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1 TNF- Mi noxi di l Effect s of T NF - and Minoxidil on Hum an Hair Growth in V itro ( )

2 TNF- Mi noxi di l Effect s of T NF - and Minoxidil on Hum an Hair Growth in V itro ( )

3 2002 7

4 TNF- Mi nox i d i l ( : ) : T NF -. T NF -,. Minoxidil. T NF - Minoxidil Minoxidil. : - i -

5 ., T NF -, Minoxidil, T NF - Minoxidil.. : T NF -, Minoxidil T NF -. : Minoxidil T NF - Minoxidil. :, T NF -, Minoxidil - ii -

6 =A bs tract = Effects of T NF - and Minoxidil on Hum an Hair Growth in V itro T ae Gyun Lim, M.D. (Director : Professor, Gwang - Seong Choi, M.D.) Department of Dermatology, College of Medicine, Inha Univer sity, Incheon, Korea B ack g roun d : T he factor s that regulate hair follicle growth are still poorly under stood. In vitro m odels may be u seful in elucidating some aspects of hair follicle biology. T NF - is potent inhibitor of hair follicle growth. T NF - induces the formation of a club - like hair follicle, similar to catagen morphology of the hair bulb. Minoxidil induces generalized hypertrichosis when administ ered sy stemically, or localized hair r egr ow th w hen applied t opically to sites of alopecia ar eata. Minoxidil inv olve the dev elopment of derm al papilla vascularization. Obje c t iv e : T he purpose of this study is to inv estigate the effect of T NF - and minoxidil on human hair growth using in vitro - iii -

7 model. M e th o d s : After the healthy hum an hair follicles w ithout any visible damage w er e collected, they w ere cultured in William s E m edium with sev eral combination of supplement s including insulin, hydr ocortisone, sodium selenite, human transferrin, fetal bovine serum at 37 in an atmosphere of 5% CO2/ 95% air incubator, and T NF - and minoxidil w ere added to the media. T he results w er e evaluat ed by measuring linear hair fiber growth and hair follicle morphology on light microsocopy. R e s ult s : T he following results were obtained from this study. 1. T NF - have an statistically significant inhibitory effect on the r ate of linear hair grow th in cultur ed hair follicles. 2. Minoxidil do not hav e an statistically significant stimulatory effect on the r ate of linear hair grow th in cultur ed hair follicles with or without T NF -. Con clu s ion : T NF - has growth - inhibitory effect and minoxidil does not have gr owth - stimulatory effect. Key W ords : Human hair follicle culture, T NF -, Minoxidil - iv -

8 List of Fig ures Figure 1. T hese photogr aphs show incr ease in length of the same hair follicle in culture without T NF - and minoxidil (contr ol group). T he arr ow indicates the hair length m easur ed. A ) 1st day, B) 4th day, C) 8th day (X40) Figure 2. T hese photogr aphs show incr ease in length of the same hair follicle in culture w ith minoxidil. T he arr ow indicates the hair length measured. A ) 1st day, B) 4th day, C) 8th day (X40) Figure 3. T hese photogr aphs show incr ease in length of the same hair follicle in culture with T NF -. T he arr ow indicates the hair length measured. A ) 1st day, B) 4th day, C) 8th day (X40) Figure 4. T hese photogr aphs show incr ease in length of the same hair follicle in culture with T NF - and minoxidil. T he arr ow indicates the hair length measured. A ) 1st day, B) 4th day, C) 8th day (X40) - v -

9 Figure 5. Effects of T NF - and/ or minoxidil on the length of hum an hair follicles gr ow n for 8 day s in vitro. - v i -

10 Lis t of T ab le T able 1. Daily human hair follicle elongation - v ii -

11 I. 1 II. 6 III. 9 IV. 17 V. 21 VI v iii -

12 I.,.,.,..,, (hair follicle). (hair matrix cell) (outer root sheath ) (hair papilla cell) (connective tissue). (anagen), (catagen), (telogen) 6, 7 (Philpott et al, 1990, Paus et al, 1999). (Messenger, 1994). (growth factors), (steroid hormone), - (dermo- epithelial interactions), (immune system ) - 1 -

