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황갈반(기미)의 발병 메커니즘에 관한 연구 진전

초록

얼굴에 잘 나타나는 황갈반은 만성적인 피부색소 대사장애로 인한 질환으로 얼굴의 미적요소에 영향을 미친다. 본 논문에서는 황갈반의 적극적인 예방과 치료에 관한 이론적인 근거를 제공하기 위하여 황갈반의 발병 메커니즘에 대해 조사 및 연구하였다. 황갈반의 최근 몇 년간 연구결과에 의하면, 황갈반의 발병 원인은 내인성 요인과 외인성 요인으로 나누어 설명할 수 있다. 내인성 요인은 주로 유전적 요인, 내분비, 지질 과산화, 혈관내피기능, 혈액 유변성, 미량원소 등이 있으며, 외인성 요인으로는 주로 자외선, 피부에 존재하는 미생물환경, 부적절한 화장품 사용 등이 있다. 황갈반의 발생원인은 내인성 요인이 주된 작용을 하고 외인성 요인이 보조 역할을 함으로써 나타난다. 황갈반의 발병 메커니즘을 보다 깊고 전면적으로 이해하기 위해서는 황갈반에 대한 적극적이고 효과적인 예방치료를 진행하여야 한다고 사료된다.

Abstract

Melanosis is a common clinical pigmentation disorder which affects patients’ facial aesthetics. This review describes the recent progress on mechanism of melanosis in order to provide the evidence for clinic therapy of melanosis. By investigating the recent progress of melanosis, we summarize the mechanism of melanosis from two aspects: endogenous and exogenous factors. Endogenous factors include genetic factors, endocrine, lipid peroxidation, endothelial function, blood rheology, trace elements and so on. Exogenous factors include ultraviolet (UV), skin microecology, improper use of cosmetics and so on. The pathogenesis of chloasma is given priority to endogenous factors. In depth and comprehensive understanding of the pathogenesis of chloasma contribute to the more effective prevention and treatment of chloasma.

中文摘要

黄褐斑是一种临床常见的面部慢性皮肤色素代谢障碍性疾病,可影响患者的面部美观。为给黄褐斑的积极预防与治疗提供理论依据,本文对黄褐斑的形成机理进行了分析。调研了黄褐斑近年的研究进展,从内源性因素和外源性因素两个角度对黄褐斑的病因病机进行了归纳总结。内源性因素主要与遗传因素、内分泌、脂质过氧化、血管内皮功能、血液流变性、微量元素等有关。外源性因素主要与紫外线、皮肤微生态、使用化妆品不当等有关。黄褐斑的发病以内源性因素为主、外源性因素为辅。深入、全面地了解黄褐斑的发病机理可以对黄褐斑进行更积极有效的防治。

Introduction

黄褐斑,中医又称之为“肝斑”、“薰黑斑”、“蝴蝶斑”,是一种常见的获得性色素沉着皮肤病。黄褐斑呈浅褐色或深褐色的色素斑点,一般对称地分布在眼周围附近、额部、颧颊部、鼻旁和口唇周围,边界清楚,未凸出皮肤,无皮屑脱落,日晒或疲劳会加深其色素,多数患者无任何自觉症状,是临床上常见而又难以治愈的皮肤病之一。其组织学特点主要是表皮黑色素细胞胞体较大,树突明显,黑素和黑素小体明显增加。角质形成细胞的细胞核尺寸变大,形状不规则,染色质不均一(Brianezi et al., 2015)。黄褐斑发病机理复杂,发病机理尚不十分清楚。现代医学认为黄褐斑与下列因素有关:内分泌失调、口服避孕药、遗传因素、紫外线照射、情绪波动等(Zou & Fu, 2010),本文对黄褐斑发病机理的最新研究进展予以综述,以期为黄褐斑的积极预防与治疗提供理论依据。

