本文選題：嬰幼兒血管瘤 + 周細胞�。� 參考：《吉林大學》2015年博士論文

【摘要】：嬰幼兒血管瘤(infantile hemangiomas,IH)是嬰幼兒最常見的良性腫瘤,其發(fā)病率呈現(xiàn)了逐年增高趨勢。該病大多數(shù)位于頭頸部,不僅影響美觀,也可能壓迫周圍器官影響生理功能。雖然是常見病,但由于發(fā)病機制不清、療效不確切,巨大的IH已成為外科領(lǐng)域的疑難疾病。普萘洛爾(propranolol,PPL)一直以來在臨床用于治療心肌梗死、冠心病等。自從2008年法國醫(yī)生首次發(fā)現(xiàn)其在治療IH有很好的效果后,該藥迅速得到人們的關(guān)注。目前該藥已成為治療IH的一線用藥,但是其治療機制一直不十分清楚。科研人員對此機制的研究主要集中在PPL對血管瘤內(nèi)皮細胞的作用上,而對嬰幼兒血管瘤周細胞的作用尚未引起關(guān)注。而周細胞包圍微血管內(nèi)皮細胞,二者共同組成了血管／組織間隙屏障。周細胞具有維持微血管壁張力、抑制內(nèi)皮細胞增殖,調(diào)控局部微血管的通透性、微血流及血管新生,以及維持微血管穩(wěn)定性等功能,其對內(nèi)環(huán)境的穩(wěn)定的維持不可或缺。此外,在臨床應(yīng)用的PPL本身為外消旋體,即是R-PPL與S-PPL兩種手性對映體1：1混合物。而大量的藥理學研究顯示兩種對映體通常表現(xiàn)為不同的藥理特性,應(yīng)該作為兩種藥物對待。那么問題產(chǎn)生了：在PPL治療IH過程中,周細胞是否參與其中?此過程中周細胞發(fā)揮了什么樣的作用?PPL的不同對映體是否會對周細胞產(chǎn)生不同的影響?是否有必要將PPL的不同對映體在將來的作用機制的研究中分別探討?這些問題已經(jīng)成為了亟待解決的研究課題。 本課題采用酶解篩分法從嬰幼兒血管瘤活體組織標本中分離獲得周細胞,對其進行形態(tài)學觀察、生長曲線測定,周細胞標志物鑒定。并以該細胞為實驗平臺,研究普萘洛爾對人嬰幼兒血管瘤周細胞增殖能力、細胞收縮和VEGF/bFGF合成的影響。探討了普萘洛爾通過抑制周細胞增殖、誘導周細胞收縮及抑制VEGF/bFGF合成及分泌進而達到治療IH的可能性。此外,還研究了普萘洛爾不同對映體對周細胞總蛋白合成情況的影響,進而闡明普萘洛爾對映體在治療IH的機制中作為單獨藥物分別研究的必要性。 綜上所述,該課題的成功對普萘洛爾對嬰幼兒血管瘤的治療機制提出了新的觀點,即周細胞是普萘洛爾治療IH的重要環(huán)節(jié)；也為把普萘洛爾對映體在IH治療機制領(lǐng)域分別進行研究提供理論基礎(chǔ)。
[Abstract]:Infantile hemangiomassus (IH) is the most common benign tumor in infants and children, and its incidence is increasing year by year. Most of the disease is located in the head and neck, which not only affects the beauty, but also affects the physiological function of the surrounding organs. Although it is a common disease, because the pathogenesis is unclear and the curative effect is not accurate, the giant IH has become a difficult disease in surgical field. Propranolol (PPL) has been used in the treatment of myocardial infarction, coronary heart disease and so on. Since French doctors first found it effective in treating IH in 2008, the drug has gained rapid attention. The drug has become a first-line treatment of IH, but its mechanism has not been very clear. The role of PPL in the endothelial cells of hemangioma is the focus of the researchers, but the role of PPL on the pericyte of hemangioma in infants has not been paid attention to. The pericytes surrounded the microvascular endothelial cells, which together formed the vascular / tissue gap barrier. Pericytes have the functions of maintaining microvascular wall tension, inhibiting endothelial cell proliferation, regulating the permeability of local microvessels, microblood flow and angiogenesis, and maintaining microvascular stability, which is indispensable to the stability of the internal environment. In addition, the clinical application of PPL itself is racemic, that is, R-PPL and S-PPL two chiral enantiomers 1:1 mixture. A large number of pharmacological studies have shown that the two enantiomers usually exhibit different pharmacological properties and should be treated as two drugs. So the question arises: are the pericytes involved in the treatment of IH by PPL? What role does pericyte play in this process? do different enantiomers of PPL have different effects on pericytes? Is it necessary to explore the different enantiomers of PPL in future studies? These problems have become an urgent research topic. Pericytes were isolated from the living tissues of hemangioma of infants by enzymolysis and sieving method. The pericytes were observed morphologically, the growth curve was determined and the markers of pericytes were identified. The effects of propranolol on proliferation, cell contraction and VEGF/bFGF synthesis of human infantile hemangioma pericytes were studied. The possibility of propranolol in treating IH by inhibiting the proliferation of pericytes, inducing the contraction of pericytes and inhibiting the synthesis and secretion of VEGF/bFGF was discussed. In addition, the effects of different enantiomers of propranolol on the synthesis of total proteins in pericytes were studied, and the necessity of studying propranolol enantiomers as separate drugs in the treatment of IH was clarified. In conclusion, the success of this project has put forward a new viewpoint on the mechanism of propranolol in the treatment of infantile hemangioma, that is, pericyte is an important part of propranolol in the treatment of IH. It also provides a theoretical basis for the study of propranolol enantiomers in the treatment mechanism of IH.
【學位授予單位】：吉林大學
【學位級別】：博士
【學位授予年份】：2015
【分類號】：R732.2

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