本文選題：嬰幼兒血管瘤 + 普萘洛爾�。� 參考：《山東大學(xué)》2014年博士論文

【摘要】：論文綱要 血管瘤(hemangioma)是嬰幼兒最常見的先天性良性腫瘤,新生兒發(fā)病率2-3%,1歲以下兒童的發(fā)病率在10%左右。普萘洛爾作為非選擇性β-腎上腺素受體阻滯劑,主要用于治療心臟疾病如高血壓、心絞痛、心動(dòng)過速等。2008年,法國(guó)醫(yī)生Leaute-Labreze C等偶然發(fā)現(xiàn)該藥可有效抑制血管瘤的增殖,并加速瘤體消退。之后,國(guó)內(nèi)外眾多學(xué)者也相續(xù)將其應(yīng)用于血管瘤的治療,廣泛的臨床應(yīng)用證實(shí)了該藥對(duì)血管瘤具有明顯療效。 口服普萘洛爾治療增生期血管瘤療效顯著,同時(shí)對(duì)消退期血管瘤也有一定效果,目前已逐步取代激素成為治療嬰幼兒血管瘤的一線用藥。然而,兒童口服普萘洛爾尚存在很多潛在的副作用,尤其是口服初期,需住院檢測(cè)心率、血壓、血糖等指標(biāo),給患兒家長(zhǎng)及醫(yī)師帶來諸多不便。能否改變給藥途徑,采取瘤體局部外涂普萘洛爾制劑的方式,以減輕口服藥物所致的潛在不良反應(yīng),鑒于此,在第一章第一部分通過對(duì)25例門診“等待觀察”的淺表型嬰幼兒血管瘤患者初步嘗試應(yīng)用1%普萘洛爾軟膏外涂治療,結(jié)果表明療效顯著且未發(fā)現(xiàn)可檢測(cè)到的與外用普萘洛爾軟膏相關(guān)的不良反應(yīng)。此外,口服普萘洛爾治療血管瘤,國(guó)內(nèi)外文獻(xiàn)較多集中在對(duì)療效評(píng)估,而對(duì)服藥期間因治療所致的副作用或不良反應(yīng)發(fā)生情況研究尚存在不足。故在本章第二部分,回顧性分析近年來我科接受口服普萘洛爾治療的106例血管瘤患兒,以評(píng)估藥物治療相關(guān)的副作用或不良反應(yīng)發(fā)生情況,為用藥安全提供依據(jù)。 Folkman等學(xué)者認(rèn)為,血管瘤是一種血管形成性質(zhì)疾病,失控的血管生成是其增殖的主要因素。該過程包括了內(nèi)皮細(xì)胞增殖、細(xì)胞外基質(zhì)的選擇性降解、細(xì)胞的遷移以及血管通透性的增加。細(xì)胞生長(zhǎng)因子是一類能誘導(dǎo)或促進(jìn)新血管形成的物質(zhì),可調(diào)控內(nèi)皮細(xì)胞的增殖,影響血管形成,對(duì)血管瘤的發(fā)生發(fā)展起關(guān)鍵作用。類表皮生長(zhǎng)因子域7(EGFL7)是一種內(nèi)皮細(xì)胞特異性分泌因子,選擇性地表達(dá)于腫瘤新生血管和增生性組織中,在血管生成過程中起關(guān)鍵作用。由此我們提出,①EGFL7是否在血管瘤組織中表達(dá)及在該病發(fā)生發(fā)展的不同時(shí)期是否存在差異表達(dá)?②普萘洛爾對(duì)血管瘤顯著的臨床療效是否通過抑制EGFL7表達(dá)?上述問題是進(jìn)一步研究普萘洛爾對(duì)血管瘤作用機(jī)制所要解決的問題。鑒于此,第二章第一部分利用免疫組織化學(xué)染色技術(shù)檢測(cè)類表皮生長(zhǎng)因子域7(EGFL7)在嬰幼兒血管瘤組織中的表達(dá),并探討其在血管瘤發(fā)生發(fā)展過程中的作用和意義。本章第二部分,通過檢測(cè)普萘洛爾干預(yù)下人臍靜脈內(nèi)皮細(xì)胞(HUVEC)增殖、成管、凋亡及EGFL7的表達(dá)影響,初步探討普萘洛爾抑制血管瘤增生的作用機(jī)制。 第一章普萘洛爾治療嬰幼兒血管瘤臨床觀察 第一部分普萘洛爾外用軟膏治療淺表型嬰幼兒血管瘤療效評(píng)估 目的探討局部外涂普萘洛爾軟膏治療淺表型嬰幼兒血管瘤的臨床療效及安全性。 