本文關(guān)鍵詞：西地那非對血管瘤內(nèi)皮細(xì)胞增殖和凋亡的影響及機制探討　出處：《山東大學(xué)》2017年博士論文　論文類型：學(xué)位論文

  更多相關(guān)文章： 西地那非 磷酸二酯酶-5(PDE-5) 血管瘤 內(nèi)皮細(xì)胞 增殖 凋亡 DNA分化抑制因子-1(Id-1)

【摘要】：研究背景血管瘤(hemangiomas)是發(fā)生在嬰幼兒的血管源性良性腫瘤,發(fā)病率高達(dá)10～12%,絕大多數(shù)在出生時或出生后不久發(fā)現(xiàn),大部分可自行消退,但仍有20%的血管瘤不能消退。根據(jù)病變發(fā)展過程可分為增殖期、消退期和消退完成期。血管瘤雖然屬于良性腫瘤,但發(fā)生在口腔頜面及頸部的病變,不僅嚴(yán)重影響面容美觀,還可能由于病變阻塞呼吸道、消化道而影響發(fā)音、進(jìn)食,甚至導(dǎo)致局部出血、窒息并危及生命。因此目前主張對該病應(yīng)積極進(jìn)行早期治療。血管瘤常用的治療方法有藥物治療、激光、手術(shù)切除、冷凍以及硬化治療等。冷凍、激光及硬化治療易導(dǎo)致增生或萎縮性瘢痕、色素沉著或色素減退等,手術(shù)切除僅適用于局限性的血管瘤的治療。藥物治療則是一種治療早期血管瘤安全、有效的方法。治療血管瘤的藥物有多種,目前國內(nèi)外常用藥物包括以下幾類:1.β-腎上腺素受體阻滯劑,以普萘洛爾(propranolol)為主;2.皮質(zhì)類固醇激素,以潑尼松(prednisolone)為主;3.其它:α-干擾素(IFN-α)、咪喹莫特(Imiquimod)、抗腫瘤藥環(huán)磷酰胺(CTX)及長春新堿(VCR)等。2008年,在《新英格蘭醫(yī)學(xué)雜志》上,Leaute-Labreze C等首次報道口服普萘洛爾引起了鼻咽部血管瘤的消退。近年來,口服普萘洛爾逐漸成為治療血管瘤的一線藥物。2012年,Swetman等首次報道口服西地那非(sildenafil)治療3名淋巴管畸形患兒后病變顯著消退,發(fā)表于《新英格蘭醫(yī)學(xué)雜志》上,提示西地那非可作為治療淋巴管畸形的一種新型藥物。但該文章僅展示了患兒病變部位的照片和核磁共振平片(magnetic resonance imaging,MRI),病變均未經(jīng)手術(shù)及病理證實為淋巴管畸形。根據(jù)MRI表現(xiàn),我們認(rèn)為此患兒更符合血管瘤伴發(fā)淋巴管畸形的診斷,且病變以血管瘤為主。西地那非是一種磷酸二酯酶-5(phosphodiesterase isoform-5,PDE-5)抑制劑,因而我們推測可能西地那非是通過抑制PDE-5的作用使該病變縮小的。在此啟發(fā)下,我們通過免疫組織化學(xué)的方法研究了 PDE-5在靜脈畸形、動靜脈畸形、淋巴管畸形、血管瘤組織中的表達(dá)。結(jié)果表明PDE-5在血管瘤組織中呈陽性表達(dá),在其它脈管畸形組織中無表達(dá)。因此,我們認(rèn)為西地那非是對血管瘤而不是淋巴管畸形起作用。目前很多文獻(xiàn)證實西地那非可增強某些類型的惡性腫瘤化療效果并對血管平滑肌、肺動脈內(nèi)皮細(xì)胞等有抗增殖及促進(jìn)凋亡的作用。因此,我們通過體外實驗進(jìn)一步研究西地那非對血管瘤內(nèi)皮細(xì)胞(HemECs)增殖及凋亡的影響,并對其相關(guān)機制進(jìn)行探討。目的1.檢測PDE-5在血管瘤及各種脈管畸形組織中的表達(dá)。2.研究西地那非對人源性HemECs的增殖和凋亡的影響。3.研究西地那非對HemECs的增殖和凋亡作用與DNA分化抑制因子-1(Id-1)表達(dá)的關(guān)系,探討該藥的作用機制。方法1.收集山東大學(xué)齊魯醫(yī)院病理科2000—2013年血管瘤及脈管畸形組織塊,通過免疫組織化學(xué)的方法分別檢測石蠟包埋的10例淋巴管畸形、8例增殖期血管瘤、2例消退期血管瘤、10例靜脈畸形以及10例動靜脈畸形組織塊中PDE-5的表達(dá)。血管瘤及脈管畸形的診斷是依據(jù)患者病史、體格檢查、MRI表現(xiàn)以及最后的病理結(jié)果確定的。淋巴管內(nèi)皮透明質(zhì)酸受體-1(LYVE-1)、細(xì)胞膜表面分化抗原34(CD 34)和葡萄糖轉(zhuǎn)運蛋白-1(GLUT-1)分別作為淋巴管內(nèi)皮細(xì)胞、血管內(nèi)皮細(xì)胞和血管瘤組織的特異性標(biāo)記物。隨后對PDE-5在血管瘤及各種脈管畸形組織的表達(dá)進(jìn)行了檢測。本研究通過了山東大學(xué)齊魯醫(yī)院醫(yī)院倫理委員會授權(quán),所有患者或監(jiān)護(hù)人均知情同意。2.收集山東大學(xué)齊魯醫(yī)院手術(shù)切除并經(jīng)病理證實為血管瘤組織標(biāo)本,利用組織塊貼壁培養(yǎng)法分離并培養(yǎng)HemECs。通過免疫細(xì)胞化學(xué)法檢測第八因子相關(guān)抗原因子vWF、CD 34和PDE-5在HemECs中的表達(dá)。體外以梯度濃度西地那非(0μM,1 μM,3 μM,5 μM,10 μM 和 15 μM)處理 HemECs 24 h、48 h 和 72 h后,MTT法檢測細(xì)胞的增殖能力。以梯度濃度的西地那非(0,1,5,10,15 μM)處理HemECs,20分鐘后分別加入50ng/mlbFGF、50ng/mlVEGF。繼續(xù)孵箱培育24 h。MTT法檢測西地那非對bFGF及VEGF誘導(dǎo)的HemECs增殖的影響。HemECs分別經(jīng)對照組(0 μM)、5 μM西地那非處理24 h后,采用流式細(xì)胞Annexin-V/PI staining assay 檢測細(xì)胞凋亡率。3.組織塊培養(yǎng)法獲得的HemECs分別經(jīng)0μM(對照組)、5μM(實驗組)西地那非處理24 h后,用TRI法提取細(xì)胞總RNA并逆轉(zhuǎn)錄成Id-1 cDNA,再通過實時熒光定量RFQ-PCR擴增cDNA,利用比較Ct值法(2-△△Ct)計算Id-l基因和內(nèi)參照基因閾值循環(huán)數(shù)差異,檢測兩組HemECs中Id-1基因的相對mRNA表達(dá)量。HemECs分別經(jīng)0 μM(對照組)、5μ(實驗組)西地那非處理24 h后,提取細(xì)胞總蛋白,通過免疫印跡法(western blot)檢測兩組HemECs中Id-1蛋白的表達(dá)水平,人舌鱗癌TCA 8113細(xì)胞系作為Id-1蛋白表達(dá)的陽性對照。結(jié)果1.免疫組織化學(xué)檢測發(fā)現(xiàn)CD34、LYVE-I和GLUT-1分別作為血管內(nèi)皮細(xì)胞、淋巴管畸形組織和血管瘤組織的特異性標(biāo)記物表達(dá)均陽性。PDE-5表達(dá)在血管瘤組織HemECs胞漿內(nèi),但在淋巴管畸形、動靜脈畸形、靜脈畸形組織中均無表達(dá)。2.MTT法檢測發(fā)現(xiàn)在西地那非濃度為5 μM時,24h后與對照組(0μM)相比開始出現(xiàn)顯著差異(t =3.220,P0.01),出現(xiàn)明顯的細(xì)胞抑制現(xiàn)象,且隨時間延長抑制作用逐漸加強。西地那非作用于HemECs 72 h時細(xì)胞的增殖活性與48 h相比無明顯差異(P0.05)。在檢測西地那非對bFGF及VEGF誘導(dǎo)的HemECs增殖的抑制作用時,西地那非濃度為5 μ時,對bFGF及VEGF誘導(dǎo)的HemECs增殖也出現(xiàn)明顯的細(xì)胞抑制現(xiàn)象(P0.05),且隨時間延長抑制作用逐漸加強。