13 (Philpott et al, 1994). (Paus et al, 1999). (Jahoda et al, 1981; Wetering s et al, 1981; Wells, 1982; Messenger et al, 1984). (keratinocyte) interleuin (IL)- 1, - 1, - 3, - 6, - 8, - 10 granulocyte- macrophage colony - stimulating factor (GM - CSF ), gr anulocyte colony - stimulating fact or (G- CSF ), tum or necrosis factor - alpha (T NF - ), (fibroblast ) IL- 1, IL- 6, IL- 8 G- CSF (Ansel et al, 1990).,.. cyclosporin A (Harper et al, 1984), (macrophage) (W estgate et al, 1991). (Philpott et al, 1995).,. T NF -. (vascular endothelial cell) - 2 -

14 (apoptosis ) (T sutomu, 1998). T NF - (inner root sheath ) (Henle layer ) (suprapapillary level) IL- 1, IL- 1, IL- 6. (cuticle) IL- 1 T NF -. (Mcdonach et al, 1993; Ahmed et al, 1996; Stenn et al, 1996). T NF - Henle, (Ahmed et al, 1996). T NF - T (T hein et al, 1997)., (Ahmed et al, 1996; Stenn et al, 1996). T NF -. T NF - (Philpott et al, 1996; Hoffmann et al, 1996)

15 (Hoffmann, 1999; Ruckert et al, 2000). Minoxidil (Clissold et al, 1987). Minoxidil DNA (Cohen et al, 1984). minoxidil mitogen minoxidil. Minoxidil, minoxidil minoxidil. Minoxidil (W eiss et al, 1983) minoxidil (Gilmore et al, 1970). vascular endothelial growth factor (VEGF ) (, 1999). VEGF minoxidil (Lachgar et al, 1998). minoxidil - 4 -

16 (Katsuoka et al, 1987; Imai et al, 1993).., T NF - minoxidil

17 II. 1. 1) (facial lift ) 2,. 2 ) Williams E medium, penicillin, streptomycin antibiotic solution ( Gibco, NY, U.S.A ), hydrocortisone, fetal bovine serum, IT S (in sulin tran sferrin selenate) liquid supplement (X 100), minoxidil, T NF - ( Sigma Chemical Co., St. Louis, MO, U.S.A ). 3 ) William se media (Gibco, NY, U.S.A ) Penicillin (50 IU/ ml), streptomycin (50 ug/ ml) antibiotics hydrocortisone(10 ng/ ml), fetal bovine serum (10 %), IT S (insulin transferrin selenate) liquid supplement (X 100). T NF -, minoxidil. 2. 1), - 6 -

18 15 scalpel blade. w atch makers ' forcep.,. 2 ) 24 w ell plate(corning, NY, U.S.A ) well 1ml 1 37, CO2 5% air 95% ). minoxidil minoxidil 200 ng/ ml. T NF - T NF U/ ml. T NF - minoxidil minoxidil 200 ng/ ml T NF U/ ml )

19 X 4 X 10 Leica 1 8, 1, 4, 8. 10% tris - buffered formalin H&E. 5 ) (SAS ), p <

20 III. 1. minoxidil 8. 8 (Fig. 1, 2) T NF - T NF - minoxidil 6, (Fig. 3, 4) minoxidil T NF - T NF - minoxidil (T able 1)(Fig. 5). 2. m in ox idil mm minoxidil 200 ng/ ml mm

21 .. 3. T N F mm T NF U/ ml mm.. 3,. 4. T N F - m in ox idil T NF U/ ml minoxidil 200 ng/ ml mm. minoxidil T NF