方法本組共25例(共28處血管瘤,女21例,男4例,年齡1月至10月,平均4個(gè)月)淺表型嬰幼兒血管瘤患兒,門診接受瘤體表面外涂1%普萘洛爾軟膏,每日3次,均勻涂于瘤體表面,時(shí)間5周至59周(平均21周),依據(jù)服藥前后瘤體表面張力、大小、顏色變化,按照顯著有效、部分有效、無效3級(jí)評(píng)分法對(duì)近期療效進(jìn)行評(píng)價(jià)。同時(shí),觀察用藥后副作用以評(píng)估用藥安全性。 結(jié)果28處血管瘤中,16(57%)例顯著有效；9(33%)例部分有效；3(10%)例為無效。1%普萘洛爾軟膏對(duì)淺表型嬰幼兒血管瘤的總有效率為90%(95%可信區(qū)間72%-98%)。所有患兒均未出現(xiàn)可檢測(cè)到的不良反應(yīng)。 結(jié)論外涂普萘洛爾軟膏能有效促進(jìn)淺表型嬰幼兒血管瘤的消退,且未發(fā)現(xiàn)口服普萘洛爾常見的不良反應(yīng),可以作為嬰幼兒血管瘤隨訪觀察期間的一種安全、有效輔助治療手段。 第二部分口服普萘洛爾治療嬰幼兒血管瘤不良反應(yīng)觀察 目的：觀察口服普萘洛爾治療嬰幼兒血管瘤不良反應(yīng),評(píng)估其用藥安全性。 方法：2009年9月至2013年11月間山東省立醫(yī)院燒傷整形美容科口服普萘洛爾治療的106例嬰幼兒血管瘤患兒,女性71例,男性35例,年齡1-14個(gè)月(平均5.1個(gè)月)。服藥劑量每日1-1.5mg/kg,分3次給藥,隨訪2-10個(gè)月,期間對(duì)出現(xiàn)的用藥相關(guān)副作用或并發(fā)癥進(jìn)行安全性評(píng)估。 結(jié)果：106例患兒服藥期間及隨訪階段瘤體均得到有效控制且有程度不同的消退。18例病人(17%,18/106,4例并發(fā)兩種以上副作用)出現(xiàn)與用藥相關(guān)的副作用,其中10(9.4%)例口服期間發(fā)生腹瀉,7(6.6%)例出現(xiàn)一過性血壓下降,2(1.9%)例溢奶,2(1.9%)例夜間睡眠差,易激和四肢末端發(fā)涼各1例(0.94%)。 結(jié)論：小劑量(1-1.5mg/kg.day)、分次口服普萘洛爾治療嬰幼兒血管瘤療效顯著,且不良反應(yīng)發(fā)生率低,用藥安全,可作為嬰治療幼兒血管瘤的用藥選擇。 第二章普萘洛爾抑制嬰幼兒血管瘤增殖的機(jī)制探討 第一部分類表皮生長(zhǎng)因子域7(EGFL7)在嬰幼兒血管瘤組織中的表達(dá)及意義 目的：檢測(cè)類表皮生長(zhǎng)因子域7(EGFL7)在不同時(shí)期嬰幼兒血管瘤組織中的表達(dá)情況并探討其在該病發(fā)生發(fā)展過程中的作用及意義。 方法：收集2007年5至2013年9月山東大學(xué)附屬省立醫(yī)院燒傷整形美容科手術(shù)切除組織病理診斷為嬰幼兒血管瘤的石蠟標(biāo)本49例(男16例,女33例),依據(jù)Mulliken標(biāo)準(zhǔn)將標(biāo)本分成增生期組、退期組、消退完成期組,以正常皮膚作為對(duì)照組。應(yīng)用免疫組織化學(xué)法對(duì)各期嬰幼兒血管瘤組織及正常皮膚中的類表皮生長(zhǎng)因子域7(EGFL7)表達(dá)情況進(jìn)行檢測(cè),利用計(jì)算機(jī)圖像分析技術(shù)分別測(cè)量其平均光密度。 結(jié)果：EGFL7陽性反應(yīng)定位于血管瘤細(xì)胞胞漿中,在血管瘤增生期強(qiáng)陽性或陽性表達(dá),消退期陽性表達(dá),消退完成期和正常皮膚中弱陽性或陰性性表達(dá)。 結(jié)論：EGFL7與增生期嬰幼兒血管瘤關(guān)系密切,參與了嬰幼兒血管瘤病理變化過程,在該病增生期和消退早期細(xì)胞增殖和血管形成階段起重要作用。 第二部分普萘洛爾對(duì)人臍靜脈內(nèi)皮細(xì)胞(HUVEC)生物學(xué)行為及EGFL-7表達(dá)的影響 目的：探討普萘洛爾對(duì)人臍靜脈內(nèi)皮細(xì)胞增殖、成管能力、凋亡及EGFL-7表達(dá)影響,為進(jìn)一步研究普萘洛爾治療嬰幼兒血管瘤機(jī)制提供理論依據(jù)。 