Moderne Aspekte der Aknepathogenese

Zusammenfassung

Akne ist weltweit die häufigste dermatologische Erkrankung. Um eine angesichts variierender klinischer Bilder geeignete Therapie ansetzen zu können, sind gute Kenntnisse über die Pathogenese der Erkrankung nötig. Acne vulgaris ist eine entzündliche Erkrankung, bei deren Entstehung Androgene, PPAR-Liganden, regulierende Neuropeptide und Umweltfaktoren beteiligt sein können. Diese Faktoren unterbrechen den natürlichen zyklischen Prozess im Talgdrüsenfollikel und unterstützen den Übergang von Mikrokomedonen zu Komedonen und entzündlichen Effloreszenzen. Proinflammatorische Lipide, Chemokine und Zytokine übernehmen die Vermittlerrolle bei der Entwicklung von Akneeffloreszenzen. P. acnes ist in diesem Stadium nicht beteiligt, sondern kann später die entzündlichen Phänomene verstärken.

Abstract

Acne is worldwide the most common skin disease. Suitable therapeutic regimens of the varying clinical phenotypes require good knowledge of the pathogenesis of the illness. Acne vulgaris is an inflammatory disorder at whose emergence androgens, PPAR ligands, regulating neuropeptides and environmental factors are probably involved. These factors interrupt the natural cycling process in the sebaceous gland follicle and support the transition of microcomedones to comedones and inflammatory lesions. Proinflammatory lipids, chemokines and cytokines overtake the role of mediators for the development of acne lesions. P. acnes is not involved in this initial acne stages but can potentate the inflammatory phenomena at a later stage.

Literatur

• 1 Zouboulis C C. Acne: Sebaceous gland action.  Clin Dermatol. 2004;  22 360-366
• 2 Zouboulis C C, Eady A, Philpott M, Goldsmith L A, Orfanos C, Cunliffe W C, Rosenfield R. What is the pathogenesis of acne?.  Exp Dermatol. 2005;  14 143-152
• 3 Zouboulis C C. Moderne Aknetherapie.  Akt Dermatol. 2003;  29 49-57
• 4 Zouboulis C C. Acne: Current aspects on pathology and treatment.  Dermatol Experiences. 1999;  1 6-37
• 5 Chiu A, Chon S Y, Kimball A B. The response of skin disease to stress: changes in the severity of acne vulgaris as affected by examination stress.  Arch Dermatol. 203;  139 897-900
• 6 Zouboulis C C, Böhm M. Neuroendocrine regulation of sebocytes - a pathogenetic link between stress and acne.  Exp Dermatol. 2004;  13 (Suppl 4) 31-35
• 7 Green J, Sinclair R D. Perceptions of acne vulgaris in final year medical student written examination answers.  Australas J Dermatol. 2001;  42 98-101
• 8 Herane M I, Ando I. Acne in infancy and acne genetics.  Dermatology. 2003;  206 24-28
• 9 Goulden V, McGeown C H, Cunliffe W J. The familial risk of adult acne: a comparison between first-degree relatives of affected and unaffected individuals.  Brit J Dermatol. 1999;  141 297-300
• 10 Walton S, Wyatt E H, Cunliffe W J. Genetic control of sebum excretion and acne - a twin study.  Brit J Dermatol. 1988;  118 393-396
• 11 Kirk K M, Evans D M, Farthing B, Martin N G. Genetic and environmental influences on acne in adolescent twins.  Twin Res. 2001;  4 190
• 12 Bekaert C, Song M, Delvigne A. Acne neonatorum and familial hyperandrogenism.  Dermatology. 1998;  196 453-454
• 13 Ostlere L S, Rumsby G, Holownia P, Jacobs H S, Rustin M HA, Honour J W. Carrier status for steroid 21-hydroxylase deficiency is only one factor in the variable phenotype of acne.  Clin Endocrinol. 1998;  48 209-215
• 14 Bataille V, Snieder H, MacGregor A J, Sasieni P, Spector T D. The influence of genetics and environmental factors in the pathogenesis of acne: a twin study of acne in women.  J Invest Dermatol. 2002;  119 1317-1322
• 15 Stewart M E, Grahek M O, Cambier L S, Wertz P W, Downing D T. Dilutional effect of increased sebaceous gland activity on the proportion of linoleic acid in sebaceous wax esters and in epidermal acylceramides.  J Invest Dermatol. 1986;  87 733-736
