激创面细胞增殖、分化和再生，减轻创面细菌定植等。 虽然ESWT在急慢性创面的治疗中显示出优越性，然而关于其对瘢痕治疗效果的研究却十分有限。本研究中，首先制备兔耳腹侧面全层组织缺损模型，造模21天后HS形成（经病理切片证实）。将白兔随机分为低能量ESWT组（能流密度0.1mJ/mm2）、高能量ESWT组（能流密度0.2mJ/mm2）和对照组。ESWT组白兔分别于造模成功后第1、4、9、14、21、28天给予不同能流密度ESWT处理，对照组未予任何处置。分别于第一次ESWT处理后1、4、7、10、14、21、28、35天观察并记录瘢痕颜色、质地变化，同时采集组织样本，通过下述分子生物学和病理学手段检测以下指标： 1.通过Antera3D成像系统测量瘢痕直径、面积、隆起体积、质地、皱褶、黑色素、血红素的变化； 2.病理学染色观察ESWT对HS组织学的影响： HE染色观察瘢痕增生指数（hypertrophic index, HI）、成纤维细胞（Fb）形态和密度、毛细血管数及炎性细胞浸润情况；Masson染色明确胶原纤维分布情况； 3.瘢痕增殖和分化的研究：逆转录-聚合酶链式反应(RT-PCR)检测增殖细胞核抗原(PCNA)和α-平滑肌肌动蛋白(α-SMA)的基因表达情况；免疫组化染色明确二者在细胞内表达情况； 4.对转化生长因子-β1（TGF-β1）/Smad通路影响的研究：RT-CPR分别检测TGF-β1、Smad2、Smad3的基因表达水平；酶联免疫吸附试验检测TGF-β1、Smad2、Smad3、Smad7的蛋白表达水平； 实验主要结果： 一、大体观察ESWT处理后3周，两ESWT组瘢痕颜色开始并略淡于对照组，并且变得扁平和软化。4周时，对照组瘢痕开始退变软化，但仍可见明显凸起，颜色较治疗组仍发红。低能量ESWT组和高能量ESWT组瘢痕变平，硬度与色泽较对照组减轻。两ESWT组间相比无明显差别。 二、 Antera3D检测结果 1.瘢痕皱褶：与对照组相比，低能量ESWT组处理14天、高能量ESWT组处理21天后瘢痕皱褶开始显著减少（t=-2.195, P=0.042；t=-2.267, P=0.037），并可持续至第四周。 2.瘢痕质地：与对照组相比，低能量ESWT组处理4周后瘢痕质地出现明显改善（t=-2.788, P=0.014）。高能量ESWT组处理后瘢痕质地未见明显改善。 3.瘢痕直径、面积、隆起体积和黑色素：与对照组相比，低能量ESWT组和高能量ESWT组对瘢痕上述参数均未见有明显影响。 4.瘢痕血色素：与对照组相比，低能量ESWT组处理两周后瘢痕血色素开始明显下降（t=-2.361, P=0.040）；处理3周后，低能量ESWT组和高能量ESWT组与对照组瘢痕血色素相比均存在显著差异（t=-2.474, P=0.043；t=-2.838, P=0.025），这一差异在第四周仍可见到。 三、兔耳瘢痕组织的组织病理学检测 1. HE染色1周：各组间炎细胞浸润、微血管增生、HI无显著差异。低能量ESWT组与高能量ESWT组、对照组相比Fb密度均显著降低，高能量ESWT组与对照组相比Fb密度也显著降低。2周-5周：与对照组相比，ESWT处理组HS真皮层较对照组变薄，炎细胞浸润减轻，微血管和胶原纤维较对照组数量减少，HI和Fb密度均显著降低, ESWT组间相比无显著性差异。 2. Masson染色1周：各组间无明显差别。2周-5周：对照组胶原纤维数量多，排列不整齐，可见漩涡状结构和胶原结节；ESWT组胶原束较细，排列较对照组疏松和规则，大致呈平行于表皮的水平方向。两ESWT组间未见明显差别。 四、 ESWT对HS增殖和分化的影响 1.对PCNA和α-SMA组织病理学检测低能量ESWT早期即可显著抑制HS组织中PCNA的表达；高能量ESWT在后期（4周）也可降低细胞内PCNA的表达水平，两组间相比无明显差别。无论是低能量ESWT还是高能量ESWT均可显著降低细胞内α-SMA的表达水平，并且在低能量ESWT组更明显。 2.对PCNA和α-SMA mRNA表达的影响与对照组相比，低能量ESWT和高能量ESWT组对HS中PCNA mRNA的表达均未见明显影响。低能量ESWT可显著降低HS中α-SMA mRNA的表达水平，高能量ESWT与对照组相比无明显差别。 五、 ESWT对TGF-β/Smad信号通路的影响 1.对TGF-β/Smad信号通路mRNA表达的影响低能量ESWT和高能量ESWT对TGF-β1mRNA的表达均未见显著影响。此外，低能量ESWT对Smad2mRNA的表达亦未见明显影响，但可显著抑制Smad3mRNA的表达。高能量ESWT则可显著上调Smad2和Smad3mRNA的表达水平。 2.对TGF-β/Smad信号通路蛋白表达的影响低能量ESWT可显著抑制Smad3的表达，对TGF-β1、Smad2和Smad7蛋白含量未见显著影响。高能量ESWT对TGF-β1、Smad2、Smad3和Smad7蛋白含量均未见显著影响。 结论： 1. ESWT无创、安全、操作方便且耐受性良好。不同能量ESWT均可软化HS，改善其色泽，减少瘢痕皱褶，但对瘢痕直径、面积和黑色素水平均未见明显影响。此外，低能量ESWT还可显著改善瘢痕粗糙度。病理学检查显示，不同能流密度ESWT均可减轻炎细胞浸润程度，减少Fb数目和密度，，降低瘢痕厚度，改善胶原纤维排列。 2.低能量ESWT可早期抑制HS组织细胞中Smad3信号转导因子和α-SMA mRNA和蛋白表达水平。高能量ESWT在后期虽可显著抑制α-SMA和PCNA mRNA和蛋白的表达水平，然而也可显著升高具有促进瘢痕形成作用的Smad2和Smad3mRNA和蛋白的表达水平，高能量ESWT对瘢痕的影响有待于进一步研究。
[Abstract]:Despite the rapid development of diagnostic and therapeutic techniques in the past few years, the prevention and treatment of hypertrophic scar (HS) remains one of the most pressing problems for clinicians. HS not only seriously affects the body's function and aesthetics, but also causes sleep disorders, anxiety, depression and symptoms of pain (or tenderness) and sensory abnormalities (itching, burning). With the social and economic level and people's attention to self-image, more and more attention has been paid to the prevention and treatment of HS.