方法：以離體的人臍靜脈內(nèi)皮細(xì)胞為實(shí)驗(yàn)對(duì)象,采用MTT法、成管實(shí)驗(yàn)、流式細(xì)胞儀測(cè)定不同濃度的普萘洛爾(0μmol/L、25μmo1/L、50μmol/L、100μmo1/L、125μmol/L、150μmol/L、175μmol/L、200μmol/L)對(duì)HUVEC增殖、成管能力、凋亡的影響及RT-PCR、western blot法測(cè)定類表皮生長(zhǎng)因子域-7的變化。 結(jié)果：普萘洛爾藥物干預(yù)24和48小時(shí)后,藥物濃度為≥25um時(shí)對(duì)人臍靜脈內(nèi)皮細(xì)胞增殖能力的抑制率與正常對(duì)照組相比有統(tǒng)計(jì)學(xué)意義(P0.01),且在25μmol/L、50μmol/L、100μmol/L、125μmol/L濃度下抑制率成明顯上升趨勢(shì)；流式細(xì)胞儀檢測(cè)不同濃度普萘洛爾實(shí)驗(yàn)組和空白組對(duì)比(24小時(shí)),細(xì)胞凋亡率逐步增加；藥物處理組24h細(xì)胞成管個(gè)數(shù)與陰性對(duì)照無統(tǒng)計(jì)學(xué)差異,48小時(shí)對(duì)成管能力有一定抑制作用；RT-PCR和Western blot實(shí)驗(yàn)結(jié)果顯示藥物處理組與空白組對(duì)比,人臍靜脈內(nèi)皮細(xì)胞的EGFL-7表達(dá)呈現(xiàn)濃度性抑制作用,有顯著差異(P0.05)。 結(jié)論：普萘洛爾抑制人臍靜脈內(nèi)皮細(xì)胞的增殖,加速細(xì)胞早期凋亡,兩者呈現(xiàn)濃度依賴性,對(duì)成管能力有一定抑制作用,呈現(xiàn)時(shí)間依賴性；普萘洛爾成濃度依賴性抑制人內(nèi)皮細(xì)胞中EGFL-7的表達(dá),由此推測(cè)普萘洛爾抑制增生期血管瘤作用機(jī)制與通過抑制EGFL-7介導(dǎo)的促血管生成作用,最終達(dá)到加速血管瘤消退。
[Abstract]:Thesis proposal
Hemangioma (hemangioma) is the most common congenital benign tumor in infants. The incidence of newborns is 2-3% and the incidence of children under 1 years old is about 10%. Propranolol is used as a non selective beta adrenergic receptor blocker, which is mainly used in the treatment of heart diseases such as hypertension, cardiac tachycardia, tachycardia, and other.2008 years, and the French doctor Leaute-Labreze C It is found that the drug can effectively inhibit the proliferation of hemangioma and accelerate the decline of the tumor body. After that, many scholars at home and abroad also continue to apply it to the treatment of hemangioma. Extensive clinical application confirms that the drug has obvious curative effect on hemangioma.
