本文選題：曲尼司特 + 瘢痕�。� 參考：《南方醫(yī)科大學(xué)》2017年碩士論文

【摘要】：1背景增生性瘢痕是傷口異常愈合所導(dǎo)致,是燒傷和外傷后常見的并發(fā)癥,常伴有疼痛、瘙癢以及關(guān)節(jié)活動(dòng)受限。燒傷后瘢痕增生常導(dǎo)致患者性格孤僻、社交恐懼、甚至自尊受損,嚴(yán)重影響其日常生活質(zhì)量。以往的研究證實(shí),瘢痕增生是由于生物體內(nèi)細(xì)胞因子分泌紊亂,成纖維細(xì)胞異常增生,Ⅰ型和Ⅲ型膠原不成比例的合成與降解造成的纖維化疾病。胎兒無瘢痕愈合實(shí)驗(yàn)驗(yàn)證,炎癥反應(yīng)是瘢痕形成的主要原因,且炎癥反應(yīng)程度的高低與肥大細(xì)胞(mastcells,MC)的含量呈正相關(guān),當(dāng)組織受到損傷時(shí),MC立即被激活并發(fā)生局部聚集,參與機(jī)體的各種損傷修復(fù)、免疫等反應(yīng)。因此降低MC含量或抑制其活性能調(diào)節(jié)傷口愈合過程中膠原的合成及Ⅰ、Ⅲ型膠原比例,從而有效抑制瘢痕的增生。曲尼司特(Tranilast,TNL)作為一種過敏介質(zhì)阻釋劑,是不同于H1、H2受體競(jìng)爭(zhēng)類抗組胺藥的新型抗變態(tài)反應(yīng)藥物,能有效預(yù)防和治療一些纖維化疾病,其中包括增生性瘢痕,因此也被認(rèn)為是一種新型的抗瘢痕治療藥物,這在一定程度上已被我們前期的研究所證實(shí)。但關(guān)于TNL最佳用藥時(shí)間及TNL外用藥作用研究甚少,因此本研究共設(shè)計(jì)兩個(gè)實(shí)驗(yàn),均以深Ⅱ度燒傷小鼠創(chuàng)面作為觀測(cè)對(duì)象,實(shí)驗(yàn)一通過不同時(shí)間點(diǎn)開始給予口服TNL干預(yù)后,定期取創(chuàng)面的新生組織行病理學(xué)觀察,以發(fā)現(xiàn)TNL抑制瘢痕增生的作用是否與藥物開始干預(yù)的時(shí)間有關(guān)并找到最佳干預(yù)時(shí)間點(diǎn);實(shí)驗(yàn)二用TNL滴眼液外滴創(chuàng)面,觀察TNL外用能否同樣有抑制瘢痕增生的作用,也為TNL臨床用于治療瘢痕類疾病提供一定的理論基礎(chǔ)。2方法2.1實(shí)驗(yàn)動(dòng)物選取、分組及燒傷模型建立實(shí)驗(yàn)一 7～8周齡清潔級(jí)雄性昆明小鼠66只,于小鼠背部制備深Ⅱ度燒傷創(chuàng)面模型,然后隨機(jī)分為對(duì)照組(n=18)、早期干預(yù)組(n=18)、中期干預(yù)組(n=18)和晚期干預(yù)組(n=12);實(shí)驗(yàn)二 7～8周齡清潔級(jí)雄性昆明小鼠18只,于小鼠背部制備深Ⅱ度燒傷創(chuàng)面模型,然后隨機(jī)分為空白對(duì)照組(n=6)、對(duì)照組(n=6)、實(shí)驗(yàn)組(n=6)。2.2給藥方法實(shí)驗(yàn)一早期干預(yù)組、中期干預(yù)組、晚期干預(yù)組分別于燒傷創(chuàng)面形成后當(dāng)天、7d、14d開始給予TNL200mg/(kg·d)灌胃,對(duì)照組于燒傷后當(dāng)天開始每天給予等體積生理鹽水灌胃;實(shí)驗(yàn)二空白對(duì)照組不做處理,對(duì)照組及實(shí)驗(yàn)組分別于燒傷創(chuàng)面形成后當(dāng)天開始給予無菌生理鹽水和TNL滴眼液(1ml注射器2-4滴,以覆蓋創(chuàng)面為準(zhǔn))外滴創(chuàng)面。2.3取材定期觀察創(chuàng)面愈合情況,實(shí)驗(yàn)一各組分別于創(chuàng)傷形成后14、28、42 d(晚期干預(yù)組于28、42d)隨機(jī)選取6只小鼠取創(chuàng)面新生組織,實(shí)驗(yàn)二各組于燒傷創(chuàng)面形成后42天統(tǒng)一處死。2.4標(biāo)本固定所取標(biāo)本一式三份,一份甲醛固定,一份戊二醛固定,一份PBS緩沖液固定后置-80℃冰箱保存。2.5檢測(cè)方法2.5.1石蠟包埋2.5.2切片2.5.3 HE 染色2.5.4甲苯胺藍(lán)染色2.5.5 Masson 染色2.5.6抗體競(jìng)爭(zhēng)法2.5.7 ELISA 法2.5.8透射電鏡技術(shù)。3結(jié)果各組小鼠創(chuàng)面愈合時(shí)間比較差異無統(tǒng)計(jì)學(xué)意義(F=1.105,P=0.371)�？诜⺄NL和外用TNL滴眼液均能使瘢痕組織中肥大細(xì)胞數(shù)量、總膠原含量、Ⅰ/Ⅱ型膠原比值、TGF-β1含量及組胺含量顯著降低;且實(shí)驗(yàn)一中早期干預(yù)組各時(shí)間點(diǎn)肥大細(xì)胞數(shù)量、總膠原含量、Ⅰ/Ⅲ型膠原比值、TGF-β1含量及組胺含量均顯著低于其它組(P0.05),與對(duì)照組相比,早、中、晚期干預(yù)組成纖維細(xì)胞的超微結(jié)構(gòu)均發(fā)生明顯改變。4結(jié)論TNL對(duì)小鼠燒傷創(chuàng)面愈合無明顯影響;但口服TNL或外用TNL滴眼液干預(yù)后能明顯降低燒傷后創(chuàng)面新生組織中MC的數(shù)量,組胺和TGF-β1的含量,抑制成纖維細(xì)胞膠原合成的能力及調(diào)節(jié)Ⅰ、Ⅲ型膠原合成的比例,從而抑制瘢痕的形成,且燒傷后即刻進(jìn)行曲尼司特干預(yù)對(duì)瘢痕形成的抑制作用最為明顯。
[Abstract]:1 background hypertrophic scar is caused by abnormal healing of the wound. It is a common complication after burn and trauma, often accompanied by pain, itching and limited joint activity. The hypertrophic scar after burn often causes the patient's character isolation, social fear and even the loss of self-esteem, which seriously affect the quality of daily life. Previous studies have confirmed that scar hyperplasia is due to Cytokine secretion disorders, fibroblast dysplasia, type I and type III collagen disproportionate synthesis and degradation of fibrotic diseases. Fetal scar free healing experiments verify that the inflammatory reaction is the main cause of scar formation, and the high degree of inflammatory reaction is positively related to the content of mastcells, MC. When the tissue is damaged, MC is immediately activated and locally aggregated to participate in various injury repair and immune responses. Therefore, reducing the content of MC or inhibiting its activity can regulate the synthesis of collagen and the proportion of type I and type III collagen during the wound healing process, thus effectively inhibiting the proliferation of the scar marks. Tranilast (TNL) is used as a kind of hypertrophy. Sensitive medium resistance release agent, a new antiallergic drug that is different from H1, H2 receptor antihistamine, can effectively prevent and treat some fibrotic diseases, including hypertrophic scars, so it is also considered as a new type of anti scar treatment drug, which has been confirmed by our previous research in a certain range. But on the most TNL There are few studies on the time of good drug use and the effect of TNL external