title: Topical antihistamines display potent anti-inflammatory activity linked in part to enhanced permeability barrier function.
abstract: Systemic antagonists of the histamine type 1 and 2 receptors (H1/2r) are widely used as anti-pruritics and central sedatives, but demonstrate only modest anti-inflammatory activity. Because many inflammatory dermatoses result from defects in cutaneous barrier function, and because keratinocytes express both Hr1 and Hr2, we hypothesized that H1/2r antagonists might be more effective if they were used topically to treat inflammatory dermatoses. Topical H1/2r antagonists additively enhanced permeability barrier homeostasis in normal mouse skin by the following mechanisms: (i) stimulation of epidermal differentiation, leading to thickened cornified envelopes; and (ii) enhanced epidermal lipid synthesis and secretion. As barrier homeostasis was enhanced to a comparable extent in mast cell-deficient mice, with no further improvement following application of topical H1/2r antagonists, H1/2r antagonists likely oppose mast cell-derived histamines. In four immunologically diverse, murine disease models, characterized by either inflammation alone (acute irritant contact dermatitis, acute allergic contact dermatitis) or by prominent barrier abnormalities (subacute allergic contact dermatitis, atopic dermatitis), topical H1/2r agonists aggravated, whereas H1/2r antagonists improved, inflammation and/or barrier function. The apparent ability of topical H1r/2r antagonists to target epidermal H1/2r could translate into increased efficacy in the treatment of inflammatory dermatoses, likely due to decreased inflammation and enhanced barrier function. These results could shift current paradigms of antihistamine utilization from a predominantly systemic to a topical approach.
authors.affiliation: Dermatology Service, Department of Veterans Affairs Medical Center, and Department of Dermatology, UCSF, San Francisco, California 94121, USA.
authors.forename: Tzu-Kai
authors.initials: TK
authors.lastname: Lin
authors.forename: Mao-Qiang
authors.initials: MQ
authors.lastname: Man
authors.forename: Juan-Luis
authors.initials: JL
authors.lastname: Santiago
authors.forename: Kyungho
authors.initials: K
authors.lastname: Park
authors.forename: Truus
authors.initials: T
authors.lastname: Roelandt
authors.forename: Yuko
authors.initials: Y
authors.lastname: Oda
authors.forename: Melanie
authors.initials: M
authors.lastname: Hupe
authors.forename: Debra
authors.initials: D
authors.lastname: Crumrine
authors.forename: Hae-Jin
authors.initials: HJ
authors.lastname: Lee
authors.forename: Maria
authors.initials: M
authors.lastname: Gschwandtner
authors.forename: Jacob P
authors.initials: JP
authors.lastname: Thyssen
authors.forename: Carles
authors.initials: C
authors.lastname: Trullas
authors.forename: Erwin
authors.initials: E
authors.lastname: Tschachler
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Feingold
authors.forename: Peter M
authors.initials: PM
authors.lastname: Elias
mesh_terms: D000287:Administration, Topical; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002927:Cimetidine / Q000494:pharmacology; D003876:Dermatitis, Atopic / Q000188:drug therapy* / Q000276:immunology*; D003877:Dermatitis, Contact / Q000188:drug therapy / Q000276:immunology; D004155:Diphenhydramine / Q000494:pharmacology; D004195:Disease Models, Animal; D004817:Epidermis / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006633:Histamine Antagonists / Q000494:pharmacology*; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D006635:Histamine H2 Antagonists / Q000494:pharmacology; D006706:Homeostasis / Q000187:drug effects / Q000276:immunology; D007509:Irritants / Q000494:pharmacology; D050356:Lipid Metabolism / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008812:Mice, Hairless; D010539:Permeability / Q000187:drug effects
chemical_list: D006633:Histamine Antagonists; D006634:Histamine H1 Antagonists; D006635:Histamine H2 Antagonists; D007509:Irritants; D002927:Cimetidine; D004155:Diphenhydramine