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    14 views9 pages

    Fisher2002.pdfmechanism of Photoaging and Chronical Skin Aging PDF

    Uploaded by

    Apriyanti Sembiring

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    © All Rights Reserved
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    rt Mechanisms of Photoaging and Chronological Skin Aging Gary J. Fisher, PRD; Sewon Kang, MD; James Varani, PhD; Zsuzsanna Bata-Csorgo, MD; Yinsheng Wan, PhD; Subhash Datta, PRD; John J Voorhees, MD uman skin, like all other organs, undergoes chronological aging. In addition, unlike other organs, skin is in direct contact with the environment and therefore undergoes aging as a consequence of environmental damage. The primary environmental factor that causes human skin aging is UV irradiation from the sun. This sun-induced skin aging (photoaging), like chronological aging, is a cumulative process. However, unlike chronologi- cal aging, which depends on the passage of time per se, photoaging depends primarily on the degree of sun exposure and skin pigment. Individuals who have outdoor lifestyles, live in sunny climates, and are lightly pigmented will experience the greatest degree of photoaging. During the last decade, substantial progress has been made in understanding cellular and molecular mechanisms that bring about chronological aging and photoaging. This emerging information reveals that chronological ag- ing and photoaging share fundamental molecular pathways. These new insights regarding conver- gence of the molecular basis of chronological aging and photoaging provide exciting new opportu- nities for the development of new anti-aging therapies. This article reviews our current understanding and presents new data about the molecular pathways that mediate skin damage by UV irradiation and by the passage of time. Arch Dermatol. 2002;138:1462-1470 Ulwaviolet irradiation from the sun dam- ages human skin, causing it to age prema- cruitment by UV irradiation ofthe cellular ‘machinery that damages skin connective is turely. This premature aging process (pho- toaging) is cumulative with sun exposure, and preferentially aects individuals with lighter skin color. During the last 10 years, substantial progress has been made in uh. derstanding the molecular mechanisms re- sponsible for photosging in human skin. (One major conceptual advance elaborated by this work is that UV irradiation invokes ‘complex sequence of specific molecular responses that damage skin connective tis- sue, These molecular processes derive from the ability of UV irradiation o exploit highly evolved cellular machinery that regulates re- sponses of cells to physiological and em ronmental extracellular stimuli, The cellu- lar machinery that mediates UV damage to human skin connective lsste includes cell surface receptors, protein kinase signal transduction pathways, transcription fac- tors, and enzymes that synthesize and de- grade structural proteins in the dermis that confer strength and resiliency to skin. Re- From the Department of Dermatology, University of Michigan, Ann Arbor sue is iniiated by photochemical geners- tion of reactive oxygen species (ROS). Ul avioletinduced ROS also cause direct deleterious chemical modifications to cel- Iular components (ie, DNA, proteins, and lipids). Chemical oxidation of cellular com- ponents and activation of cellular machin- ery, both brought about by UV-induced oxidative stress, actin concert to cause pho- oaging. Insights gained into the molecu- lar basis of photoaging provide new oppor- Uunities for therapeutic intervention aimed at prevention. UV-INDUCED SIGNAL TRANSDUCTION PATHWAYS MEDIATE DAMAGE TO. SKIN CONNECTIVE TISSUE UV Irradiation Activates Cell Surface Growth Factor and Cytokine Receptors Signal transduction pathways that are activated by UV irradiation in human skin are depicted in Figure ¥. Ultraviolet (©2002 American Medical Association, All ights reserved. Downloaded From: by a Universidad de Barcelona User on 01/08/2019 Growth Factor Cytokine Receptors t Signal Transduction Cascade © Lal © Procollagen MNP Promoters Promoters Growth Factor Cytokine Receptors Z 1 Signal Transduction Cascade Nucleus Dermal Matrix Breakdown Impertect Repair —» Photoaging Figure 1, Model depicing slr UV aration damage asin connacve cus Uavetiadaton jagged rows) actnaee growth ator aed tine por nthe surface Keratnogyos (KC) and brabats (F)Actted eceplors simul sigalvansdction cascades hat nde ansaponfactar {AP which stimulates vansripion of matt metaoprtinase (MMP) genes. In rclsts, AP-t also ints procolagen gone expression Mat ttaloprteinase te secae rom aratnacjtes nd firsts and break dv clan and oa protein tat compris te dermal etal mati ing ropa te rina darageinpars th funciona and stucturalnegy ofthe exacslult mari Rapened su expose cases eecumulatan cof darmal mage hat evantualy ess mcharaterst ining of photodamage sk, irradiation causes activation of cell surface cytokines and ‘growth factor receptors. Epidermal growth factor (EGP), Interleukin (IL) 1, and tumor necrosis factor « (TNF-«) receptors are activated within 15 minutes following UV ‘exposure (twice the minimal erythema dose) in human skin in vivo, Functional activation of these receptors fe {quires stimulation of distinct tyrosine kinase activities." This addition of phosphate groups to tyrosine residues ‘on the receptors and their associated adaptor proteins is the initial biochemical event in receptor activation and provides specific dacking sites for molecules involved in signal propagation within the cell The primary mechanism by which UV irradiation, Initiates molecular responses in human skin is by pho- tochronical generation of ROS. These ROS include st- peroxide anton, peroxide, and singlet oxygen, The mechs- nism(s) of receptor activation by UY irradiation are not well understood. One possibility, which is supported by indirect experimental evidence, is that photochemical ‘generation of ROS oxidize, and thereby inhibit specific protein-tyrosine phosphatases, which function in oppo- sition to receptof-activated protein-tyrosine kinases by removing phosphate group from receptots of their as- sociated adaptor proteins,” The result would be a nei ‘crease in receptor phosphorylation (activation).* This mechanism of UV activation of cell surface receptors is ‘supported by several publications,”* although direct evi- (©2002 American Med Downloaded From: by a Universidad de Barcelona User on 01/08/2019 dence that protein-tyrosine phosphatases regulate the ac- Livation state of cell surface receptors is lacking, UY Irradiation Activates NADPH Oxidase, Which Generates Hydrogen Peroxide Irrespective of mechanism, UV irradiation activates cell surface receptors, as does ligand binding, and triggers downstream signal transduction pathways, Several std- tes have demonstrated that UV irradiation stimulates pro- duction of hydrogen peroxide, which induces multiple signaling pathways, although the mechanism(s) by which hydrogen peroxide acts s not clear. In human skin in vivo and human keratinocytes, hydrogen peroxide levels are ‘mereased within 15 minutes following UV irradiation and continue to accumulate for approximately 60 minutes a- ter UV exposure (Figure 2A). Its important to appre- ciate that this generation of hydrogen peroxide after UV exposure is distinct from photochemical generation of ROS described above, which occurs only during UV ex- posure and abates following UV exposure. Phagocytes contain a multi-subunit complex, nico- tinamide adenine dinucleotide phosphate (NADPH) ox dase, which catalyzes the reduction of molecular oxy- gen to superoxide anion.’ The superoxide produced is, quantitatively converted to hydrogen peroxide, which is less damaging to cells and serves as a cosubstrate for per- 1 Association, All rights reserved. AOS eet haan Uae 7 Ti OT aes Tu cy a Pots t P06 06 ets peas TO kan, RET To ee Mins tr W ron ED) Ta Figure 2. Utravlt iraiaion stimulates geerato af fy éogen paroxide (80) inhuran laratinocytes, A, Time course for acaruaton of HO, {alowing WV iadation ferme UVRIUV-#2 sure of human ‘ranacys 8 Time cause of WY stimulation of atirarige adenine

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