Endogenous factors of chloasma pathogenesis

1. Genetic factors

黄褐斑被认为是一种多基因遗传的疾病(Yuan & Liu, 2013)。30%–47%的黄褐斑患者有家族史,尤其是男性黄褐斑患者多与遗传有关(Javaheri et al., 2001)。黄褐斑的发病几率在不同人种之间有明显的差异,白色人种的发病率明显低于黄色人种和黑色人种(Tang et al., 2013)。 Kang等人(Kang et al., 2011)对7个白人,12个韩国人的黄褐斑皮损活组织切片进行检测,结果显示有279种基因发生变化。Kim等人(Kim et al., 2010)发现黄褐斑患者中H19基因的下调会减少miR-675的表达。miR-675的下调可直接促进黑素细胞(melanocyte cell, MC)中小眼畸形转录因子(microphthalmia-associated transcription factor, MITF)的表达(Kim et al., 2014);或是通过间接增加成纤维细胞和角质形成细胞(keratinocyte cell, KC)中的钙粘着蛋白CDH11的表达,激活相邻黑素细胞中经典Wnt和细胞凋亡信号调节激酶(apoptosis signal–regulating kinase, Akt)信号通路,使MITF的转录活性增加,酪氨酸酶及酪氨酸酶相关蛋白1、2生成增多(Lee, 2015)。酪氨酸酶是黑素合成过程中的限速酶,该酶在黑素细胞中将多巴胺氧化成多巴醌,再氧化成一系列中间产物最后合成黑色素,其活性与黄褐斑的形成正相关(Zhang & Liang, 2010)。

2. Endocrine

女性黄褐斑患者的发病与内分泌功能紊乱、下丘脑-垂体-卵巢轴失衡有显著关系。妇女妊娠期、月经周期紊乱、性生活不协调及精神压抑、口服避孕药等易造成体内性激素较大变化。雌激素会与黑素细胞中雌激素受体结合,从而激活蛋白激酶A(protein kinase A , PKA)通路(Ohata et al., 2008), 启动MITF的转录活性,使酪氨酸酶的表达增加(Jian et al., 2011)。雌激素还可以通过解除谷胱甘肽或巯基(-SH)对酪氨酸酶的抑制作用, 使黑色素形成增加。孕激素能促进黑色素颗粒的转运(Zhang et al., 2015)。促肾上腺皮质激素(adrenocorticotropic hormone, ACTH)、肾上腺皮质激素及垂体间叶分泌的促黑色素激素(melanocyte-stimulating hormone, MSH),可通过提高血清铜离子浓度使酪氨酸酶活性增强。同时黑素细胞内存在高密度的黑皮素受体蛋白(melanocortin 1 receptor, MC1R),MC1R与α-MSH 结合后,使酪氨酸酶及酪氨酸酶相关蛋白1、2生成增多(Im et al ., 2002)。四碘甲腺原氨酸(thyroxine, T4)
是氧化过程刺激剂,可促进酪氨酸和黑素的氧化过程,并使表皮中的巯基(-SH)减少,促进黑素形成(Lin et al., 2009)。

3. Lipid peroxidation

人体内有许多抗氧化酶体系,如超氧化物歧化酶(superoxide dismutase, SOD)、过氧化氢酶(catalase, CAT)、 谷胱甘肽过氧化酶(glutathione peroxidase, GSH-Px)、谷胱甘肽(glutathione, GSH)等,当脂质过氧化物(lipid peroxide, LPO)增强或自由基水平增高时,在人体正常的自我调控保护机制下,人体内的氧化/抗氧化始终处于动态平衡。黄褐斑患者这一调节系统可能存在某些障碍,致使抗氧化酶系统的活性不能随LPO增多而增强,导致 LPO的蓄积(Bai & Tian, 2005)。LPO作为启动因素使黑素细胞内酪氨酸氧化系列反应加快,黑色素的生成量大量增加。LPO极不稳定,分解产生具有强氧化作用的丙二醛(malondialdehyde, MDA), 使蛋白质分子发生分子内和分子间交联,形成荧光发色团(fluorescent chromophore)。同时,LPO还能对蛋白质分子产生抽氢加成作用,依次对蛋白质不断加成,促进蛋白质的化学反应(Zhou & Chen, 1984)。谢明峰等人用珍珠四白膏治疗肝郁型黄褐斑患者,发现黄褐斑患者治疗后,各组血清 MDA水平均较治疗前显著下降,血清SOD水平均较治疗前显著上升,有显著性差异(p<.01, p<.05)(Xie & Liu, 2011)。证实自由基确实与黄褐斑有关,且可通过提高局部皮肤及血清的SOD活性,清除多余氧自由基,从而抑制黑素形成,消除黄褐斑。

