PH Directly Regulates Epidermal Permeability Barrier Homeostasis, and Stratum Corneum Integrity/Cohesion Jean-Pierre Hachem, Debra Crumrine, Joachim.

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pH Directly Regulates Epidermal Permeability Barrier Homeostasis, and Stratum Corneum Integrity/Cohesion Jean-Pierre Hachem, Debra Crumrine, Joachim Fluhr, Barbara E. Brown, Kenneth R. Feingold, Peter M. Elias, MD Journal of Investigative Dermatology Volume 121, Issue 2, Pages 345-353 (August 2003) DOI: 10.1046/j.1523-1747.2003.12365.x Copyright © 2003 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 single topical applications of two superbases acutely increase SC pH. (A), (B) Both TMG and DBU 1:100 in propylene glycol:ethanol, 7:3 vol/vol, increase SC pH. (C) The coapplication of an SPI (PMSF) did not prevent the TMG-induced increase in SC pH. (D) pH dose–response curve 3 h after TMG applications at concentrations from 1:100 to 1:1000 vol/vol. (E) Surface pH recovers to normal values by 24 h following applications of TMG (1:100). (E), (F) The TMG-related increase in SC pH is sustainable and extends throughout the depth of the SC, with a significant increase in comparison to nTMG-treated sites at all levels of the SC. Results shown represent mean±SD (n=4–6 animals in each group). Journal of Investigative Dermatology 2003 121, 345-353DOI: (10.1046/j.1523-1747.2003.12365.x) Copyright © 2003 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Superbase treatment produces neither toxicity nor inflammation. Hematoxylin and eosin stained paraffin sections (6 μM) of biopsies at 3 and 24 h after TMG (1%) and nTMG (1%) application show comparable, normal cellular and epithelial structure, without evidence of inflammation or cytotoxicity. Magnification bars: 10 μm. Journal of Investigative Dermatology 2003 121, 345-353DOI: (10.1046/j.1523-1747.2003.12365.x) Copyright © 2003 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Both superbases produce abnormalities in SC integrity and cohesion. SC integrity (A, B, C) and cohesion (D, E, F) 3 h after a single application of either TMG or DBU versus nTMG or nDBU (1:100 or 1:1000 vol/vol) to intact skin. Integrity reflects the rate of change of TEWL with each stripping. Cohesion reflects the total protein removed from pooled D-Squame strippings taken from each treatment site. Results are shown as the mean±SD (n=4–6 animals in each group). Journal of Investigative Dermatology 2003 121, 345-353DOI: (10.1046/j.1523-1747.2003.12365.x) Copyright © 2003 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 The superbase-induced increase in SP activity is inhibited by coapplied SPI. (A)-(C) In situ zymography of changes in SP activity 20 min, 1 h, and 3 h after superbase treatment demonstrates a progressive increase in enzyme activity in TMG- but not in nTMG-treated sites (D). (E), (F) Coapplication of two chemically unrelated SPI (soybean trypsin inhibitor and PMSF) with TMG inhibits superbase-induced SP activation. En face views of SC show SP activity to be localized to SC membrane domains (A versus D, insets). Magnification bars: 10 μm. Journal of Investigative Dermatology 2003 121, 345-353DOI: (10.1046/j.1523-1747.2003.12365.x) Copyright © 2003 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 In situ SP activation is pH dependent.In situ acidification of sections from TMG-treated skin sections with MES buffer reverses SP activation (B versus A). Bars: 10 μm. Journal of Investigative Dermatology 2003 121, 345-353DOI: (10.1046/j.1523-1747.2003.12365.x) Copyright © 2003 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 6 The decline in CD density after SC neutralization is reversed by an SPI. Quantitative electron microscopy analysis for CD density shows a significant decline in CD density as early as 1 h after superbase (TMG) applications, with a further decline by 3 h after superbase applications. CD density normalizes in superbase-treated skin with 3 h coapplications of an SPI, PMSF, with TMG. The ratio between the length of the CD and the total length of the first SC cell layer was determined using a planimeter and converted to percentage. Results shown are the mean±SD (n=4–6 for each experimental group). Journal of Investigative Dermatology 2003 121, 345-353DOI: (10.1046/j.1523-1747.2003.12365.x) Copyright © 2003 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 7 Superbase-induced degradation of DSG1 is reversed by a coapplied SPI. Protein extracts from SC (n=2 in each group) were loaded onto Tris-glycine polyacrylamide gels, and after transfer onto nitrocellulose membrane incubated further with DSG1 antibody at 4°C overnight. Blots show a decrease in DSG1 staining in TMG- versus nTMG-treated SC, and skin treated with TMG plus the SPI, PMSF. Journal of Investigative Dermatology 2003 121, 345-353DOI: (10.1046/j.1523-1747.2003.12365.x) Copyright © 2003 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 8 The delay in barrier recovery in neutralized SC is attributable to reversible inactivation of a key lipid-processing enzyme.In situ zymography shows a decrease in β-GlcCer'ase activity in skin sections taken from TMG-treated skin immediately following acute barrier disruption by tape stripping (B versus A). The decrease in enzyme activity is reversible by re-acidification (C) but not by a coapplied SPI (PMSF). Magnification bars: 10 μm. Journal of Investigative Dermatology 2003 121, 345-353DOI: (10.1046/j.1523-1747.2003.12365.x) Copyright © 2003 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 9 Superbase-induced delay in barrier recovery is attributable to abnormal lipid processing. (A) When either nTMG or vehicle alone (Veh) are applied immediately after tape stripping (TS) of normal skin, mature lamellar bilayers begin to appear at and just above the stratum granulosum-SC interface (A, open white arrows). (B) In TMG (superbase) treated sites, incompletely processed lamellar membranes (solid arrows) persist two to three cell layers above the stratum granulosum–SC interface. (A), (B) RuO4 postfixation. Magnification bars: 0.25 μm. SB, superbase (TMG) treated. Journal of Investigative Dermatology 2003 121, 345-353DOI: (10.1046/j.1523-1747.2003.12365.x) Copyright © 2003 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 10 Methods for experimental increase in SC pH and mechanistic consequences. Journal of Investigative Dermatology 2003 121, 345-353DOI: (10.1046/j.1523-1747.2003.12365.x) Copyright © 2003 The Society for Investigative Dermatology, Inc Terms and Conditions