• 16 Pochi P E, Strauss J S. Sebaceous gland response in man to the administration of testosterone, Δ4-androstenedione, and dehydroisoandrosterone.  J Invest Dermatol. 1969;  52 32-36
• 17 Chen W, Yang C-C, Sheu H-M, Seltmann H, Zouboulis C C. Expression of sex-determining genes in human sebaceous glands and their possible roles in pathogenesis of acne.  J Eur Acad Dermatol Venereol. ;  in Druck
• 18 Cunliffe W, Forster R. Androgen control of the pilosebaceous duct?.  Brit J Dermatol. 1987;  116 449
• 19 Thiboutot D, Knaggs H, Gilliland K, Lin G. Activity of 5-alpha-reductase and 17-beta-hydroxysteroid dehydrogenase in the infrainfundibulum of subjects with and without acne vulgaris.  Dermatology. 1998;  196 38-42
• 20 Lucky A W, Biro F M, Huster G A, Leach A D, Morrison J A, Ratterman J. Acne vulgaris in premenarchal girls.  Arch Dermatol. 1994;  130 308-314
• 21 Stewart M E, Downing D T, Cook J S, Hansen J R, Strauss J S. Sebaceous gland activity and serum dehydroepiandrosterone sulfate levels in boys and girls.  Arch Dermatol. 1992;  128 1345-1348
• 22 Marynick S P, Chakmajian Z H, McCaffree D L, Herdon J H. Androgen excess in cystic acne.  N Engl J Med. 1983;  308 981-986
• 23 Schmidt J B, Spona J, Huber J. Androgen receptor in hirsutism and acne.  Gynecol Obstet Invest. 1986;  22 206-211
• 24 Thiboutot D, Harris G, Iles V, Cimis G, Gilliland K, Hagari S. Activity of the type 1 5 alpha-reductase exhibits regional differences in isolated sebaceous glands and whole skin.  J Invest Dermatol. 1995;  105 209-214
• 25 Zouboulis C C. Therapie der Akne mit Antiandrogenen - Eine evidenzbasierte Übersicht.  JDDG. 2003;  1 535-546
• 26 Imperato-McGinley J, Gautier T, Cai L Q, Yee B, Epstein J, Pochi P. The androgen control of sebum production. Studies of subjects with dihydrotestosterone deficiency and complete androgen insensitivity.  J Clin Endocrinol Metabol. 1993;  76 524-528
• 27 Rosenfield R L, Deplewski D, Kentsis A, Ciletti N. Mechanisms of androgen induction of sebocyte differentiation.  Dermatology. 1998;  196 43-46
• 28 Fimmel S, Saborowski A, Térouanne B, Sultan C, Zouboulis C C. Inhibition of the androgen receptor by antisense oligonucleotides regulates the biological activity of androgens in SZ95 sebocytes.  Horm Metab Res. ;  in Druck
• 29 Chen W, Yang C-C, Sheu H-M, Seltmann H, Zouboulis C C. Expression of peroxisome proliferator-activated receptor and CCAAT/enhancer binding protein transcription factors in cultured human sebocytes.  J Invest Dermatol. 2003;  121 441-447
• 30 Alestas T, Ganceviciene R, Fimmel S, Müller-Decker K, Zouboulis C C. Enzymes involved in the biosynthesis of leukotriene B₄ and prostaglandin E₂ are active in sebaceous glands.  J Mol Med. 2006;  84 75-87
• 31 Makrantonaki E, Zouboulis C C. Testosterone metabolism to 5α-dihydrotestosterone and synthesis of sebaceous lipids is regulated by the peroxisome proliferator-activated receptor ligand linoleic acid in human sebocytes.  Brit J Dermatol. ;  in Druck
• 32 Wróbel A, Seltmann H, Fimmel S, Müller-Decker K, Tsukada M, Bogdanoff B, Mandt N, Blume-Peytavi U, Orfanos C E, Zouboulis C C. Differentiation and apoptosis in human immortalized sebocytes.  J Invest Dermatol. 2003;  120 175-181
• 33 Zouboulis C C, Nestoris S, Adler Y D, Picardo M, Camera E, Orth M, Orfanos C E, Cunliffe W J. A new concept for acne therapy: a pilot study with zileuton, an oral 5-lipoxygenase inhibitor.  Arch Dermatol. 2003;  139 668-670
• 34 Zouboulis C C, Saborowski A, Boschnakow A. Zileuton, an oral 5-lipoxygenase inhibitor, directly reduces sebum production.  Dermatology. 2005;  210 36-38