4. Endothelial function

大量研究表明,血管内皮不仅是一层屏障,而且是一个具有许多生理功能的活性器官。内皮细胞衍生的血管收缩因子主要有内皮素(endothelin, ET)、血管舒张因子主要有一氧化氮(nitric oxide, NO),生理状态下,ET与NO相互作用与调节,处于动态平衡之中。在皮肤组织中,内皮素系统主要作为角质形成细胞和黑素细胞之间相互作用的桥梁,参与黑素细胞的发育和黑素合成等过程。人皮肤组织中表达的内皮素主要是 ET-1(Leslie et al., 2004),ET-1通过与内皮素受体(endothelin receptor type B, ETRB)结合后激活黑素细胞膜上的 G 蛋白并启动细胞内 G 蛋白偶联信号转导通路,启动下游二脂酰甘油(diacylglycerol, DAG)/ PKC 途径或环磷酸腺苷(cyclic adenosine monophosphate, cAMP)/ PKA途径, 促进黑素细胞增殖并提高酪氨酸酶活性,从而使黑素的合成增加。ET-1可促进培养的黑素细胞树突数量增加,延长树突长度,且呈剂量依赖性(Liu & Chen, 2012)。NO是黑素合成的强效激活因子,可以攻击细胞膜上的脂肪酸产生过氧化物加速机体衰老,同时 NO亦可引起黑素合成增多(Chen et al., 2014)。林新瑜等人(Lin et al., 2007)检测了39 例黄褐斑患者血中NO及ET-1的水平,结果显示黄褐斑患者血清NO及血浆ET-1水平高于健康组(p<.05)。通过降低黄褐斑患者体内NO、ET-1含量,可以达到改善黄褐斑的目的(Wang, 2013)。

5. Blood rheology

现代医学研究发现,黄褐斑患者存在着血液动力学指标异常。血液黏度增加会使血液瘀滞从而导致黄褐斑的发生(Yuan & Liu, 2013)。人面部毛细血管走形丰富,细小血管众多,极易发生血液循环障碍,导致供血供氧不足,皮肤末梢代谢产生的有害物质不能很好地转移,SOD等氧自由基清除剂无法随血液循环到达而产生黄褐斑(Zhang et al., 2015)。Kim 等(Kim et al., 2007)认为与周围正常皮肤相比,黄褐斑皮损区血管内皮生长因子(vascular endothelial growth factor, VEGF)的表达明显增高,真皮层血管密度及管腔直径较正常皮肤明显增加。在大量的临床病例中,相当一部分黄褐斑的患者同时伴有局部毛细血管的扩张,而在治疗毛细血管扩张的同时,附近的色素也有所减淡(He, 2012)。

6. Trace elements

人体内有40多种微量元素,虽然含量微小却能产生重要的生理作用。研究发现,体内微量元素水平的高低与黄褐斑的发生存在着一定关系。酪氨酸酶是铜结合蛋白,在体内催化酪氨酸形成黑色素的能力与活性中心铜离子的数量成正比,血清铜水平的升高,会使皮肤酪氨酸酶活性增强, 色素沉着增加而发生黄褐斑(Lin et al., 2009)。血清铁增多可与表皮激素结合,使其对酪氨酸酶的抑制解除,黑素形成增加(Yuan & Liu, 2013)。锌作为SOD的辅酶可催化超氧离子发生歧化反应。锌缺乏可以使总SOD活性下降,使酪氨酸酶活性增强,色素增加(Ni et al., 2007)。

