医学专题—皮肤光老化及其防治20282.docx

皮肤光老化及其防治吴景东 周鸿波辽宁中医学院 110023皮老化是机体衰老的一部分，机体的衰老在皮肤上表现最清楚。皮肤老化分为有遗传因素及不可抗力因素（如重力，机体内分泌及免疫功能随机体衰老的改变）引起的固有老化又称自然老化或内源性老化；及有环境因素如紫外线，吸烟，风吹，接触化学物质引起的外源性老化，由于日光中紫外线长期反复照射是环境中影响皮肤老化的最重要因素，故外源性老化又指光老化。1 紫外线与皮肤大量研究表明日光中的紫外线（UVR）与皮肤老化有着密切的关系，是“光老化”中的最重要因素。根据UVR的波长和不同的生物学作用，分成三段：长波紫外线（UVA）波长320nm400n；中波紫外线UVB波长280nm320nm;短波紫外线UVC波180nm280nm。波长短于160nm的紫外线被空气完全吸收,天然环境中几乎不存在。在自然界中，UVR约占太阳光、的13%,到达地面时，大部分UVB和几乎全部的UVC被大气平留层的臭氧层所吸收，因此，自然界的UVA约占97%UVB只占3%。对于地区上的生物来说，主要作用的是UVA和少量UVB。UVB照射皮肤可达表皮基地层，它可产生红斑效应，DNA损伤甚至诱发皮肤癌,UVA尽管能量底穿透力较强，可达真皮深部，UVA UVB在皮肤老化中起着重要作用。先进认为UVA对皮肤DNA的损伤能力是UVB的30倍，且由于UVA比UVB更多，更容易达到真皮层，UVA是导致皮肤结缔组织重要损伤的主要因素。.2 光老化的临床表现多表现为暴露皮肤松弛，粗深皱皮，结节皮革样外观，色素斑增多毛细血管扩张，原有几何外观明显改变或消失，肤色呈灰黄色，可发生各种良性，癌前期或恶性肿瘤。3 光老化的组织形态学在组织形态学上，光损伤的表皮早期反映是过度增殖样修复，表皮增厚，细胞异质性增强角质形成细胞急性消失晚期表现为表皮急性畏缩，照射部位皮肤黑素细胞增多，色素分布不均，郎葛罕细胞数量减少50%使得抗原体提升及加工能力下降，免疫功能受到限制，可使静止的肿瘤细胞逃避或超越机体的防御能力引起皮肤癌或癌性改变。还有研究表明，光老化部位皮肤电镜下可见葛罕细胞中birbeckds颗粒(郎葛罕细胞中的特殊细胞)明显少于自然老化的皮肤光老化皮肤真皮改变明显。胶原减少，增粗，可溶性下降。弹力纤维增粗，卷曲，变性，绛解为颗粒或不定形团块，氨基多糖的结构种类均发生改变，功能异常，水合能力下降，过多的日晒使真皮附属器也有改变，小血管减少，血管壁变薄，汗腺数量减少，分泌汗腺能力下降，皮脂腺增生，但总皮脂分泌量减少。上述真皮结构的改变引发光暴露部位皮肤干燥、皱纹较粗、较深、松弛及皮革样变。4 光老化的发生机制4.1光老化与非酶糖基化反应：糖基化终末产物（AGEs）在体内积累，使相邻的大分子交联，尤其是引起胶原分子间交联。不但降低了结缔组织的通透性，使养料及废物的扩散性能减弱，组织硬度增加，而且难以被胶原酶水解，从而造成皮肤弹性下降，皱纹不易平复而不断加深。Wondrak等通过体外实验验证了，在UVA引起的光老化皮肤过氧化反应中，非酶糖基化蛋白质是体内皮肤细胞紫外线过氧化损伤的光感物这一假说。 4.2光化与皮肤免疫系统，紫外线照射通过多种途径引起免疫抑制造成皮肤感染性疾病恶化、皮肤衰老，甚至皮肤癌。UV抑制抗原的表达，刺激有免疫抑制作用的细胞因子的释放并引起有抑制表型的淋巴细胞产生。在光老化皮肤中，表皮郎格罕细胞的特征性改变使细胞数量减少、形态萎缩、缺乏树突形成和缺少Birbeck颗粒。 4.3 光老化与自由基学说：1956年，Harman提出了衰老的自由基学说。自由基具有极强的氧化能力，可使生物膜中不饱和脂类发生过氧化，形成过氧化脂质，其中产物丙二醛（MDA）是强胶联剂。与蛋白质、核酸或脂类结成难溶性物质使生物膜硬化导致通透性降低，影响细胞物质交换，继而使之破裂死亡。自由基可改变胶原分子，使其易受酶的作用，使透明脂酸解聚，减少蛋白聚糖合成，降解基底膜等。UV的照射产生的自由基对机体内各种大分子都有损伤作用。它们可引起皮肤细胞过氧化，产生的自由基增多，并在皮肤中产生过氧化脂质，与皮肤中的胶原蛋白作用使皮肤角质化过度，使皮肤变的粗糙，松弛，出现皱纹等老化现象。但健康机体同时还存在着强大的防护机制对抗自由基的损害。随年龄增长及各种外界环境的刺激，尤其是日光中的紫外线作用的损害，使体内抗氧化酶类减少。防护功能减退或发生障碍，自由基累积性增加，造成体内各种大分子损伤，导致机体、皮肤的病变和衰老。 4.4 线粒体突变学说：线粒体DNA（mtDNA）是哺乳动物细胞内唯一的核外遗传物质，由于缺乏组蛋白保护及相应的修复系统，易受外界因素诱发突变并累积。线粒体DNA突变在人类衰老及许多退行性疾病中的作用已被广泛证实，线粒体DNA突变及累积被认为是人类皮肤老化尤其是皮肤光老化的重要因素。甚至有研究表明，氧自由基对生物膜及mtDNA的损害，使DNA的损害，使DNA突变和破裂，从而导致线粒体结构的改变和功能的退化，最终影响ATP的生成，能量供应不足而使机体代谢能力下降，发生一系列衰老变化。 4.5 细胞凋亡与皮肤光老化：细胞凋亡时最突出的特征是细胞DNA的有控裂解。有许多研究资料显示这种有控裂程序的启动与“细胞凋亡相关基因”有关研究发现bcl-2多位于细胞内氧自由基产生较多的位置和线粒体、内质网和核膜等，这与细胞的抗氧化自我保护不无关系。已经发现bcl-2基因是细胞凋亡研究中最受重视的癌基因之一，它不同于其他癌基因，是延长细胞的生命期限，通过阻断细胞凋亡信号传递系统的最后的共同通道抑制细胞凋亡从而促进细胞存活，是一种重要的细胞生存基因。Bax与bcl-2有高度的同源性，Bax过表达可以拮抗bcl-2的促进细胞生存的代表，二者表达水平之间的平衡结果，决定了细胞生存死亡。机体受到过量的紫外线的照射不仅是光老化的直接原因，也可使体内的酶性的抗脂质过氧化机制遭到破坏，进一步导致和加剧光老化的进展。皮肤细胞在接触到过量的紫外线后形成的所谓“晒伤细胞”就是凋亡的角质形成细胞。其中活性氧、脂质过氧化和原癌基因等的表达与调控起到非常重要的作用。4.6光老化的其它学说：基质合成与降解等。5 光老化治疗的方法 光老化的最好治疗方法是预防，即应该避免过度的日晒。我国人群的皮肤特点是易晒黑不易晒伤，因此对我们而言，防止紫外线危害很重要的防治UVA的危害。儿童期就应该开始重视避免过度的日光暴晒。最有效的方法就是适当的穿着、戴帽、打伞，并正规的使用广谱防晒剂。主要分为两大类一是非手术疗法：包括药物疗法、化学剥脱术、微波疗法、激光疗法等。一是手术疗法：包括擦皮术、皮下填充术、面部整形术等（后两者主要与皮肤自然老化的治疗）。5.1抗氧化剂：抗氧化剂可以通过抑制紫外线所致DNA损伤，达到防止皮肤光老化的目的。主要的抗氧化剂为：谷胱甘肽，B-胡萝卜素，过氧化氢酶，SOD，其中以B-胡萝卜素和SOD的作用要显著。此外，还有一些抗氧化剂如三羟基苯乙烯多酚、生姜提取物、黄芩甘、黄氏提取物、芦荟等均可抗皮肤光老化。