VEGF受体酪氨酸激酶抑制剂对兔耳增生性瘢痕抑制作用的实验研究
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摘要
目的:建立新西兰大白兔增生性瘢痕动物模型,采用血管内皮生长因子受体酪氨酸激酶抑制剂对瘢痕局部注射,观察其对增生性瘢痕新生毛细血管及I型胶原在兔耳瘢痕表达的影响。为血管内皮生长因子受体酪氨酸激酶抑制剂对增生性瘢痕防治提供实验和理论依据。
方法:新西兰大白兔16只,随机分为3组:动态模型组、实验组(注射血管内皮生长因子受体酪氨酸激酶抑制剂)、对照组(注射生理盐水)。动态模型组于术后6天、16天、22天、30天、56天切取兔耳瘢痕标本,采用大体观察及形态学检查了解创面愈合及瘢痕增生情况;实验组与对照组术后10天行瘢痕内药物注射,其后创面每两天注射1次,共6次。在术后第30天切取兔耳瘢痕标本,采用形态学观察瘢痕增生情况;HE染色观察瘢痕增生指数(SEI)。免疫组织化学法检测瘢痕组织中CD34、VEGF与bFGF变化,RT-PCR法检测增生性瘢痕中I型前胶原mRNA的表达。
结果:成功制作兔耳瘢痕模型后,大体观察发现瘢痕上皮化时间约为10-15天,HE染色可见成纤维细胞及胶原纤维增多,术后18天瘢痕增生明显,突出皮面为正常皮肤的3倍。术后30天瘢痕增生达最高峰,50天左右瘢痕逐渐软化退变。瘢痕持续时间约90-100天。经VEGF受体酪氨酸激酶抑制剂干预后的增生性瘢痕色泽变淡,厚度降低,瘢痕持续时间缩短,同期瘢痕面积明显小于对照组(P<0.05)。HE染色显示,实验组镜下染色微血管数少于生理盐水对照组。(P<0.05);实验组中瘢痕增生指数与对照组比较明显降低(P<0.05)。Masson染色显示,VEGF受体酪氨酸激酶抑制剂组成纤维细胞较少,胶原稀疏并且排列较整齐,生理盐水对照组可见大量成纤维细胞,胶原纤维粗大并成旋涡状排列。免疫组织化学法实验结果显示,VEGF受体酪氨酸激酶抑制剂注射30天后CD34可见瘢痕组织中微血管的生成受到抑制(P<0.05),同时对VEGF,bFGF的表达也产生了明显的抑制作用(P<0.05)。RT-PCR结果显示,与对照组相比较,实验组I型前胶原蛋白mRNA表达明显降低(P<0.05)。
结论:实验结果表明,瘢痕增生早期行瘢痕内局部注射VEGF受体酪氨酸激酶抑制剂,可以明显抑制兔耳增生性瘢痕的形成,减轻瘢痕的增生程度。这也为临床治疗增生性瘢痕寻找新药物提供了新的实验依据。
Objective: To investigate the possibility of pathologic scar treated in VEGF Receptor Tyrosine Kinases,by observing the effects of expression of collagen type I in hyperplastic scar and neogenesis,capillary of Pathologic scars treated in VEGF Receptor Tyrosine Kinases,through establishing models of Hypertrophic scar in rabbit ear and injecting VEGF Receptor Tyrosine Kinases.
Methods: 16 New Zealand white rabbits were used to estabilish the model of hypertrophic scar in rabbit ears,which was randomly divided into 3groups: Dynamic model group. using general and morphological observation of wound healing and scar formation; On days 6、12、16、22、30、42、56after modeling,the change of texture and healing of wound surface were observed.Experiment group (VEGF Receptor Tyrosine Kinases injected) Model group(NS injected ).10 days after surgery,the hypertrophic scar were injected intralesionally with VEGF Receptor Tyrosine Kinases II and NS.2 days injection of once for every wound,a total of six times.The scars were harvested 8days after the last injection for measurement of scar elevation index(SEI).The groups are evaluated through pathological sections HE Masson staining, The change of CD34,VEGF,bFGF were addressed by immunohistochemistry.The expression of type I pro-collagen mRNA were assessed by reverse transcription polymerase chain reaction(RT-PCR).