22 A B C Fig. 1 : T hese photogr aphs show incr ease in length of the same hair follicle in culture without T NF - and minoxidil (contr ol gr oup). T he arrow indicates the hair length measured. A ) 1st day, B) 4th day, C) 8th day (X40)

23 A B C Fig. 2 : T hese photogr aphs show incr ease in length of the same hair follicle in cultur e w ith minoxidil. T he arrow indicates the hair length measur ed. A ) 1st day, B) 4th day, C) 8th day (X40)

24 A B C Fig. 3 : T hese photogr aphs show incr ease in length of the same hair follicle in culture with T NF -. T he arrow indicates the hair length measur ed. A ) 1st day, B) 4th day, C) 8th day (X40)

25 A B C Fig. 4 : T hese photogr aphs show incr ease in length of the same hair follicle in culture with T NF - and minoxidil. T he arrow indicates the hair length measured. A ) 1st day, B) 4th day, C) 8th day (X40)

26 Fig. 5 : Effects of T NF - and/ or minoxidil on the length of human hair follicles gr own for 8 day s in vitr o

27 T able 1. Daily human hair follicle elongation Group T NF - Control T NF - Min ox idil Day + Min ox idil 1th n d a 1)2 ) a a a 3rd a a b a b b 4th a b a b 5th a b a b 6th a b a b 7th a b a b 8th a b a b 1) T he data present the mean SD, n =20 2) With different lett er s within ev ery groups ar e significantly different from each other at =0.05 as determined by Duncan ' s multiple range test (a >b )

28 IV.,.,.,, mm/ d.(, 2001) mm/ d.,,

29 T NF ,. 6,.. Minoxidil. minoxidil. minoxidil minoxidil. Minoxidil. minoxidil. minoxidil. minoxidil

30 . T NF - minoxidil T NF -. minoxidil. minoxidil, T NF - minoxidil minoxidil. minoxidil. minoxidil minoxidil (Cohen et al, 1984; Philpott et al, 1990). minoxidil minoxidil.. minoxidil minoxidil monixidil. T NF

31 T NF -. minoxidil minoxidil

32 V.. 1. T NF -,. 2. minoxidil,. 3. T NF - minoxidil minoxidil. T NF -,,. T NF - minoxidil minoxidil.,

33 VI. Ahmed AA, Nor dlind K, Schult zberg M, Brakenhoff J, Bristulf J, Novick D, at al. Immunohistochemical studies of proinflammatory cytokines and their receptor s in hair follicles of normal human skin. A cta Derm Vener eol. 1996;76: An sel J, Perry P, Br own J, Damm D, Phan T, Hart C, Luger T, Hefeneider S. Cytokine modulation of ker atinocyte cyt okines. J Inv est Dermatol. 1990;94:101S- 107S Clissold SP, Heel RC. T opical minoxidil. A pr eliminary review of it s pharmacodynamic pr operties and therapeutic efficacy in alopecia ar eat a and alopecia androgenetica. Drug s. 1987;33: Cohen RL, Alves ME, W eis s VC, West DP, Chamber s DA. Direct effect s of minoxidil on epidermal cells in culture. J Inv est Dermatol. 1984;82:90-3 Gilm or e E, Weil J, Chidsey C. T r eatm ent of essential hypertension w ith a new v asodilator in combination with beta - adrenergic blockade. N Engl J Med. 1970;282:521-7 Harper JI, Kendra JR, Desai S, Staughton RC, Barrett AJ, Hobbs