5.2内用防光剂：营养缺乏时易发生皮肤损伤，而补充维生素、类胡萝卜素和不饱和脂肪酸等营养素具有保护皮肤少受紫外线的作用。防晒剂5.3外用防光剂：紫外线吸收剂，以及使紫外线射的散射剂，或散射作用和吸收作用相结合的方法。紫外线散射剂主要是利用某些无机物质对紫外线的散射或减少紫外线对皮肤的侵害。如高岭土、氧化锌、滑石粉、氧化钛及新型有机粉等。氧化钛及新型有机粉等。他们主要是在皮肤表面形成阻挡层，以防紫外线直接照射到皮肤上，但这种物质具有用量大，防晒效果差等缺点，过多使用易阻塞毛孔，造成皮肤的新疾病等不良后果。目前所说的防晒剂是指对紫外线具有吸收作用的紫外光吸收剂。它们的分子从紫外线中吸收的光能与引起分子“光化学激发”所需要的能量相等，这样就可以把光能转化成热能或无害的可见光放射出来，从而有效地防止紫外线对皮肤的晒黑和晒伤作用。5.4 化学剥脱术：化学剥脱也叫化学剥蚀，是将具有剥脱作用的化学涂剂于治疗区域，使之立即发生角质层的的分离和蛋白凝固，而使表皮和真皮乳头不同程度的坏死而引起剥脱。基底细胞层和真皮网状层以上受损，可通过上皮细胞的再生而自然愈合。皮肤剥脱术就是运用这一原理，除去病变皮肤的表层，包括皮肤癌前病变，软化痤疮瘢痕。控制痤疮，促进新生的健康上皮覆盖病变区，同时刺激皮肤弹力纤维收缩，使皮肤收紧，促进表浅皱纹消失。目前人们经常采用的化学剥脱剂按照剥脱创伤的程度分为3类，即表浅性、中度和深度。5.5 微波疗法：原理是不同波长的微波作用与皮肤和皮下层次，可促进恢复皮弹性活力，刺激胶原纤维增生修复，此外，还可通过电离渗透作用，促进皮肤吸收水分营养，促进腺体活动，微循环和新陈代谢。5.6 其他疗法：激光疗法、擦皮术等。参考文献1. Gichrest BA. A review of skin ageing and its medical therapy J .Br J Deramatol, 1996:13(6):867-8752. Castanet J, Ortonne JP. Pigmentary changes in aged and photoaged skin J.Arch Dermatol,1997:133(10):1296-12993. Laker RM,Gerbreick GF, Veres d,et alCumulative effects from repeated exposures tosuberythe mal does for UVB and UVA in hu man skinJ.J Am acad dermatol , 1995,32:53-62.4. wondrak GT et,al. Photosensitized growth inhibition of cultured human skincells: mechanism and suppression of oxidative syress from solar irradiation of glycated proteins.J Invest Dermatol 2002 Aug;119(2):489-985. Schwarz T.Photoinmiunosuppression.Photodermatal Photoinhunol Photomed 2002Jun;18(3):141-56. GreweM.Chronological ageing and Photoageing of dendritic cells. Clin Exp Dermatol 2001Oct;26(7):608-127. 刘承煌。皮肤病理生理学M.北京：中国医药科技出版社，1991.37-338. Miquel J. Can Antioxidant drite supplemention protect against age-related mitochondrialdaamage?J. Ann N Y Acad Sci,2002,959:508.9. Fryer M. Evidence for the photoprotect ive effects of Vitamin E J. Photochem Photobiol,1993,58:304.10. 刘仲荣 等.线粒体DNA突变与皮肤老化.国外医学皮肤性病学分册，2003： 29（3）：173-17611. Brirch-Machin MA et al. J Invest Dermatol,1998:110(2):149-15212. 曾昭惠 等.自由基氧化致线粒体DNA损伤与细胞凋亡.国外医学临床生物与检验学分册，1999：20. （4）：167-168皮肤光老化及其防治一文，对皮肤光老化的发病机理，从生理、生化、组织学与胚胎学等方面，进行了详尽专业科学的陈述，参考文献、资料真实可靠，具有很强的专业性，对皮肤光老化的治疗方法的阐述也十分全面、可行、收效良好。 The Aging of the Skin and its Prevention and Cure Wu Jingdong, ZhouHongbo Liaoning College of Traditional Chinese Medicine 110023 The aging of the skin is a part of organism senile and the senile of the organism appears most clearly on the skin. The aging of the skin can be divided in two categories , one is intrinsic aging also called natural aging or endogenous aging caused by heredity factor and the factor that can not be avoid ( such as gravity ,endocrine of the organism and immunity function change with Organism senile ) . The other is exogenous aging caused environment factor such as ultraviolet ray, smoking, wind blowing, chemical substance contacting. Because the long-term and repeat shinning of ultraviolet ray in sunlight is the most important factor that affects the aging of the skin, so exogenous aging is also called sunlight aging.1. Ultraviolet Ray ad Skin: Lots of