Results: General observation: The epithelization time of the wounds is in 10-15days.18 days after epitheliazation,the high of excess dermal scarring is as 3 times high as original ventol skin,color is pink,the blood vessel is abundant;The scars begin to soften in about 50 days,the excess scarring can last nearly90-100days;The color and luster of scar after treating in VEGF Receptor Tyrosine Kinases become light,the thickness is reduced.and become smooth.The area of scar in experiment groups is obviously less than model groups(p<0.01).Pathological section: the counts of capillaries in experiment groups are obviously less than control groups(p<0.01);On the contrary,blood capillary and fibrocyte hyperplasia,the collagen deposits in a large amout.The expression of VEGF and bFGF in hypertrophic scar on ears of rabbits were also studied by immunohistochemistry staining at the thirtieth day after VEGF Receptor Tyrosine Kinases being injected.The results show that the expression of VEGF and bFGF were clearly depressed(p<0.05).The expression of type I pro-collagen mRNA decreased in model group,which showed statistical difference compared with Experiment groups.(P<0.05).
Conclusion: The results of animal experiments suggest that VEGF Receptor Tyr- osine Kinases II is able to inhibit the proliferation process of hypertrophic scar in rab- bit ears and to remarkably decrease the degree of fibrosis in the scar. VEGF Receptor Tyrosine Kinases would become a new clinical treatment of hypertrophic in the fut- ure.
方法:新西兰大白兔16只,随机分为3组:动态模型组、实验组(注射血管内皮生长因子受体酪氨酸激酶抑制剂)、对照组(注射生理盐水)。动态模型组于术后6天、16天、22天、30天、56天切取兔耳瘢痕标本,采用大体观察及形态学检查了解创面愈合及瘢痕增生情况;实验组与对照组术后10天行瘢痕内药物注射,其后创面每两天注射1次,共6次。在术后第30天切取兔耳瘢痕标本,采用形态学观察瘢痕增生情况;HE染色观察瘢痕增生指数(SEI)。免疫组织化学法检测瘢痕组织中CD34、VEGF与bFGF变化,RT-PCR法检测增生性瘢痕中I型前胶原mRNA的表达。
结果:成功制作兔耳瘢痕模型后,大体观察发现瘢痕上皮化时间约为10-15天,HE染色可见成纤维细胞及胶原纤维增多,术后18天瘢痕增生明显,突出皮面为正常皮肤的3倍。术后30天瘢痕增生达最高峰,50天左右瘢痕逐渐软化退变。瘢痕持续时间约90-100天。经VEGF受体酪氨酸激酶抑制剂干预后的增生性瘢痕色泽变淡,厚度降低,瘢痕持续时间缩短,同期瘢痕面积明显小于对照组(P<0.05)。HE染色显示,实验组镜下染色微血管数少于生理盐水对照组。(P<0.05);实验组中瘢痕增生指数与对照组比较明显降低(P<0.05)。Masson染色显示,VEGF受体酪氨酸激酶抑制剂组成纤维细胞较少,胶原稀疏并且排列较整齐,生理盐水对照组可见大量成纤维细胞,胶原纤维粗大并成旋涡状排列。免疫组织化学法实验结果显示,VEGF受体酪氨酸激酶抑制剂注射30天后CD34可见瘢痕组织中微血管的生成受到抑制(P<0.05),同时对VEGF,bFGF的表达也产生了明显的抑制作用(P<0.05)。RT-PCR结果显示,与对照组相比较,实验组I型前胶原蛋白mRNA表达明显降低(P<0.05)。
结论:实验结果表明,瘢痕增生早期行瘢痕内局部注射VEGF受体酪氨酸激酶抑制剂,可以明显抑制兔耳增生性瘢痕的形成,减轻瘢痕的增生程度。这也为临床治疗增生性瘢痕寻找新药物提供了新的实验依据。
Objective: To investigate the possibility of pathologic scar treated in VEGF Receptor Tyrosine Kinases,by observing the effects of expression of collagen type I in hyperplastic scar and neogenesis,capillary of Pathologic scars treated in VEGF Receptor Tyrosine Kinases,through establishing models of Hypertrophic scar in rabbit ear and injecting VEGF Receptor Tyrosine Kinases.
