Short-Term Glucocorticoid Treatment Compromises Both Permeability Barrier Homeostasis and Stratum Corneum Integrity: Inhibition of Epidermal Lipid Synthesis.

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Short-Term Glucocorticoid Treatment Compromises Both Permeability Barrier Homeostasis and Stratum Corneum Integrity: Inhibition of Epidermal Lipid Synthesis Accounts for Functional Abnormalities Jack S. Kao, Joachim W. Fluhr, Mao-Qiang Man, Ashley J. Fowler, Jean-Pierre Hachem, Debra Crumrine, Sung K. Ahn, Barbara E. Brown, Peter M. Elias, Kenneth R. Feingold Journal of Investigative Dermatology Volume 120, Issue 3, Pages 456-464 (March 2003) DOI: 10.1046/j.1523-1747.2003.12053.x Copyright © 2003 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Topical GC perturb permeability barrier homeostasis and decrease SC integrity in humans. Clobetasol 0.05% or vehicle was applied twice daily for 3d to the volar forearm. Barrier recovery was measured following tape stripping (A). SC integrity was measured as described in Materials and Methods (B). Results are expressed as mean±SEM. n=7 in both groups. Journal of Investigative Dermatology 2003 120, 456-464DOI: (10.1046/j.1523-1747.2003.12053.x) Copyright © 2003 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Topical GC perturb permeability barrier homeostasis after disruption by tape stripping and acetone. Clobetasol 0.05% (A, E), 0.025% (B), or 0.0125% (C), or vehicle (contralateral flank and separate animal) was applied twice daily for 3d to the flanks of hairless mice followed by tape stripping (A, B, C, D) or acetone treatment (clobetasol 0.05%, E). Barrier recovery was determined at 3, 6, and 24h. The dose–response of barrier recovery at 3h is shown in panel D. The 100% value is from the control animals treated with vehicle alone. Hairless mice were treated with dexamethasone 8μg or vehicle intraperitoneally for 3d. Barrier recovery determined 6h following disruption by tape stripping (F). Results are expressed as mean±SEM. n=4 (A, B, C, D, F); n=15 (E). *p<0.05, **p<0.005, #p<0.01, ##p<0.0001; ns, not statistically significant. Journal of Investigative Dermatology 2003 120, 456-464DOI: (10.1046/j.1523-1747.2003.12053.x) Copyright © 2003 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 GC decreases SC integrity and cohesion. Clobetasol 0.05%, 0.025%, or 0.0125% was applied twice daily for 3d to the flanks of hairless mice. The contralateral flanks were treated with vehicle alone as were a separate group of control animals (vehicle animals). A group of untreated control animals was also included. SC integrity (A) and cohesion (B) were measured as described in Materials and Methods. A dose–response of topical clobetasol on integrity assessed by TEWL after four D-Squame tape strippings is shown in panel C. Results are expressed as mean±SEM. n=13 clobetasol, n=13 vehicle-treated flank, n=6 vehicle-treated animal, and n=6 no treatment animals. Journal of Investigative Dermatology 2003 120, 456-464DOI: (10.1046/j.1523-1747.2003.12053.x) Copyright © 2003 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Topical GC decrease lamellar body production and secretion in the basal state. Hairless mice were treated topically twice per day for 3d with 0.05% clobetasol or vehicle. (A) Electron micrograph of the SG–SC junction in the epidermis of clobetasol-treated mice shows a thin layer of lamellar material (open arrows) and fewer lamellar bodies in the cytosol of SG cells (solid arrowheads). (B) The SG–SC junction in the epidermis of vehicle-treated mice demonstrates normal bilayer formation (solid arrows) and abundant lamellar bodies (short open arrows). Magnification bars: 0.50μm. Journal of Investigative Dermatology 2003 120, 456-464DOI: (10.1046/j.1523-1747.2003.12053.x) Copyright © 2003 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 Topical GC impairs lamellar body formation and secretion following barrier disruption. Hairless mice were treated topically twice per day for 3d with 0.05% clobetasol or vehicle and then the barrier was disrupted by tape stripping. (A, B) Electron micrograph of the SG–SC junction of clobetasol-treated mouse epidermis 3h after acute barrier disruption by tape stripping. The quantity of secreted lamellar material continues to be thin (A, B, open