然而,當(dāng)西地那非濃度為15 μM時,與濃度為10 μM相比對HemECs的增殖抑制作用無明顯差別(P0.05)。因此,濃度為5 μM和作用時間為24 h分別是西地那非抑制HemECs的最適有效濃度和最適有效作用時間。用5 μM西地那非處理HemECs 24 h后,在光學(xué)顯微鏡下可見到HemECs隨著細(xì)胞間連接的破壞和胞漿內(nèi)不斷增加的顆粒,細(xì)胞形態(tài)發(fā)生了改變。流式細(xì)胞學(xué)分析結(jié)果表明5 μM西地那非處理HemECs 24 h后凋亡率為10.5%,高于對照組(2.53%)。因此,體外實驗中濃度5 μM的西地那非處理24 h后顯著抑制了 HemECs的增殖并促進(jìn)了其凋亡。3.通過實時熒光定量RFQ-PCR方法,根據(jù)2-△△Ct公式,用5μM西地那非處理HemECs 24 h后,細(xì)胞內(nèi)Id-1的mRNA相對表達(dá)量減少了 44.2%,(t = 9.749,df=4,P = 0.00060.01)。根據(jù)Western blot實驗取得的免疫印跡條帶的灰度值比較分析,用5 μM西地那非處理HemECs 24 h后,細(xì)胞內(nèi)Id-1的蛋白表達(dá)也降低。結(jié)論1.血管瘤組織中存在磷酸二酯酶-5。2.西地那非在體外能抑制HemECs增殖和促進(jìn)其凋亡。3.西地那非抑制HemECs增殖和促進(jìn)其凋亡作用可能是通過下調(diào)Id-1基因來實現(xiàn)的。
[Abstract]:The research background of hemangioma (hemangiomas) occurred in vascular benign tumors in infants, the incidence rate of 10 ~ 12%, the vast majority at birth or shortly after birth, most can fade, but there are still not 20% hemangioma disappeared. According to the pathological development process can be divided into proliferating, involuting and complete regression period. Although hemangioma is benign tumor, but occurred in the oral maxillofacial and neck disease, not only affects the face appearance, also may be due to lesions of digestive tract and respiratory tract obstruction, influence of pronunciation, eating, and even lead to local hemorrhage, asphyxia and life-threatening. Therefore the claim of the disease should be performed early treatment treatment of hemangioma. Methods commonly used drugs, laser, surgery, refrigeration and hardening treatment. Freezing, laser hardening treatment and easily lead to hyperplasia or atrophic scars, pigmentation or pigment reduction Back, treatment of hemangioma resection is only applicable to limitations. Drug therapy is an early treatment of hemangioma is safe, effective method. There are many drugs for the treatment of hemangioma, the drugs commonly used at home and abroad include the following categories: 1. beta adrenergic receptor blockers, with propranolol (propranolol); 2. corticosteroids prednisone (prednisolone); the other 3.: interferon alpha (IFN- alpha), imiquimod (Imiquimod), antitumor drug cyclophosphamide (CTX) and vincristine (VCR),.2008, < > in the new England Journal of medicine, Leaute-Labreze C reported the first oral propranolol caused regression of nasopharyngeal hemangioma. In recent years, oral propranolol in the treatment of hemangioma has gradually become the first-line drugs.2012, Swetman reported the first oral sildenafil (sildenafil) treatment of 3 children with lymphatic malformation lesions were significantly. Back, published in the new England Journal of medicine < >, suggesting a new drug Sildenafil can be used as the treatment of lymphatic malformation. But the article only shows children lesion photos and MRI plain film (magnetic resonance imaging, MRI), the lesions were not confirmed by surgery and pathology of lymphatic malformation. According to the MRI, we think this is more in line with the children with hemangioma associated with lymphatic malformation diagnosis, and patients with hemangioma. Sildenafil is a phosphodiesterase -5 (phosphodiesterase isoform-5 PDE-5) inhibitor, so we may infer sildenafil by inhibition of PDE-5 activity of the lesions reduced. Under this inspiration, we study PDE-5 in venous malformation