Oral propranolol has a significant effect on the treatment of hyperplastic hemangioma and also has some effect on the hemangioma in the subsiding period. At present, the hormone has gradually replaced the hormone as a first-line drug for the treatment of infantile hemangioma. However, there are many potential side effects in children's oral propranolol, especially in the early stage of oral administration, which need to be hospitalized to detect heart rate, blood pressure, blood sugar and so on. The index can bring many inconvenience to the parents and doctors. Can we change the way of drug delivery, take the way of applying propranolol to reduce the potential adverse reactions caused by oral medicine. In the first chapter, the first part of the first chapter is to try the initial attempt of 25 cases of superficial infantile hemangioma "waiting for observation" in the outpatient clinic. The treatment with 1% propranolol ointment showed significant effect and no detectable adverse reactions associated with the external propranolol ointment. In addition, the oral propranolol was more concentrated in the treatment of hemangioma at home and abroad, and the side effects or adverse reactions caused by treatment during the medication were studied. In the second part of this chapter, a retrospective analysis of 106 cases of hemangioma treated by oral propranolol in recent years was reviewed to assess the side effects or adverse reactions related to drug treatment, and to provide a basis for the safety of drug use.
Folkman and other scholars believe that hemangioma is a angiogenic disease. Out of control angiogenesis is a major factor in its proliferation. This process includes endothelial cell proliferation, selective degradation of extracellular matrix, cell migration, and increased vascular permeability. Cell growth is a class of substances that can induce or promote new vascular formation. Cytoplasm, which regulates the proliferation of endothelial cells and affects angiogenesis, plays a key role in the development of angioma. The epidermal growth factor domain 7 (EGFL7) is a specific secretory factor of endothelial cells, which is selective in neovascularization and proliferative tissue of tumor, and plays a key role in the process of blood Guan Shengcheng. Therefore, we propose, (1) EGFL Is there any difference in expression of 7 in hemangioma tissue and in different periods of the development of the disease? 2. Is the significant clinical effect of propranolol on hemangioma by inhibiting EGFL7 expression? The above question is a further study of the problem of propranolol's mechanism of action on hemangioma. In view of this, the first part of the second chapter is beneficial. Immunohistochemical staining was used to detect the expression of epidermal growth factor domain 7 (EGFL7) in the tissue of infantile hemangioma, and to explore its role and significance in the development of hemangioma. The second part of this chapter is to detect the proliferation, tube, apoptosis and EGFL7 expression of human umbilical vein endothelial cells (HUVEC) under the intervention of propranolol. The mechanism of propranolol inhibiting hemangioma proliferation was preliminarily explored.
Chapter 1 clinical observation of propranolol in treatment of infantile hemangioma
Part I: propranolol external ointment in the treatment of superficial infantile hemangioma
Objective to investigate the clinical efficacy and safety of topical propranolol ointment in the treatment of superficial infantile hemangioma.
Methods a total of 25 cases (28 cases of hemangioma, 21 women, 4 men, 4 men, from January to October, 4 months, average 4 months) were treated with 1% propranolol ointment on the surface of the tumor, 3 times a day, evenly coated on the surface of the tumor for 5 to 59 weeks (21 weeks flat), according to the surface tension, size and color changes of the tumor before and after the medication. The short-term efficacy was evaluated according to the significant, effective, invalid and 3 grade scoring method. Meanwhile, the side effects of medication were observed to evaluate the safety of medication.
Results of the 28 hemangiomas, 16 (57%) cases were significantly effective, 9 (33%) were partially effective, and 3 (10%).1% propranolol ointment had a total effective rate of 90% (95% confidence interval 72%-98%) for superficial infantile hemangioma. All the children had no detectable adverse reactions.
Conclusion the application of propranolol ointment can effectively promote the decline of superficial infantile hemangioma, and not found the common adverse reaction of oral propranolol. It can be used as a safe and effective adjuvant therapy for the follow-up observation of infantile hemangioma.
The second part of oral propranolol treatment of infantile hemangioma adverse reactions observed
Objective: To observe the adverse reaction of propranolol in the treatment of infantile hemangioma and evaluate its safety.
Methods: from September 2009 to November 2013, 106 children with infantile hemangioma treated by oral propranolol, the Department of burn and plastic surgery, Shangdong Province-owned Hospital, were treated with 106 cases of infant hemangioma, 71 women, 35 males, 1-14 months of age (average 5.1 months). The dosage of the medicine was given for 2-10 months, and the drug related side effects were observed for 2-10 months. A safety assessment of the disease.