At present, the mechanism of HS formation mainly includes cell factor, cytokine factor, microcirculation factor, immune factor, gene expression factor, wound factor and so on. The aim of HS treatment is to restore function, relieve symptoms, improve appearance and prevent recurrence. Surgical treatment, physical therapy (such as laser therapy, compression therapy, massage, etc.), radiation therapy, cryotherapy, gene therapy, and so on. Although there are a variety of options, the above-mentioned treatments have different degrees of inadequacies, such as surgical trauma, pulsed dye laser can cause local pigment changes and relatively thick HS effect is not satisfactory. In addition to causing pain and pigmentation changes, intrascar drug injections can also cause blisters, ulcers and necrosis at the injection site. Compression therapy can cause discomfort due to high pressure, restrict activity and affect appearance and reduce patient compliance. Therefore, it is of great significance to seek a non-invasive, safe, effective and economical treatment for hypertrophic scars.
Extracorporeal shock wave therapy (ESWT) has the advantages of noninvasiveness, safety and easy operation. It has been widely used in urinary and digestive calculi, nonunion or delayed union of fractures, periarthritis of shoulder, and chronic soft tissue diseases of external epicondylitis of humerus. The mechanisms of ESWT include promoting wound angiogenesis, increasing tissue blood supply, inhibiting early inflammatory reaction, promoting mesenchymal stem cells and endothelial progenitor cells to the wound, stimulating wound cell proliferation, differentiation and regeneration, and reducing bacterial colonization.
Although ESWT has shown superiority in the treatment of acute and chronic wounds, the research on its therapeutic effect on scars is very limited. In this study, a rabbit model of ventral full-thickness tissue defect was established, and HS was formed 21 days after modeling (confirmed by pathological section). The rabbits were randomly divided into low-energy ESWT group (energy flow density 0.1mJ/mm2) and high-energy ESWT group (energy flow density 0.1mJ/mm2). The rabbits in ESWT group were treated with different energy flow density ESWT on the first, fourth, nineteen, fourteen, twenty-one and twenty-eight days after successful modeling, while the rabbits in control group were not treated with any treatment. Molecular biology and pathology were used to detect the following indicators:
1. The scar diameter, area, bulge volume, texture, wrinkles, melanin and heme were measured by Antera 3D imaging system.
2. Histological changes of HS were observed by pathological staining: HE staining was used to observe the hypertrophic index (HI), fibroblast (Fb) morphology and density, capillary number and inflammatory cell infiltration; Masson staining was used to determine the distribution of collagen fibers.