research have made clearly that the ultraviolet ray (UVR) in light has close relationship with aging of skin, which is the most important element in “light aging”. According the length of UVR and different biological function, It can be divided into three wave bands， they are long wave ultraviolet ray ( UVA ) which wavelength is 320nm400mn ,medium wave ultraviolet ray (UVA ) which wavelength is 280nm320nm and short wave ultraviolet ray (UVC ) which wavelength is 180nm28nm.The ultraviolet ray whose wavelength is shorter than 160nm will be adsorbed by air completely, which almost cant be found in natural environment. In natural environment, UVR takes up about 13% of the light .When reaching the earth, most of the UVR and almost all the UVC is absorbed by O3. In the stratosphere of the air, so, there is about 97% UVA, while there is only 3% UVB in the nature .As for the creatures on the earth, which mainly have affection on them is UVA and a little UVB, UVB can reach the basal lamina of the epidermis when it irradiate the skin, and it can produce erythrism effect, DNA damaging even inducing carcinoma cutis. Although UVA is low in energy and has strong penetrating power can reach basal lamina of the corium lesion, VVB has great important function in skin aging, It is believed that the damage power of UVR to the DNA of the skin is 30 times as much as that of the UVB, and because UVA can reach the corium layer more in amount easier than UVB, UVA is the main factor which leads to the severe damage of connective tissue of the skin.2. Clinical Manifestations of Aging of Skin: It usually appears as the dermatolysis of exposure part, wide and deep wrinkle, tuberculum parchment-like outward appearance, increasing pigmented spots, capillare ctasia, obvious changing or disappearing of the original geometrical figure, the skin usually appears yellow and grey, also it can produce all kinds of benign , precancerous injury or malignant tumor. 3. Histomorphology Change of Skin Aging: In his to morphology, the premature reaction of light injured skin is over proliferous, renovation, the epidern becoming thicker, cell heterogeneity increasing cut ion taking-shape and cell polarity, it appears as the severe atrophy of the epidern. skin melancyte increases in the part that is irradiated, pigment misdistribution, the amount causes antigen increasing and processing ability descending, restraining immunologic function and making quiescent cell tumour and leading to skin precancer pathologic changing power and leading to skin precancer pathologic changing or carcinous pathologic changing, also making clear that we can see Birbecks granule in langerhans cell (special cell organ in langerhans cell ) less than these of natural aging skin obviously. Corium changes apparently on light aging skin. Collagen reduces and became thicker and solubility descending. Elastic fibers will become thicker, crimping, clenaturating, degradating