34 JR. Derm atological aspect s of the u se of Cy closporin A for prophylaxis of graft - v er su s- host disease. Br J Dermatol. 1984;110: Hoffmann R, Eicheler W, Huth A, W enzel E, Happle R. Cytokines and gr owth factor s influence hair gr ow th in vitr o. Pos sible implication s for the pathogenesis and tr eatment of alopecia ar eata. Ar ch Dermatol Res. 1996;288:153-6 Hoffmann R. T he potential r ole of cytokines and T cells in alopecia areata. J Inv estig Dermat ol Symp Pr oc. 1999;4:235-8 Imai R, Jindo T, Miura Y, Mochida K, T akamori K, Ogaw a H. Or gan cultur e of human hair follicles in serum - fr ee medium. Arch Dermatol Res. 1993;284: Jahoda C, Oliv er RF. T he gr owth of vibrissa dermal papilla cells in vitro. Br J Dermatol. 1981;105:623-7 Kat suoka K, Schell H, Wessel B, Hornstein OP. Effect s of epidermal gr ow th factor, fibr oblast gr owth factor, minoxidil and hydrocortisone on gr ow th kinetics in human hair bulb papilla cells and r oot sheath fibr oblast s cultur ed in vitr o. Arch Derm atol Res. 1987;279:

35 Lachgar S, Charv eron M, Gall Y, Bonafe JL. Minoxidil upr egulates the expr ession of v ascular endothelial grow th fact or in hum an hair dermal papilla cells. Br J Dermatol. 1998;138: Mcdonagh AJ, Snow den JA, Stierle C, Elliott K, Messenger A G. HLA and ICAM - 1 expression in alopecia areata in vivo and in vitro: the r ole of cytokines. Br J Derm atol. 1993;129:250-6 Messenger AG. T he culture of dermal papilla cells from human hair follicles. Br J Dermatol. 1984;110:685-9 Mes senger AG. Control of hair grow th and pigmentation. In Olsen EA, eds. Disorders of hair growth. NY: McGrow - Hill, Inc, 1994:39-58 Pau s R, Cot sarelis G. Mechanism of disease: T he biology of hair follicles. N Engl J Med. 1998;341:491-7 Philpott MP, Gr een MR, Kealey T. Human hair grow th in vitro. J Cell Sci. 1990;97: Philpott MP, Sander s D, Kealey T. Cultur ed human hair follicles and grow th factor s. J Inv est Dermatol. 1995;104(5Suppl):44S - 45S

36 Philpott MP, Sander s D, W est gate GE, Kealey T. Human hair gr ow th in vitro: a model for the study of hair follicle biology. J Dermatol Sci. 1994;7Suppl:S55-72 Philpott MP, Sander s DA, Kealey T. Whole hair follicle culture. Dermatol Clin. 1996;14: Ruckert R, Lindner G, Bulfone- Pau s S, Pau s R. High - dose proinflammatory cytokines induce apoptosis of hair bulb keratinocytes in vivo. Br J Dermatol. 2000;143: Soma T, Ogo M, Suzuki J, T akahashi T, Hibino T. Analy sis of apoptotic cell death in human hair follicles in viv o and in vitro. J Inv est Dermatol. 1998;111: Stenn KS, Combat es NJ, Eilert sen KJ, Gordon JS, Par dinas JR, Parim oo S, at al. Hair follicle grow th controls. Derm atol Clin. 1996;14: T hein C, Str ange P, Han sen ER, Baadsgaar d O. Lesional alopecia ar eat a T lymphocytes dow nr egulate epithelial cell pr oliferation. Ar ch Dermatol Res. 1997;289:384-8 W eis s VC, West DP, Fu T S, Robin son LA, Cook B, Cohen RL,

37 Chamber s DA. Alopecia areata tr eated w ith topical minoxidil. Ar ch Dermatol. 1984;120: W ells J. A simple technique for est ablishing cultur es of epithelial cells. Br J Dermatol. 1982;107:481-2 W estgate GE, Cr agg s RI, Gibson WT. Immune privilege in hair gr ow th. J Inv est Dermatol. 1991;97: W etering s PJ, Vermorken AJ, Bloemendal H. A method for culturing human hair follicle cells. Br J Dermatol. 1981;104:1-5,,,. Vascular Endothelial Growth Factor ;37:23-30,. substance P ;39:

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee University College of Medicine & Hospital E mail : ycell2@yahoo.co.kr Abstract