3. Study on scar proliferation and differentiation: Reverse transcription-polymerase chain reaction (RT-PCR) was used to detect the gene expression of proliferating cell nuclear antigen (PCNA) and alpha-smooth muscle actin (alpha-SMA); immunohistochemical staining was used to determine the expression of PCNA and alpha-SMA in the cells.
4. Effects of transforming growth factor-beta 1 (TGF-beta 1) / Smad pathway: TGF-beta 1, Smad2, Smad3 gene expression levels were detected by RT-CPR, and TGF-beta 1, Smad2, Smad3, Smad7 protein expression levels were detected by enzyme-linked immunosorbent assay (ELISA).
Main results of the experiment are as follows:
First, after 3 weeks of ESWT treatment, the scar color of the two ESWT groups began to fade slightly, and became flat and softened. At 4 weeks, the scar of the control group began to degenerate and soften, but the color of the control group was still redder than that of the treatment group. The scar of the low-energy ESWT group and the high-energy ESWT group flattened, and the hardness and color of the two ESWT groups were lighter than that of the control group. There is no obvious difference between them.
Two, Antera3D test results
1. Cicatricial folds: Compared with the control group, the low-energy ESWT group treated for 14 days, the high-energy ESWT group treated for 21 days began to significantly reduce the cicatricial folds (t = - 2.195, P = 0.042; t = - 2.267, P = 0.037), and lasted until the fourth week.
2. Scar texture: Compared with the control group, the low-energy ESWT group showed significant improvement (t =-2.788, P =0.014) after 4 weeks of treatment. The high-energy ESWT group showed no significant improvement in the scar texture.
3. Scar diameter, area, bulge volume and melanin: Compared with the control group, low-energy ESWT group and high-energy ESWT group had no significant effect on the above parameters of scar.
4. Scar hemoglobin: Compared with the control group, the low-energy ESWT group began to decrease significantly after two weeks of treatment (t = - 2.361, P = 0.040); after three weeks of treatment, the low-energy ESWT group and high-energy ESWT group were significantly different from the control group in scar hemoglobin (t = - 2.474, P = 0.043; t = - 2.838, P = 0.025), the difference was still acceptable at the fourth week. See.
Three, histopathological examination of rabbit ear scar tissue.
1. HE staining for 1 week: There was no significant difference in inflammatory cell infiltration, microvascular proliferation and HI among the groups. The density of Fb in low-energy ESWT group and high-energy ESWT group was significantly lower than that in the control group. The density of Fb in high-energy ESWT group was also significantly lower than that in the control group. Compared with the control group, the number of microvessels and collagen fibers decreased, and the density of HI and Fb decreased significantly. There was no significant difference between the ESWT groups.
2. Masson staining for 1 week: there was no significant difference between the groups. 2 weeks to 5 weeks: the number of collagen fibers in the control group was large, arranged irregularly, and there were vortex-like structures and collagen nodules. The collagen bundles in the ESWT group were finer, looser and more regular than those in the control group, and were roughly parallel to the epidermis.
Four, the effect of ESWT on proliferation and differentiation of HS.
1. PCNA and alpha-SMA histopathological examination showed that low-energy ESWT could significantly inhibit the expression of PCNA in HS tissues at the early stage, and high-energy ESWT could also reduce the expression of PCNA in HS cells at the late stage (4 weeks), there was no significant difference between the two groups. In low energy ESWT group, it is more obvious.
2. Compared with the control group, low energy ESWT and high energy ESWT groups had no significant effect on the expression of PCNA mRNA in HS. Low energy ESWT could significantly reduce the expression of alpha-SMA mRNA in HS, and high energy ESWT had no significant difference compared with the control group.
Five, the effect of ESWT on TGF- beta /Smad signaling pathway.
1. The effect of low-energy ESWT and high-energy ESWT on the expression of TGF-beta 1 mRNA was not significant. In addition, low-energy ESWT had no significant effect on the expression of Smad2 mRNA, but could significantly inhibit the expression of Smad3 mRNA. High-energy ESWT could significantly up-regulate the expression of Smad2 and Smad3 mRNA.
2. The expression of Smad3 was significantly inhibited by low-energy ESWT, but not by TGF-beta 1, Smad2 and Smad7. High-energy ESWT had no significant effect on the contents of TGF-beta 1, Smad2, Smad3 and Smad7.