Methods: 16 New Zealand white rabbits were used to estabilish the model of hypertrophic scar in rabbit ears,which was randomly divided into 3groups: Dynamic model group. using general and morphological observation of wound healing and scar formation; On days 6、12、16、22、30、42、56after modeling,the change of texture and healing of wound surface were observed.Experiment group (VEGF Receptor Tyrosine Kinases injected) Model group(NS injected ).10 days after surgery,the hypertrophic scar were injected intralesionally with VEGF Receptor Tyrosine Kinases II and NS.2 days injection of once for every wound,a total of six times.The scars were harvested 8days after the last injection for measurement of scar elevation index(SEI).The groups are evaluated through pathological sections HE Masson staining, The change of CD34,VEGF,bFGF were addressed by immunohistochemistry.The expression of type I pro-collagen mRNA were assessed by reverse transcription polymerase chain reaction(RT-PCR).
Results: General observation: The epithelization time of the wounds is in 10-15days.18 days after epitheliazation,the high of excess dermal scarring is as 3 times high as original ventol skin,color is pink,the blood vessel is abundant;The scars begin to soften in about 50 days,the excess scarring can last nearly90-100days;The color and luster of scar after treating in VEGF Receptor Tyrosine Kinases become light,the thickness is reduced.and become smooth.The area of scar in experiment groups is obviously less than model groups(p<0.01).Pathological section: the counts of capillaries in experiment groups are obviously less than control groups(p<0.01);On the contrary,blood capillary and fibrocyte hyperplasia,the collagen deposits in a large amout.The expression of VEGF and bFGF in hypertrophic scar on ears of rabbits were also studied by immunohistochemistry staining at the thirtieth day after VEGF Receptor Tyrosine Kinases being injected.The results show that the expression of VEGF and bFGF were clearly depressed(p<0.05).The expression of type I pro-collagen mRNA decreased in model group,which showed statistical difference compared with Experiment groups.(P<0.05).
Conclusion: The results of animal experiments suggest that VEGF Receptor Tyr- osine Kinases II is able to inhibit the proliferation process of hypertrophic scar in rab- bit ears and to remarkably decrease the degree of fibrosis in the scar. VEGF Receptor Tyrosine Kinases would become a new clinical treatment of hypertrophic in the fut- ure.
引文
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[2] Ribatti D.The crucial role of vascular Permreability factor/vascular Endothelial growth factor in angiogenesis:a historical review.Br J Haematol,2005,128(3):303-309.
[3] Couffinhal T,Kearney M Witzenbichler B,Chen D.Murohara T, Losordo DW Symes J,Isner JM. Vascular endothelial growth factor/vascular Permeability factor(VEGF/VPF)in normal and atherosclerotic human arteries.Am J Pathol.1997 May;150(5):1673-1685.
[4]Becrgsland EK.Vascular endothelial growth factor as a therapeutic target in cancer Am J Health Syst Pharm.2004:61(21SuPP15):54-61.
[5]沈锐,利天增.等.血管内皮细胞生长在烧伤后肉芽组织和增生性瘢痕中的表达[J].中国康复理论与实践,2002 ,8 (1):104-107.
[6] Shibuya M.Role of VEGF-flt receptor system in normal and tumor angiogenesis [J].Adv Cancer Res,1995,67:281-316.
[7] Soker S,Takashima S,Miao HQ,et a1.Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor [J].Cell,1998,92(6):735-745.
[8] DORIANOF,DAVIDP,ALEXM.Protein tyrosine kinase inhibitors:new treatment modalities.Current Opinion in Pharmacology,2002,2(4):374-381
[9]钟毅,李志裕,尤启冬.血管内皮生长因子受体酪氨酸激酶抑制剂的研究进展.中国新药杂志,2006,15(3):182- 184
[10]欧杨,傅得兴,郭秀丽.新型多靶点酪氨酸激酶抑制剂苏尼替尼的研究进展.中国新药杂志,2007,16(1):91-94.
[11]张秀华,林莉萍,丁健.靶向血小板源生长因子受体酪氨酸激酶抑制剂的临床研究进展.中国新药与临床杂志,2006,25(6):454-458.
[12]Wheatley-Price P,Shepherd FA.Epidermal growth factor receptor inhibitors in the treatment of lung cancer:reality and hopes.Curr Opin Oncol.2008,20(2):162-175.
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