本文選題：增生性瘢痕 + 動(dòng)物模型　； 參考：《第三軍醫(yī)大學(xué)》2006年博士論文

【摘要】： 盡管?chē)?guó)內(nèi)外學(xué)者長(zhǎng)期以來(lái)對(duì)增生性瘢痕(hypertrophic scar,HS)進(jìn)行了大量、不懈的研究,但有關(guān)HS的形成機(jī)制目前還不清楚,臨床上也缺少特別有效的防治手段,造成這種局面的原因之一就是缺少一種理想的HS動(dòng)物模型。只有人才會(huì)自然發(fā)生HS,這是HS的特征之一,依據(jù)“內(nèi)因是事物發(fā)展的根據(jù),它決定著事物發(fā)展的基本趨向”這一自然辯證法則,我們推測(cè)HS的形成是人類(lèi)皮膚的某種或某些內(nèi)在的因素所決定的,因此通過(guò)將人皮膚移植于裸鼠的方法可以建立HS動(dòng)物模型。本課題研究旨在通過(guò)移植人皮膚于裸鼠體表建立HS動(dòng)物模型,較系統(tǒng)地觀(guān)察瘢痕形成病理過(guò)程,并就瘢痕增生的形成機(jī)制進(jìn)行相關(guān)實(shí)驗(yàn)研究,主要結(jié)果與結(jié)論如下: 1.人全厚皮片移植于裸鼠體表后會(huì)發(fā)生一定程度的排斥反應(yīng),移植皮片的表皮及部分真皮逐漸脫落。但由于裸鼠是T細(xì)胞免疫缺陷動(dòng)物,這種排斥反應(yīng)發(fā)生遲,程度較輕,移植人皮片的真皮層部分得以存活,并成為移植皮片干痂脫落后瘢痕增生的基礎(chǔ)。我們的結(jié)果一方面說(shuō)明裸鼠體內(nèi)存在非T細(xì)胞依賴(lài)的免疫機(jī)制,另一方面說(shuō)明長(zhǎng)期的慢性免疫反應(yīng)可能是瘢痕增生的促進(jìn)因素。 2.移植人全厚皮片的表皮及部分真皮脫落后,局部可以發(fā)生明顯的瘢痕增生,該瘢痕無(wú)論在大體外觀(guān)、增生特性還是病理組織學(xué)特性上都與人的HS相似。 3.用免疫組織化學(xué)的方法研究模型瘢痕中的TGFβ-1的變化規(guī)律,發(fā)現(xiàn)增生期模型瘢痕中TGF-β1持續(xù)高水平表達(dá),而消退期則顯著降低。 4.體外細(xì)胞培養(yǎng)實(shí)驗(yàn)結(jié)果表明,模型瘢痕成纖維細(xì)胞與人HS成纖維細(xì)胞形態(tài)上非常相似,細(xì)胞增殖及膠原合成活性亦無(wú)顯著差別。 5.對(duì)比模型瘢痕組織以及正常皮膚中膠原酶活性,發(fā)現(xiàn)增生期的模型瘢痕膠原酶活性低,表明模型瘢痕中膠原等細(xì)胞外基質(zhì)降解減少。 6.以模型瘢痕組織和正常人皮膚組織及人HS組織的DNA為模板進(jìn)行PCR,結(jié)果發(fā)現(xiàn)都可以擴(kuò)增出人源性特異性基因,說(shuō)明模型瘢痕組織中肯定存在有人源性DNA。 7.只有移植人的全厚皮片才會(huì)發(fā)生明顯的瘢痕增生,而移植人的刃厚皮片以及大鼠的全厚皮片則根本不發(fā)生瘢痕增生,移植人中厚皮片雖然部分可以發(fā)生一定程度的瘢痕增生,但增生程度及發(fā)生率均明顯不如移植人的全厚皮片。這說(shuō)明人皮膚真皮層是HS發(fā)生的決定因素。本發(fā)現(xiàn)在人體外證實(shí)了只有人皮膚才會(huì)發(fā)生HS這一現(xiàn)象,并證明了人皮膚真皮層是HS發(fā)生的決定因素,而不是表皮層或其他外界環(huán)境因素,進(jìn)一步揭示了HS的發(fā)生機(jī)制。 上述結(jié)果表明,人皮膚移植于裸鼠后會(huì)發(fā)生一定程度的排斥反應(yīng),排斥反應(yīng)的發(fā)生使移植的人皮膚的表皮及部分真皮壞死脫落,但仍有部分真皮存活,存活的這部分人真皮是HS發(fā)生的基礎(chǔ)。真皮中的人成纖維細(xì)胞在局部炎性反應(yīng)的持續(xù)刺激下功能狀態(tài)發(fā)生改變,細(xì)胞增殖旺盛,并合成大量的膠原等細(xì)胞外基質(zhì),從而導(dǎo)致瘢痕的持續(xù)增生。該模型瘢痕增生明顯,增生持續(xù)時(shí)間長(zhǎng),瘢痕的大體形態(tài)、生長(zhǎng)特性、組織學(xué)特點(diǎn)等都和人HS相似,具有很好的代表性,可用于瘢痕形成機(jī)制及臨床防治的相關(guān)研究。 結(jié)論: 1.通過(guò)在裸鼠背部體表移植人全厚皮片的方法可以建立HS動(dòng)物模型; 2.人皮膚移植于裸鼠體表后可以發(fā)生不完全的排斥反應(yīng),其表皮及部分真皮受排斥而逐漸脫落,但有部分真皮長(zhǎng)期存活; 3.該模型無(wú)論在大體外觀(guān)、生長(zhǎng)特性、組織學(xué)特點(diǎn)以及遺傳學(xué)特性等方面都和人的HS相似,且具有很好的可控性,能觀(guān)察瘢痕發(fā)生發(fā)展的全過(guò)程,是一種較為理想的人HS動(dòng)物模型; 4.人皮膚真皮是發(fā)生HS的內(nèi)在決定因素,而局部的持續(xù)炎性反應(yīng)則是重要的促進(jìn)因素。
[Abstract]:Although scholars at home and abroad have been doing a lot of research on hypertrophic scar (HS) for a long time, the formation mechanism of HS is still unclear, and there is a lack of special effective control methods in clinic. One of the reasons for this situation is the lack of an ideal animal model of HS. Only the talent will naturally occur H. S, which is one of the characteristics of HS, is based on "the internal cause is the basis of the development of things, it determines the basic trend of the development of things", the natural dialectics. We speculate that the formation of HS is determined by some or some intrinsic factors of the human skin. Therefore, the animal model can be established by migrating the human skin to nude mice. This class can be established in this course. The purpose of this study is to establish the HS animal model by transplantation of human skin to nude mice and to systematically observe the pathological process of scar formation and to study the mechanism of scar formation. The main results and conclusions are as follows:
The skin and part of the dermis of the transplanted skin were gradually shedding off the skin and part of the skin of the transplanted skin. However, the repulsive reaction occurred late and light, and the dermis of the transplanted skins survived and became a skin graft after the scab of the transplanted skin after the skin graft of the nude mice. The skin and part of the dermis of the transplanted skin were gradually falling off. Our results, on the one hand, illustrate the existence of non T cell dependent immune mechanisms in nude mice, and on the other hand, long-term chronic immune responses may be a contributing factor to scar proliferation.