into granular ball or unsetting ball. The structure of amino-group poly saccharide (GAGS), types all changes, and dysfunction appears, hydrate descending, and dysfunction appear, hydrate descending excess sunlight makes corium accessory organ have some changes, such as small vessels reduce, vascular become thinner, the number of sweat gland decrease, the power of secreting sweat descending and sebaceous glands proliferating which the total amount of sebum secreting descending. Above-mentioned changes of corium structure can initiate the region of the skin that exposing below the sunlight to be dry, flabbily parchment-like and have thick and deep wrinkle.4. Occurrence Mechanism of Light Aging4.1 Light aging and non-ferment glycosylation reaction: the product of glycosylation, which accumulates in human body makes adjacent macromolecular crosslink with each other, especially makes collagen molecule crosslink with each other. Not only does it make the permeability descend but also make the spreading nature of trash and nutriment descend, enhance the tissue hardness to make it hard be hydrolysised collagenase which causing skin resiliency to descend, the wrinkle hard to be smoothed and became deep continuously. Wondrak and others proved the hypothesis by experiment that non-glycosylation protein is the photophil product of the per oxidation injury of the skin cell ultraviolet ray in the peroxidation of light aging skin caused by UVA.4.2 Light Aging and Skin Immunologic System: Ultraviolet ray causes immunologic restrained which leading to exacerbation of skin infective illness of the skin even carcinoma cutis through many ways .Uv can retrain the expression of the skin and stimulate the releasing of the cell factor which has immunsuppression function and causes the producing of the lymphocytes which have antigenic phenotypic. In the light aging skin, the characteristic lesions of the epidermis Lange Hanss cell makes the amount of cells reduce, its figure atrophies, deficits the forming of the dendrite and be lack of Birbeck granule.4.3 Light Aging and Free Radical Theory: In 1956, Harman put forward senile free radical theory. Free radical has extremely strong oxidation powers, which can oxidated the lipid in biological membranes and form into oxidated ester which terminal product (MDA) is strong cement, and it can mix with protein, nucleic acid forming into dysubstance making biological merebrane leading into the descending of its permeability and affecting the cell exchanges of substance then making it rapture and die. Free radical can change collagen molecule, making it to be affected by ferment and hyaluronic acid degradated, reducing the producing of the albumen polysugar, depredating basement membrane and so on. The free radical is produce by the irradiation of the UV can damage all kinds of macromolecular in the human body. They can cause the skin cell to be oxidated, the free radical produced by