title: pH directly regulates epidermal permeability barrier homeostasis, and stratum corneum integrity/cohesion.
abstract: Both exposure of stratum corneum to neutral pH buffers and blockade of acidification mechanisms disturb cutaneous permeability barrier homeostasis and stratum corneum integrity/cohesion, but these approaches all introduce potentially confounding variables. To study the consequences of stratum corneum neutralization, independent of hydration, we applied two chemically unrelated superbases, 1,1,3,3-tetramethylguanidine or 1,8-diazabicyclo [5,4,0] undec-7-ene, in propylene glycol:ethanol (7:3) to hairless mouse skin and assessed whether discrete pH changes alone regulate cutaneous permeability barrier function and stratum corneum integrity/cohesion, as well as the responsible mechanisms. Both 1,1,3,3-tetramethylguanidine and 1,8-diazabicyclo [5,4,0] undec-7-ene applications increased skin surface pH in parallel with abnormalities in both barrier homeostasis and stratum corneum integrity/cohesion. The latter was attributable to rapid activation (<20 min) of serine proteases, assessed by in situ zymography, followed by serine-protease-mediated degradation of corneodesmosomes. Western blotting revealed degradation of desmoglein 1, a key corneodesmosome structural protein, in parallel with loss of corneodesmosomes. Coapplication of serine protease inhibitors with the superbase normalized stratum corneum integrity/cohesion. The superbases also delayed permeability barrier recovery, attributable to decreased beta-glucocerebrosidase activity, assessed zymographically, resulting in a lipid-processing defect on electron microscopy. These studies demonstrate unequivocally that stratum corneum neutralization alone provokes stratum corneum functional abnormalities, including aberrant permeability barrier homeostasis and decreased stratum corneum integrity/cohesion, as well as the mechanisms responsible for these abnormalities.
authors.affiliation: University of California San Francisco Medical Center, Department of Dermatology, San Francisco, California, USA.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Hachem
authors.forename: Debra
authors.initials: D
authors.lastname: Crumrine
authors.forename: Joachim
authors.initials: J
authors.lastname: Fluhr
authors.forename: Barbara E
authors.initials: BE
authors.lastname: Brown
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Feingold
authors.forename: Peter M
authors.initials: PM
authors.lastname: Elias
mesh_terms: D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D003896:Desmosomes / Q000648:ultrastructure; D004789:Enzyme Activation; D004817:Epidermis / Q000378:metabolism / Q000502:physiology* / Q000648:ultrastructure; D006146:Guanidines / Q000494:pharmacology; D006706:Homeostasis; D006863:Hydrogen-Ion Concentration; D008297:Male; D051379:Mice; D008812:Mice, Hairless; D010539:Permeability; D011522:Protons; D020127:Recovery of Function / Q000187:drug effects; D012697:Serine Endopeptidases / Q000378:metabolism; D013997:Time Factors
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D006146:Guanidines; D011522:Protons; D012697:Serine Endopeptidases; C031033:1,8-diazabicyclo(5.4.0)undec-7-ene; C477069:1,1,3,3-tetramethylguanidine