Conclusion:
1. ESWT is noninvasive, safe, easy to operate and well tolerated. Different energy ESWT can soften HS, improve its color and reduce scar folds, but has no significant effect on scar diameter, area and melanin level. In addition, low energy ESWT can significantly improve scar roughness. Pathological examination shows that different possible flow density ESWT can alleviate inflammation. The degree of cell infiltration can reduce the number and density of Fb, reduce the thickness of scar and improve the arrangement of collagen fibers.
2. Low-energy ESWT can inhibit the expression of Smad3 signal transduction factor and alpha-SMA mRNA and protein in HS cells at an early stage. High-energy ESWT can significantly inhibit the expression of alpha-SMA and PCNA mRNA and protein at a later stage, but it can also significantly increase the expression of Smad 2 and Smad3 mRNA and protein, which can promote scar formation. The effect of WT on scar remains to be further studied.
【学位授予单位】：吉林大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R622
本文编号：2200905
[Abstract]:Despite the rapid development of diagnostic and therapeutic techniques in the past few years, the prevention and treatment of hypertrophic scar (HS) remains one of the most pressing problems for clinicians. HS not only seriously affects the body's function and aesthetics, but also causes sleep disorders, anxiety, depression and symptoms of pain (or tenderness) and sensory abnormalities (itching, burning). With the social and economic level and people's attention to self-image, more and more attention has been paid to the prevention and treatment of HS.
At present, the mechanism of HS formation mainly includes cell factor, cytokine factor, microcirculation factor, immune factor, gene expression factor, wound factor and so on. The aim of HS treatment is to restore function, relieve symptoms, improve appearance and prevent recurrence. Surgical treatment, physical therapy (such as laser therapy, compression therapy, massage, etc.), radiation therapy, cryotherapy, gene therapy, and so on. Although there are a variety of options, the above-mentioned treatments have different degrees of inadequacies, such as surgical trauma, pulsed dye laser can cause local pigment changes and relatively thick HS effect is not satisfactory. In addition to causing pain and pigmentation changes, intrascar drug injections can also cause blisters, ulcers and necrosis at the injection site. Compression therapy can cause discomfort due to high pressure, restrict activity and affect appearance and reduce patient compliance. Therefore, it is of great significance to seek a non-invasive, safe, effective and economical treatment for hypertrophic scars.
Extracorporeal shock wave therapy (ESWT) has the advantages of noninvasiveness, safety and easy operation. It has been widely used in urinary and digestive calculi, nonunion or delayed union of fractures, periarthritis of shoulder, and chronic soft tissue diseases of external epicondylitis of humerus. The mechanisms of ESWT include promoting wound angiogenesis, increasing tissue blood supply, inhibiting early inflammatory reaction, promoting mesenchymal stem cells and endothelial progenitor cells to the wound, stimulating wound cell proliferation, differentiation and regeneration, and reducing bacterial colonization.
Although ESWT has shown superiority in the treatment of acute and chronic wounds, the research on its therapeutic effect on scars is very limited. In this study, a rabbit model of ventral full-thickness tissue defect was established, and HS was formed 21 days after modeling (confirmed by pathological section). The rabbits were randomly divided into low-energy ESWT group (energy flow density 0.1mJ/mm2) and high-energy ESWT group (energy flow density 0.1mJ/mm2). The rabbits in ESWT group were treated with different energy flow density ESWT on the first, fourth, nineteen, fourteen, twenty-one and twenty-eight days after successful modeling, while the rabbits in control group were not treated with any treatment. Molecular biology and pathology were used to detect the following indicators:
1. The scar diameter, area, bulge volume, texture, wrinkles, melanin and heme were measured by Antera 3D imaging system.
2. Histological changes of HS were observed by pathological staining: HE staining was used to observe the hypertrophic index (HI), fibroblast (Fb) morphology and density, capillary number and inflammatory cell infiltration; Masson staining was used to determine the distribution of collagen fibers.
3. Study on scar proliferation and differentiation: Reverse transcription-polymerase chain reaction (RT-PCR) was used to detect the gene expression of proliferating cell nuclear antigen (PCNA) and alpha-smooth muscle actin (alpha-SMA); immunohistochemical staining was used to determine the expression of PCNA and alpha-SMA in the cells.
4. Effects of transforming growth factor-beta 1 (TGF-beta 1) / Smad pathway: TGF-beta 1, Smad2, Smad3 gene expression levels were detected by RT-CPR, and TGF-beta 1, Smad2, Smad3, Smad7 protein expression levels were detected by enzyme-linked immunosorbent assay (ELISA).