• 35 Trivedi N R, Cong Z, Nelson A M, Albert A J, Rosamilia L L, Sivarajah S, Gilliland K L, Liu W, Mauger D T, Gabbay R A, Thiboutot D M. Peroxisome proliferator-activated receptors increase human sebum production.  J Invest Dermatol. ;  in Druck
• 36 Norris J F, Cunliffe W J. A histological and immunocytochemical study of early acne lesions.  Brit J Dermatol. 1988;  118 651-659
• 37 Cunliffe W J, Holland D B, Clark S M, Stables G I. Comedogenesis: some new aetiological, clinical and therapeutic strategies.  Brit J Dermatol. 2000;  142 1084-1091
• 38 Jeremy A HT, Holland D B, Roberts S G, Thomson K F, Cunliffe W J. Inflammatory events are involved in acne lesion initiation.  J Invest Dermatol. 2003;  121 20-27
• 39 Zouboulis C C. Is acne vulgaris a genuine inflammatory disease?.  Dermatology. 2001;  203 277-279
• 40 Ingham E, Eady E A, Goodwin C E, Cove J H, Cunliffe W J. Pro-inflammatory levels of interleukin-1 alpha-like bioactivity are present in the majority of open comedones in acne vulgaris.  J Invest Dermatol. 1992;  98 895-901
• 41 Zouboulis C C, Xia L, Akamatsu H, Seltmann H, Fritsch M, Hornemann S, Ruhl R, Chen W, Nau H, Orfanos C E. The human sebocyte culture model provides new insights into development and management of seborrhoea and acne.  Dermatology. 1998;  196 21-31
• 42 Antilla H S, Reitamo S, Saurat J H. Interleukin 1 immunoreactivity in sebaceous glands.  Brit J Dermatol. 1992;  127 585-588
• 43 Boehm K D, Yun J K, Strohl K P, Elmets C A. Messenger RNAs for the multifunctional cytokines interleukin-1 alpha, interleukin-1 beta and tumor necrosis factor-alpha are present in adnexal tissues and in dermis of normal human skin.  Exp Dermatol. 1995;  4 335-341
• 44 Guy R, Green M, Kealey T. Modeling of acne in vitro.  J Invest Dermatol. 1996;  106 176-182
• 45 Toyoda M, Nakamura M, Makino T, Kagoura M, Morohashi M. Sebaceous glands in acne patients express high levels of neutral endopeptidase.  Exp Dermatol. 2002;  11 241-247
• 46 Thielitz A, Reinhold D, Vetter R, Lendeckel U, Kähne T, Bank U, Helmuth M, Neubert K, Faust J, Hartig R, Wrenger S, Zouboulis C C, Ansorge S, Gollnick H. Inhibitors of dipeptidyl peptidase IV (DP IV, CD26) and aminopeptidase N (APN, CD13) target major pathogenetic steps in acne initiation.  J Invest Dermatol. ;  in Druck
• 47 Zouboulis C C, Seltmann H, Hiroi N, Chen W, Young M, Oeff M, Scherbaum W A, Orfanos C E, McCann S M, Bornstein S R. Corticotropin releasing hormone: an autocrine hormone that promotes lipogenesis in human sebocytes.  Proc Natl Acad Sci USA. 2002;  99 7148-7153
• 48 Böhm M, Schiller M, Stander S, Seltmann H, Li Z, Brzoska T, Metze D, Schiöth H B, Skottner A, Seiffert K, Zouboulis C C, Luger T A. Evidence for expression of melanocortin-1 receptor in human sebocytes in vitro and in situ.  J Invest Dermatol. 2002;  118 533-539
• 49 Krause K, Schnitger A, Fimmel S, Glass E, Zouboulis C C. Corticotropin-releasing hormone skin signalling is receptor-mediated and is predominant in the sebaceous glands.  Horm Metab Res. ;  in Druck
• 50 Alesci S, Bornstein S R. Neuroimmunoregulation of androgens in the adrenal gland and the skin.  Horm Res. 2000;  54 281-286
• 51 Slominski A T, Botchkarev V, Choudhry M, Fazal N, Fechner K, Furkert J, Krause E, Roloff B, Sayeed M, Wei E, Zbytek B, Zipper J, Wortsman J, Paus R. Cutaneous expression of CRH and CRH-R. Is there a „skin stress response system?”.  Ann N Y Acad Sci. 1999;  885 287-311
• 52 Zouboulis C C. The human skin as a hormone target and an endocrine gland.  Hormones. 2004;  3 9-26
• 53 Letawe C, Boone M, Pierard G E. Digital image analysis of the effect of topically applied linoleic acid on acne microcomedones.  Clin Exp Dermatol. 1998;  23 56-58
• 54 Zhang Q, Seltmann H, Zouboulis C C, Konger R L. Involvement of PPAR-gamma in oxidative stress-mediated prostaglandin E₂ production in SZ95 human sebaceous gland cells.  J Invest Dermatol. 2006;  126 42-48