Exogenous factors of chloasma pathogenesis

1. Ultraviolet

紫外线照射是引起的黄褐斑发生的主要外源性因素(Passeron, 2013)。紫外线能直接刺激黑素细胞增殖,中波紫外线使黑素细胞对MSH的反应性增加(Zhang et al ., 2015)。紫外线能刺激角质形成细胞释放NO,使黑素合成增多(Lee, 2015)。紫外线也会刺激成纤维细胞释放干细胞因子(stem cell factor, SCF),SCF通过其受体c-KIT介导的信号转导通路刺激黑素细胞,调控黑素细胞的增值和分化(Shin et al., 2012)。一定剂量的紫外线照射还能使皮肤中的-SH氧化,维生素D3合成增多, 使黑色素细胞中酪氨酸酶的含量增加,引起皮肤色素沉着。夏季紫外线照射强烈,冬季转弱,故黄褐斑患者多呈夏重冬轻的变化(Yuan & Liu, 2013)。Kang的组织学研究证实,经常照射太阳光的黄褐斑患者,皮损区色素沉着重于正常皮肤。因此,防晒是预防和减轻黄褐斑的最重要措施之一(Kang et al., 2002)。

2. Skin microecology

正常情况下皮肤表面有大量微生物存在,根据其存在情况不同分为: 常驻菌如痤疮丙酸杆菌、表皮葡萄球菌;暂驻菌如棒杆菌、需氧革兰氏阴性杆菌及产色素的微球菌(Zou & Fu, 2010)。各菌群之间存在着共生或拮抗作用,共同构成了皮肤局部的微生态环境。如果皮肤微生态失衡,就会造成皮肤的病理损害。黄褐斑患者皮损区常驻菌痤疮丙酸杆菌数量明显低于正常皮肤,使皮肤对外来菌的阻抗力下降、菌群之间的竞争性抑制作用减弱。产色素微球菌大量繁殖,并与表皮黏附、结合,产生的色素超过皮肤局部的自净能力,被皮肤吸收并沉积于表皮内(Bai et al., 2006)。调整皮肤的正常菌群,维护皮肤菌群生态平衡, 增强皮肤的定植抗力和皮肤免疫及代谢功能,是防治皮肤黄褐斑的重要手段之一。

3. Improper use of cosmetics

研究发现劣质化妆品中所含的水杨酸、氧化亚油酸、枸橼酸、金属、防腐剂和香料等成分浸入局部皮肤后,会引发皮肤炎症反应,破坏基底细胞层,导致色素失禁和/或巨噬细胞吞噬基底层KC和MC,使黑素在真皮浅层停留时间延长,加速黄褐斑的产生 (Cui & Cen, 2004)。长期浓妆艳抹,使用过期劣质化妆品以及汞剂等重金属超标化妆品等会导致或诱发黄褐斑并使原色斑加深(Yuan & Liu, 2013)。

Conclusion

黄褐斑的发病以内源性因素为主。作为一种影响患者容颜美观的皮肤疾病,黄褐斑给患者生活带来很大困扰,且其发病机理复杂,目前仍是治疗难题。治疗原则主要包括抑制酪氨酸酶活性、促进酪氨酸酶降解以及抑制黑素细胞活性或合成、破坏和清除黑色素小体等。科学的发展、新技术的应用虽然为黄褐斑提供了更多的治疗途径,但目前所有治疗措施均不能阻止黄褐斑的复发(Kang & Ortonne, 2010),且仍然缺乏规范化的治疗方法及长期随访调查。深入了解其发病机制从而为治疗黄褐斑提供理论依据,寻找有效无副作用的治疗手段都是亟待解决的。

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