to be excess, and produces per oxidation lipid in the skin and makes the skin lose its resiliency with the function of the collagen albumen In the skin, also the tree radical can make elastic fibers cross link and polymerize which causing the degradation of elastin and collagen leading to the excess cornification of the skin, making the skin rough, relaxing and wrinkle, aging phenomenon appearance. But there is the damage of the resistive free radical caused by the powerful protection system exists in the health organism at the same time with the increasing of the age and all kinds of outside stimulatation especially the damage caused by the action of the ultraviolet ray in the sunlight makes the resistive oxidation ferment reduce in human body, protection power go down or occurrence of the disturbance, accumulate action of free radical increase which causing the damage of the macromolecular in human body leading to the pathological changes and senility of the skin and organsm.4.4. Mitochondrion Mutation Theory: mitochondrion DNA (mtDNA) is the only extra nuclear in mammal cell. It is easy to be indicted to mutate by outer sphere factor, because of lacking of tissue protection and homologues re notation system. The function of mitochondrion mutation in human being senile and many retrograde illnesses is diffusely proved, mitochondrion DNA mutation and accumulating is also considered as the important factor in aging of the skin especially light aging of the skin. Even research shows clearly that the incidence of the Mito chondrion DNA mutation has nothing to do with age but has close relation with the degree of light aging of the skin. The experiment has also proved that the damage of the oxygen free radical to biological membrane and mitDNA makes DNA mutate and split, which cause the change of the structure and do generation of the function of the mitochondrion and finally affect the producing of ATP, lacking of energy supply leading to the descending of organism super session ability and accruing a serials of senile changes reveal.4.5 The Wither of the Cell and Light ageing of the Skin: the most out-standing feature of the cell is the controlled splitting of the cell DNA .many research materials reveal that the start of this controlled splitting has something to do with “the correlation gene of the withering and death of the cell. The research found that bcl-2 usually locates in the place where can produce more oxygen free radical such as mitochondrion, endoplasmic, reticulum and so on, which have some relation with the protection of the cell. We have already found that bcl-2 gene is one oncogene in the reassert of withering of the cell which is different with the other gene and can extend the life term of the cell, it restrain the cell withering by blocking the common thoroughfare of the delivering system of the withering signal to advance the survival of the cell and is a important cell existing ge