• 55 Schaefer O. When the Eskimo comes to town.  Nutr Today. 1971;  6 8-16
• 56 Steiner P E. Necropsies on Okinawans: anatomic and pathologic observations.  Arch Pathol. 1946;  42 359-380
• 57 Simopoulos A P. Evolutionary aspects of diet and essential fatty acids.  World Rev Nutr Diet. 2001;  88 18-27
• 58 Cordain L, Lindeberg S, Hurtado M, Hill K, Eaton S B, Brand-Miller J. Acne vulgaris: a disease of Western civilization.  Arch Dermatol. 2002;  138 1584-1590
• 59 Thiboutot D M, Strauss J S. Diet and acne revisited.  Arch Dermatol. 2002;  138 1591-1592
• 60 Schäfer T, Nienhaus A, Vieluf D, Berger J, Ring J. Epidemiology of acne in the general population: the risk of smoking.  Brit J Dermatol. 2001;  145 100-104
• 61 Firooz A, Sarhangnejad R, Davoudi S M, Nassiri-Kashani M. Acne and smoking: is there a relationship?.  BMC Dermatol. 2005;  5 2
• 62 Galobardes B, Davey Smith G, Jeffreys M, Kinra S, McCarron P. Acne in adolescence and cause-specific mortality: lower coronary heart disease but higher prostate cancer mortality: the Glasgow Alumni Cohort Study.  Am J Epidemiol. 2005;  161 1094-1101
• 63 Klaz I, Kochba I, Shohat T, Zarka S, Brenner S. Severe acne vulgaris and tobacco smoking in young men.  J Invest Dermatol. ;  in Druck
• 64 Tithof P K, Elgayyar M, Cho Y, Guan W, Fisher A B, Peters-Golden M. Polycyclic aromatic hydrocarbons present in cigarette smoke cause endothelial cell apoptosis by a phospholipase A2-dependent mechanism.  FASEB J. 2002;  16 1463-1464
• 65 Zouboulis C C. Human skin: An independent peripheral endocrine organ.  Horm Res. 2000;  54 230-242
• 66 Thompson R L, Pyke S, Scott E A, Thompson S G, Wood D A. Cigarette smoking, polyunsaturated fats, and coronary heart disease.  Ann N Y Acad Sci. 1993;  686 130-138
• 67 Kim J, Ochoa M T, Krutzik S R, Takeuchi O, Uematsu S, Legaspi A J, Brightbill H D, Holland D, Cunliffe W J, Akira S, Sieling P A, Godowski P J, Modlin R L. Activation of toll-like receptor 2 in acne triggers inflammatory cytokine responses.  J Immunol. 2002;  169 1535-1541
• 68 Pivarcsi A, Bodai L, Rethi B, Kenderessy-Szabo A, Koreck A, Szell M, Beer Z, Bata-Csorgoo Z, Magocsi M, Rajnavolgyi E, Dobozy A, Kemeny L. Expression and function of Toll-like receptors 2 and 4 in human keratinocytes.  Int Immunol. 2003;  15 721-730
• 69 Ingham E, Walters C E, Eady E A, Cove J H, Kearney J N, Cunliffe W J. Inflammation in acne vulgaris: failure of skin micro-organisms to modulate keratinocyte interleukin 1 alpha production in vitro.  Dermatology. 1998;  196 86-88
• 70 Nagy I, Pivarcsi A, Koreck A, Szell M, Urban E, Kemény L. Distinct strains of Propionibacterium acnes induces selective human β-defensin-2 and interleukin-8 expression in human keratinocytes through Toll-like receptors.  J Invest Dermatol. 2005;  124 931-938
• 71 Oeff K M, Seltmann H, Hakiy N H, Bogdanoff B, Nastos A, Walters R J, Fimmel S, Bornstein S R, Zouboulis C C. Differential modulation of Toll-like receptor 2 and 4 expression in human sebocytes.  J Invest Dermatol. 2002;  119 319
• 72 Seltmann H, Zouboulis C C. Human sebocytes express CD14 molecules and their IL8 production is induced by both CD14-dependent and independent pathways.  J Invest Dermatol. 2001;  117 804
• 73 Georgel P, Crozat K, Lauth X, Makrantonaki E, Seltmann H, Sovath S, Hoebe K, Du X, Rutschmann S, Jiang Z, Bigby T, Nizet V, Zouboulis C C, Beutler B. A TLR2-responsive lipid effector pathway protects mammals against Gram-positive bacterial skin infections.  Infect Immun. 2005;  73 4512-4521
• 74 Nagy I, Pivarcsi A, Kis K, Koreck A, Bodai L, McDowell A, Seltmann H, Patrick S, Zouboulis C C, Kemény L. Propionibacterium acnes and LPS induce the expression of antibacterial peptides and proinflammatory cytokines/chemokines in human sebocytes.  Microbes Infect. ;  in Druck