2. the epidermis and part of the epidermis of all thick skin graft and partial dermis fall off, local scar hyperplasia can occur locally. The scar is similar to human HS in appearance, proliferation and histopathological characteristics.
3. the change of TGF beta -1 in the model scar was studied by immunohistochemical method. The expression of TGF- beta 1 in the hyperplastic scar was found to be high level, but the decline period was significantly reduced.
4. the results of cell culture in vitro showed that the model scar fibroblasts were very similar to the human HS fibroblasts, and there was no significant difference in cell proliferation and collagen synthesis.
5. the activity of collagenase in the model scar tissue and normal skin was compared. It was found that the hypertrophic scar collagenase activity was low, indicating that the degradation of collagen and other extracellular matrix in the model scar was reduced.
6. the model scar tissue and normal human skin tissue and the DNA of human HS tissue were used as the template for PCR. The results showed that all human specific genes could be amplified, indicating that there must be human DNA. in the model scar tissue.
7. only the full thickness skin graft of the transplant person will have obvious scar hyperplasia, and the transplant people's thick skin slice and the whole thick skin slice of the rat do not have scar proliferation at all. The thickness of the transplanted medium and thick skin can occur to a certain degree of scar hyperplasia, but the degree and incidence of hyperplasia are obviously inferior to that of the whole thick skin graft. The dermis of the human skin is a determinant of the occurrence of HS. This discovery has confirmed that HS is the only phenomenon that only human skin occurs, and that the dermis of the human skin is a determinant of the occurrence of HS, not the epidermis or other external environmental factors, and further reveals the mechanism of the birth of HS.
The results showed that a certain degree of rejection occurred after the human skin transplantation in nude mice. The rejection occurred in the skin and partial dermal necrosis of the transplanted human skin, but some of the dermis still survived. The survival of this part of the human dermis was the basis of HS. The human fibroblasts in the dermis continued to be localized in the local inflammatory response. The function state changes, the cell proliferation is exuberant, and a large number of collagen and other extracellular matrix can be synthesized, which leads to the continuous hyperplastic scar. The model has obvious hyperplastic scar, long duration of proliferation, the gross morphology, growth characteristics and histological characteristics of the scar are similar to those of human HS, which are very representative and can be used for scar formation. The study of mechanism and clinical prevention and treatment.
Conclusion:
1. HS animal model can be established by transplantation of human full-thickness skin on the back of nude mice.
After the skin transplantation of 2. people to the surface of the nude mice, an incomplete rejection could occur, and the epidermis and part of the dermis were gradually removed, but some of the dermis survived for a long time.
3. the model is similar to human HS in terms of gross appearance, growth characteristics, histology and genetic characteristics. It has good controllability and can observe the whole process of scar development. It is an ideal human HS animal model.
The dermal dermis of 4. person is the intrinsic factor determining the occurrence of HS, while local persistent inflammatory reaction is an important promoting factor.

【學(xué)位授予單位】：第三軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2006
【分類(lèi)號(hào)】：R622;R-332

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