Main results of the experiment are as follows:
First, after 3 weeks of ESWT treatment, the scar color of the two ESWT groups began to fade slightly, and became flat and softened. At 4 weeks, the scar of the control group began to degenerate and soften, but the color of the control group was still redder than that of the treatment group. The scar of the low-energy ESWT group and the high-energy ESWT group flattened, and the hardness and color of the two ESWT groups were lighter than that of the control group. There is no obvious difference between them.
Two, Antera3D test results
1. Cicatricial folds: Compared with the control group, the low-energy ESWT group treated for 14 days, the high-energy ESWT group treated for 21 days began to significantly reduce the cicatricial folds (t = - 2.195, P = 0.042; t = - 2.267, P = 0.037), and lasted until the fourth week.
2. Scar texture: Compared with the control group, the low-energy ESWT group showed significant improvement (t =-2.788, P =0.014) after 4 weeks of treatment. The high-energy ESWT group showed no significant improvement in the scar texture.
3. Scar diameter, area, bulge volume and melanin: Compared with the control group, low-energy ESWT group and high-energy ESWT group had no significant effect on the above parameters of scar.
4. Scar hemoglobin: Compared with the control group, the low-energy ESWT group began to decrease significantly after two weeks of treatment (t = - 2.361, P = 0.040); after three weeks of treatment, the low-energy ESWT group and high-energy ESWT group were significantly different from the control group in scar hemoglobin (t = - 2.474, P = 0.043; t = - 2.838, P = 0.025), the difference was still acceptable at the fourth week. See.
Three, histopathological examination of rabbit ear scar tissue.
1. HE staining for 1 week: There was no significant difference in inflammatory cell infiltration, microvascular proliferation and HI among the groups. The density of Fb in low-energy ESWT group and high-energy ESWT group was significantly lower than that in the control group. The density of Fb in high-energy ESWT group was also significantly lower than that in the control group. Compared with the control group, the number of microvessels and collagen fibers decreased, and the density of HI and Fb decreased significantly. There was no significant difference between the ESWT groups.
2. Masson staining for 1 week: there was no significant difference between the groups. 2 weeks to 5 weeks: the number of collagen fibers in the control group was large, arranged irregularly, and there were vortex-like structures and collagen nodules. The collagen bundles in the ESWT group were finer, looser and more regular than those in the control group, and were roughly parallel to the epidermis.
Four, the effect of ESWT on proliferation and differentiation of HS.
1. PCNA and alpha-SMA histopathological examination showed that low-energy ESWT could significantly inhibit the expression of PCNA in HS tissues at the early stage, and high-energy ESWT could also reduce the expression of PCNA in HS cells at the late stage (4 weeks), there was no significant difference between the two groups. In low energy ESWT group, it is more obvious.
2. Compared with the control group, low energy ESWT and high energy ESWT groups had no significant effect on the expression of PCNA mRNA in HS. Low energy ESWT could significantly reduce the expression of alpha-SMA mRNA in HS, and high energy ESWT had no significant difference compared with the control group.
Five, the effect of ESWT on TGF- beta /Smad signaling pathway.
1. The effect of low-energy ESWT and high-energy ESWT on the expression of TGF-beta 1 mRNA was not significant. In addition, low-energy ESWT had no significant effect on the expression of Smad2 mRNA, but could significantly inhibit the expression of Smad3 mRNA. High-energy ESWT could significantly up-regulate the expression of Smad2 and Smad3 mRNA.
2. The expression of Smad3 was significantly inhibited by low-energy ESWT, but not by TGF-beta 1, Smad2 and Smad7. High-energy ESWT had no significant effect on the contents of TGF-beta 1, Smad2, Smad3 and Smad7.
Conclusion:
1. ESWT is noninvasive, safe, easy to operate and well tolerated. Different energy ESWT can soften HS, improve its color and reduce scar folds, but has no significant effect on scar diameter, area and melanin level. In addition, low energy ESWT can significantly improve scar roughness. Pathological examination shows that different possible flow density ESWT can alleviate inflammation. The degree of cell infiltration can reduce the number and density of Fb, reduce the thickness of scar and improve the arrangement of collagen fibers.
2. Low-energy ESWT can inhibit the expression of Smad3 signal transduction factor and alpha-SMA mRNA and protein in HS cells at an early stage. High-energy ESWT can significantly inhibit the expression of alpha-SMA and PCNA mRNA and protein at a later stage, but it can also significantly increase the expression of Smad 2 and Smad3 mRNA and protein, which can promote scar formation. The effect of WT on scar remains to be further studied.
【学位授予单位】：吉林大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R622
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