by immunohistochemical method, arteriovenous malformation, lymphatic malformations, expression of vascular tumor tissues. The results showed that PDE-5 was positive in hemangioma The expression of vascular malformations in other tissues without expression. Therefore, we believe that sildenafil is on hemangioma instead of lymphatic malformation effect. At present a lot of literatures demonstrate that sildenafil can enhance chemotherapy effect of certain types of vascular smooth muscle, anti proliferation and promote the apoptosis of pulmonary artery endothelial cells. So, we study the effect of sildenafil on vascular endothelial cells and further in vitro experiments (HemECs) proliferation and apoptosis, and the related mechanisms were discussed. The expression of.2. on proliferation and apoptosis of sildenafil in human HemECs.3. effect of sildenafil on HemECs proliferation and apoptosis and DNA differentiation inhibitory factor -1 1. detection PDE-5 in the form of abnormal tissue vascular hemangioma (Id-1) and the expression of the relationship, to explore the mechanism of action of the drug. Methods 1. collection of Shandong University Qilu medicine Institute of disease science from 2000 to 2013 in hemangioma and vascular malformation tissue were detected in 10 cases of paraffin embedded lymph tube defects by immunohistochemical method, 8 cases of hemangioma, 2 cases of hemangioma, 10 cases of venous malformation and 10 cases of arteriovenous malformation tissue expression of PDE-5 in vascular. Hemangioma and vascular malformation diagnosis is based on patient history, physical examination, MRI and final pathological results determined. Lymphatic endothelial hyaluronan receptor -1 (LYVE-1), cell surface differentiation antigen 34 (CD 34) and glucose transporter -1 (GLUT-1) respectively as lymphatic endothelial cell specific markers. From vascular endothelial cells and tumor tissues. The expression of PDE-5 in hemangioma and vascular malformations tissue were detected. This study through the authorization of Qilu Hospital of Shandong University hospital ethics committee, and all patients or guardians Informed consent was obtained from Qilu Hospital of Shandong University.2. surgery and pathologically confirmed hemangioma tissues by tissue adherent method were isolated and cultured by HemECs. factor related antigen eighth factor immunocytochemical method for detection of vWF expression of CD 34 and PDE-5 in HemECs. In vitro with gradient concentration of sildenafil (0 M, 1 M, 3 M, 5 M, 10 M and 15 M) HemECs 24 h, 48 h and 72 h, the cell proliferation was determined by MTT. The concentrations of sildenafil (0,1,5,10,15 M) HemECs, 20 minutes after 50ng/ mlbFGF were added to 50ng/mlVEGF., continue to affect the hatch box cultivate 24 h.MTT method to detect the effect of sildenafil on the proliferation of HemECs induced by bFGF and VEGF.HemECs respectively by the control group (0 M), 5 M sildenafil treatment after 24 h Annexin-V/PI staining assay by flow cytometry to detect the apoptosis rate of.3. tissue culture Method to obtain HemECs respectively by 0 M (control group), 5 M (experimental group) and sildenafil treatment after 24 h extracted with TRI cell total RNA and reverse transcription into Id-1 cDNA by real-time fluorescent quantitative RFQ-PCR amplification of cDNA, using the