arrows), and the expected increased lamellar body production in response to disruption does not occur (A, arrowhead). There was also evidence of abnormal lamellar secretion and extracellular processing (B, white arrowheads). Entombed lamellar bodies (B, white arrowheads) indicate incomplete secretion. (D) SG–SC junction of vehicle-treated mouse epidermis 3h after acute barrier disruption. Note the mature bilayers (arrowheads) and abundant lamellar secretion (solid arrows). Magnification bars: 0.50μm. Journal of Investigative Dermatology 2003 120, 456-464DOI: (10.1046/j.1523-1747.2003.12053.x) Copyright © 2003 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 6 GC inhibit epidermal lipid synthesis. Hairless mice were topically treated twice per day with 0.05% clobetasol or vehicle alone for 3d and then skin samples were obtained for the determination of epidermal lipid synthesis either in the basal state (panel A) or 3h following barrier disruption by tape stripping (panel B). In separate experiments hairless mice were administered a daily intraperitoneal injection of 8μg dexamethasone or vehicle alone and skin samples were obtained in the basal state for the determination of epidermal lipid synthesis (panel C). Skin samples were incubated for 2h with 14C acetate and incorporation into the various lipid classes was determined as described in Materials and Methods. Dexamethasone decreased the lipid synthesis in normal human keratinocytes from foreskin, grown in KGM with 0.02mM Ca2+ to 90%–95% confluence and subsequently changed to KGM with 1.2mM Ca2+ for 3d, and then changed to KGM with 1.2mM Ca2+ without growth factors for 2d. Finally, the normal human keratinocytes were changed to KGM + 1.2mM Ca2+ without growth factor, with or without 0.1μM dexamethasone. Results are expressed as mean±SEM and control values equal 100%. n=4 for all groups except normal human keratinocytes where n=5. Journal of Investigative Dermatology 2003 120, 456-464DOI: (10.1046/j.1523-1747.2003.12053.x) Copyright © 2003 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 7 Topical GC reduce SC corneodesmosomes. Corneodesmosome (CD) density is profoundly reduced in clobetasol-treated SC (panel A) versus vehicle-treated SC (panel B). The topical GC treatment reduced the density of CD at the SG–SC interface. Panel A shows only a CD remnant (black arrowhead) whereas prominent, large, intact CD could be seen in vehicle-treated SC (panel B, black arrowhead). The densities of corneodesmosomes were also quantified in coded, randomized micrographs by an unbiased observer (see text). A, B, RuO4 postfixation. Journal of Investigative Dermatology 2003 120, 456-464DOI: (10.1046/j.1523-1747.2003.12053.x) Copyright © 2003 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 8 Treatment with topical lipids improves barrier homeostasis and SC integrity and cohesion in GC-treated animals. Hairless mice were topically treated twice per day with 0.05% clobetasol or vehicle alone for 3d. Immediately after each clobetasol treatment, animals were topically treated with either a lipid mixture containing fatty acids, cholesterol, and ceramides or vehicle alone. Three groups were studied: clobetasol/vehicle, clobetasol/lipid mixture, vehicle/vehicle. Barrier recovery was determined at 3, 6, and 24h after disruption of the barrier by tape stripping (A). SC integrity (B) and cohesion (C) were determined as described in Materials and Methods. Integrity reflects changes in TEWL, measured as ppm per cm2 per h. Data in panel D show hairless mice topically treated twice per day with 0.05% clobetasol or vehicle for 3d. Immediately after barrier disruption by tape stripping animals were treated topically with either a lipid mixture containing fatty acids, cholesterol, and ceramides or vehicle alone and barrier recovery was determined at 3, 6, and 24h. The pairwise comparison was performed after ANOVA testing (p<0.05 in all cases). Panel D, control versus clobetasol, p<0.01 for all strips; control versus clobetasol+lipids, p<0.05 for two and three strips. Results are expressed as mean±SEM. n=7 (A, B, C); n=22 (D). Journal of Investigative Dermatology 2003 120, 456-464DOI: (10.1046/j.1523-1747.2003.12053.x) Copyright © 2003 The Society for Investigative Dermatology, Inc Terms and Conditions