普萘洛尔及其对映体对婴幼儿血管瘤周细胞影响的研究

发布时间：2018-05-30 14:52

本文选题：婴幼儿血管瘤 + 周细胞　；参考：《吉林大学》2015年博士论文

【摘要】：婴幼儿血管瘤(infantile hemangiomas,IH)是婴幼儿最常见的良性肿瘤,其发病率呈现了逐年增高趋势。该病大多数位于头颈部,不仅影响美观,也可能压迫周围器官影响生理功能。虽然是常见病,但由于发病机制不清、疗效不确切,巨大的IH已成为外科领域的疑难疾病。普萘洛尔(propranolol,PPL)一直以来在临床用于治疗心肌梗死、冠心病等。自从2008年法国医生首次发现其在治疗IH有很好的效果后,该药迅速得到人们的关注。目前该药已成为治疗IH的一线用药,但是其治疗机制一直不十分清楚。科研人员对此机制的研究主要集中在PPL对血管瘤内皮细胞的作用上,而对婴幼儿血管瘤周细胞的作用尚未引起关注。而周细胞包围微血管内皮细胞,二者共同组成了血管／组织间隙屏障。周细胞具有维持微血管壁张力、抑制内皮细胞增殖,调控局部微血管的通透性、微血流及血管新生,以及维持微血管稳定性等功能,其对内环境的稳定的维持不可或缺。此外,在临床应用的PPL本身为外消旋体,即是R-PPL与S-PPL两种手性对映体1：1混合物。而大量的药理学研究显示两种对映体通常表现为不同的药理特性,应该作为两种药物对待。那么问题产生了：在PPL治疗IH过程中,周细胞是否参与其中?此过程中周细胞发挥了什么样的作用?PPL的不同对映体是否会对周细胞产生不同的影响?是否有必要将PPL的不同对映体在将来的作用机制的研究中分别探讨?这些问题已经成为了亟待解决的研究课题。本课题采用酶解筛分法从婴幼儿血管瘤活体组织标本中分离获得周细胞,对其进行形态学观察、生长曲线测定,周细胞标志物鉴定。并以该细胞为实验平台,研究普萘洛尔对人婴幼儿血管瘤周细胞增殖能力、细胞收缩和VEGF/bFGF合成的影响。探讨了普萘洛尔通过抑制周细胞增殖、诱导周细胞收缩及抑制VEGF/bFGF合成及分泌进而达到治疗IH的可能性。此外,还研究了普萘洛尔不同对映体对周细胞总蛋白合成情况的影响,进而阐明普萘洛尔对映体在治疗IH的机制中作为单独药物分别研究的必要性。综上所述,该课题的成功对普萘洛尔对婴幼儿血管瘤的治疗机制提出了新的观点,即周细胞是普萘洛尔治疗IH的重要环节；也为把普萘洛尔对映体在IH治疗机制领域分别进行研究提供理论基础。
[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.
【学位授予单位】：吉林大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R732.2

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