use. Therefore, two experiments were designed in this study. All the wounds of deep second degree burn mice were taken as the observation objects. The experiment one was given the prognosis of oral TNL by oral administration at different time points. The pathological observation of the newborn tissues of the wound was taken regularly to find out whether the effect of TNL on the inhibition of scar hyperplasia was related to the drug. The time of the intervention was related and the best time for intervention was found. Experiment two with TNL eye drops was used to observe whether the external use of TNL could also inhibit scar hyperplasia. It also provided a theoretical basis for the clinical application of TNL in the treatment of cicatricial diseases by.2 method 2.1 experimental animal selection, group and burn model establishment experiment 7~8. 66 week old male Kunming mice were prepared for deep second degree burn wound model on the back of mice, and then randomly divided into control group (n=18), early intervention group (n=18), medium-term intervention group (n=18) and late intervention group (n=12), and 18 mice of two 7~8 weeks old male clean grade mice were tested on the back to prepare deep second degree burn wound model in the back of mice, and then the model of deep second degree burn wound was made in the back of mice. Then, the model of deep second degree burn wound was made in the back of mice. Randomly divided into the blank control group (n=6), the control group (n=6), the experimental group (n=6).2.2 administration method experiment one early intervention group, the middle intervention group, the late intervention group on the day after the burn wound formation, 7d, 14d began to give TNL200mg/ (kg. D) to the stomach, the control group began to give the same volume of normal saline day after the day after the burn; the experiment was two empty. The white control group did not do the treatment. The control group and the experimental group began to observe the wound healing by using the aseptic saline and TNL eyedrops (2-4 drops of 1ml syringe and covering the wound surface) on the same day after the formation of the burn wound. The experimental groups were respectively 14,28,42 d after the formation of the trauma (late intervention group in 28,42d). 6 mice were randomly selected to take the wound tissue of the wound. In the experiment two, 42 days after the formation of the burn wound, three parts of the.2.4 specimens were executed. One portion of formaldehyde was fixed, a glutaraldehyde was fixed, a PBS buffer was fixed after -80 centigrade and.2.5 was stored in the freezer, 2.5.1 paraffin embedded 2.5.2 section 2.5.3 HE and 2.5.4 a HE 2.5.5 Masson staining with aniline blue staining 2.5.6 antibody competition method 2.5.7 ELISA 2.5.8 transmission electron microscope technique.3 results there was no significant difference in the wound healing time of each group (F=1.105, P=0.371). The number of mast cells, the total collagen content in the scar tissue, the ratio of type I / II collagen, TGF- beta 1 and the ratio of type I / II collagen in the scar tissue were not statistically significant (F=1.105, P=0.371). Content and histamine content decreased significantly, and the number of mast cells, total collagen content, type I / III collagen ratio, TGF- beta 1 content and histamine content in the early intervention group were significantly lower than those of the other groups (P0.05). Compared with the control group, the ultrastructure of the early, middle and late intervened fiber cells significantly changed the.4 conclusion TNL There was no obvious effect on the healing of burn wounds in mice, but the number of MC, the content of histamine and TGF- beta 1, the ability to inhibit the synthesis of collagen in fibroblasts and the regulation of the synthesis of type I and type III collagen were significantly reduced after the oral TNL or external TNL eye drops. The inhibition of cicrst intervention on scar formation was most obvious.
【學(xué)位授予單位】：南方醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R644

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