Results: 106 cases of.18 patients were effectively controlled and varying degrees of tumor withdrawal during and follow-up period (17%, 18/106,4 cases with more than two side effects) associated with the side effects, including 10 (9.4%) cases of oral diarrhea, 7 (6.6%) cases of transient blood pressure decline, 2 (1.9%) cases of spilled milk, 2 (1.9%) cases. Night sleep was poor, irritability and cold extremities were found in 1 cases (0.94%).
Conclusion: small dose (1-1.5mg/kg.day) and oral propranolol are effective in the treatment of infantile hemangioma, and the incidence of adverse reactions is low. The drug is safe and can be used as a choice for infant hemangioma.
The second chapter is the mechanism of propranolol inhibiting the proliferation of infantile hemangioma.
Expression and significance of epidermal growth factor domain 7 (EGFL7) in infantile hemangioma tissues
Objective: to detect the expression of epidermal growth factor domain 7 (EGFL7) in the tissues of infantile hemangioma at different times and to explore its role and significance in the development of the disease.
Methods: 49 paraffin specimens (16 males and 33 females) diagnosed as infantile hemangiomas were collected from 5 to September 2013 of Shandong University from 5 to September 2013 in 2007. According to the standard, the specimens were divided into the hyperplastic period group, the retreating group, the subsiding completion period, and the normal skin as the control group. Histochemical method was used to detect the expression of epidermal growth factor domain 7 (EGFL7) in the tissues of infantile hemangioma and normal skin, and the average optical density was measured by computer image analysis.
Results: the positive reaction of EGFL7 was located in the cytoplasm of hemangioma cells. The positive or positive expression of the hemangioma was positive or positive, the positive expression in the subsiding stage, the fading phase and the weak positive or negative expression in the normal skin.
Conclusion: EGFL7 is closely related to the hyperplastic infantile hemangioma, and participates in the pathological changes of the infantile hemangioma, which plays an important role in the stage of proliferation and the stage of angiogenesis and angiogenesis in the early stage of the disease.
The second part of propranolol affects the biological behavior and EGFL-7 expression of human umbilical vein endothelial cells (HUVEC).
Objective: To investigate the effect of propranolol on the proliferation, tubular capacity, apoptosis and EGFL-7 expression of human umbilical vein endothelial cells, and to provide a theoretical basis for the further study of propranolol in the treatment of infantile hemangioma.
Methods: using the isolated human umbilical vein endothelial cells as the experimental object, the MTT method was used to test the proliferation of propranolol (0, 25, 50, 50, 50, 100, 125 u mol/L, 150 mol/L, 175, mol/L, 200 micron) for HUVEC colonization, the effect of tubular capacity, apoptosis and RT-PCR, Western assay The changes in the epidermal growth factor domain -7.
Results: after 24 and 48 hours of propranolol intervention, the inhibition rate of the proliferation ability of human umbilical vein endothelial cells was significantly higher than that of the normal control group (P0.01), and the inhibition rate of the human umbilical vein endothelial cells was significantly higher than that of the normal control group (P0.01), and the inhibition rate of the human umbilical vein endothelial cells was significantly increased at 25 u mol/L, 50 mu, 100 mu mol/L, and 125 u mol/L concentration; the flow cytometry was used to detect the different concentrations. The apoptosis rate of the propranolol experiment group and the blank group (24 hours) increased gradually. The number of 24h cells in the drug treatment group was not statistically different from that of the negative control. 48 hours had a certain inhibitory effect on the ability of the tube formation. The results of RT-PCR and Western blot showed that the drug treatment group was compared with the blank group, and the EG of the human umbilical vein endothelial cells was EG. FL-7 expression showed a significant inhibitory effect (P0.05).
Conclusion: propranolol inhibits the proliferation of human umbilical vein endothelial cells and accelerates the early apoptosis of the cells. Both of them have a concentration dependence and have a certain inhibitory effect on the ability of tube formation. Propranolol inhibits the expression of EGFL-7 in human endothelial cells, thus suppresses the effect of propranolol to inhibit the proliferation of hemangioma. The mechanism can ultimately accelerate the regression of hemangioma by inhibiting EGFL-7 mediated angiogenesis.
【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2014
【分類號(hào)】：R732.2

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