Ct value comparison method (2- Delta Ct) gene and Id-l calculation the reference gene threshold cycle number difference, relative to the mRNA detection of Id-1 two in the HemECs group the expression of.HemECs gene respectively by 0 M (control group), 5 (experimental group) and sildenafil treatment after 24 h, the total proteins were extracted, by immunoblotting (Western blot) to detect the expression of Id-1 two in the HemECs group protein, positive control of human tongue squamous cell carcinoma cell line TCA 8113 as the expression of Id-1 protein. Results 1. immunohistochemical detection of chemical found in CD34, LYVE-I and GLUT-1 respectively as vascular endothelial cells, lymphatic malformations and vascular tumor specific marker expression were positive expression of.PDE-5 in blood The tube of HemECs in tumor tissue in the cytoplasm, but in lymphatic malformations, arteriovenous malformation, venous malformation tissues were not found in the.2.MTT method to detect the expression of sildenafil concentration is 5 M, 24h and control group (0 M) appeared significant difference compared (t =3.220, P0.01), apparent cell inhibition, and the longer the time the inhibition effect gradually strengthened. The proliferation activity of sildenafil in HemECs 72 h cells and 48 h showed no significant difference (P0.05). The inhibition induced by bFGF and VEGF in the detection of sildenafil HemECs proliferation, sildenafil concentration is 5, the induction of bFGF and VEGF the proliferation of HemECs cell inhibition phenomenon is obvious (P0.05), and with the prolonging of the inhibition effect gradually strengthened. However, when the concentration of sildenafil is 15 M, and the concentration of 10 M compared to the inhibitory effect of HemECs was no significant difference (P0.05). Therefore, concentrated Of 5 M and reaction time was 24 h sildenafil inhibited HemECs optimal effective concentration and the optimal effective time. With 5 M HemECs 24 h after sildenafil treatment, under the microscope can be seen with the HemECs connection between the cell damage in the cytoplasm and increasing particles changed cell morphology. Flow cytometry analysis showed that 5 M sildenafil treatment HemECs after 24 h apoptosis rate was 10.5%, higher than the control group (2.53%). Therefore, the concentration of the in vitro experiments of 5 M sildenafil treatment after 24 h significantly inhibited the proliferation of HemECs and promote the apoptosis of.3. by real-time fluorescence quantitative RFQ-PCR method. According to the 2- Delta Ct formula, with 5 M HemECs 24 h after sildenafil treatment, intracellular Id-1 mRNA relative expression decreased by 44.2% (t = 9.749, P = df=4, 0.00060.01). According to the immune blot achieved Western blot Experimental Zone Comparative analysis of gray value, with 5 M HemECs 24 h after sildenafil treatment, the expression of Id-1 protein also decreased. Conclusion there are 1. hernangioma phosphodiesterase -5.2. Sildenafil can promote the apoptosis of.3. and inhibit the proliferation of HemECs and sildenafil in inhibiting the proliferation of HemECs cells and promote their apoptosis through down-regulation of Id-1 gene may be realized in in vitro.

【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：R732.2

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