Topical Antihistamines Display Potent Anti-Inflammatory Activity Linked in Part to Enhanced Permeability Barrier Function Tzu-Kai Lin, Mao-Qiang Man,

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Topical Antihistamines Display Potent Anti-Inflammatory Activity Linked in Part to Enhanced Permeability Barrier Function Tzu-Kai Lin, Mao-Qiang Man, Juan-Luis Santiago, Kyungho Park, Truus Roelandt, Yuko Oda, Melanie Hupe, Debra Crumrine, Hae-Jin Lee, Maria Gschwandtner, Jacob P. Thyssen, Carles Trullas, Erwin Tschachler, Kenneth R. Feingold, Peter M. Elias Journal of Investigative Dermatology Volume 133, Issue 2, Pages 469-478 (February 2013) DOI: 10.1038/jid.2012.335 Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Topical H1/2r (histamine type 1 and 2 receptors) antagonists enhance permeability barrier homeostasis in normal skin. The flanks of hairless mice (n=4–5 each) were treated with topical applications of either diphenhydramine chlorhydrate (H1r), cimetidine (H2r), or ethanol (vehicle) twice daily for 4 days (see Materials and Methods for further details). At the end of treatments, changes in basal barrier function, assessed as (a) transepidermal water loss (TEWL), (b) surface pH, and (c) electrical conductance (SC) hydration, were measured. (d) Barrier disruption was induced by sequential cellophane tape strippings until TEWL levels ≥10-fold increase over baseline, and barrier recovery rates were assessed 2 and 4 hours later (**P<0.05 vs. vehicle, *P<0.01 vs. vehicle, ***P<0.001 vs. vehicle and vs. H1r+H2r). (e) Percentage of barrier recovery was compared in mast cell–deficient KitW/KitW-v double-heterozygote mice (MCDM) with wild-type (WBB6F1) mice 2 and 4 hours after tape stripping, as described above. Journal of Investigative Dermatology 2013 133, 469-478DOI: (10.1038/jid.2012.335) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Topical H1/H2r (histamine type 1 and 2 receptors) antagonists stimulate epidermal differentiation. (a–i) Hairless mice were treated as described above, and paraffin-embedded sections (6μm) were then immunostained to detect changes in filaggrin, involucrin, and loricrin content and localization. (j) In parallel, mRNA was isolated from freshly obtained epidermal sheets after treatments as in Figure 1, above (n=4), and changes in mRNA levels for filaggrin, loricrin, and involucrin were assessed by real-time quantitative PCR (see Materials and Methods and Supplementary Table S2 online for further details). Bar=50μm. Veh, vehicle. Journal of Investigative Dermatology 2013 133, 469-478DOI: (10.1038/jid.2012.335) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Topical H1r/H2r (histamine type 1 and 2 receptors) antagonists enhance corneocyte envelope (CE) thickness. (a–c) Electron micrographs of biopsies of H1/2r antagonist–treated skin were processed for electron microscopy, as described in Methods. (d) Ten micrographs each of perpendicular sections taken at random from six different biopsy samples. CE dimensions were measured directly on the electron microscope, as described in Materials and Methods. a–c; Osmium tetroxide postfixation. Bar=100μm. Veh, vehicle. Journal of Investigative Dermatology 2013 133, 469-478DOI: (10.1038/jid.2012.335) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Global stimulation of epidermal lipid synthesis by topical H1/2r (histamine type 1 and 2 receptors) antagonists. Hairless mice were treated as described above (Figure 1), and biopsies were snap-frozen in liquid nitrogen. (a–c) Frozen sections (5μm) were incubated with either the fluorophore, nile red, or vehicle, and viewed under a fluorescence microscope, as described in Materials and Methods (arrows depict sites of enhanced staining for lipids in the epidermis). (d) Freshly obtained, full-thickness skin biopsies were incubated with 14C-acetate, followed by epidermal isolation, lipid extraction, saponification, fractionation by thin-layer chromatography, and quantification of changes in non-saponifiable (NSL) and saponifiable (total fatty acid) lipids, as described in Materials and Methods. (e–j) mRNA was isolated from epidermal sheets as described above (n=4 mice each), and changes in mRNA levels for lipid synthetic enzymes (HMGCoA reductases, serine palmitoyl transferase (SPT), fatty acid modifying enzyme, fatty acid 2-hydroxylase (FA2H), and the acylceramide-generating elongation of very-long chain fatty acid-4 (ELOVL4)) were assessed by real-time quantitative PCR, as described in Materials and Methods and Supplementary Table S2 online. Bar=10μm. Journal of Investigative Dermatology 2013 133, 469-478DOI: (10.1038/jid.2012.335) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 Topical H1/2r (histamine type 1 and 2 receptors) antagonists stimulate lamellar production and/or secretion. Biopsies of H1/2r antagonist- and vehicle-treated skin samples (as in Figure 1) were processed for electron microscopy, as described in Materials and Methods. Solid arrows point to individual or aggregated lamellar bodies, and open arrows depict changes in secreted contents at the stratum granulosum (SG)–SC interface. Representative samples of the outer epidermis of (a) vehicle-treated (Veh), (b and c) H1r antagonist (diphenhydramine chlorhydrate)–treated, and (d) H2r (cimetidine)-treated skin. Note increased organelle density in the SG of H2r-treated epidermis, and premature secretion of lamellar bodies in H1r antagonist–treated skin, (b–e), as well as enhanced secretion of lamellar body contents at the stratum granulosum (SG)–SC interface (H2r>H1r). (f) Enhanced formation of lamellar bodies correlated with increased mRNA levels of ABCA12 in H2r antagonist–treated skin (n=4); the increase in ABCA12 mRNA following H1r antagonist treatments did not achieve statistical significance. a–e: Osmium tetroxide postfixation. Bar=0.5μm. GAPDH, glyceraldehyde-3-phosphate dehydrogenase. Journal of Investigative Dermatology 2013 133, 469-478DOI: (10.1038/jid.2012.335) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 6 Topical H1/2r (histamine type 1 and 2 receptors) antagonists improve inflammatory dermatosis, independent of benefits for barrier function. (a) Changes in ear thickness in acute irritant and acute allergic contact dermatitis (AICD and AACD, respectively) 16hours after previous topical application of the H1/2r antagonists. (b) Changes in transepidermal water loss 16hours after a single topical application of the H1r or H2r antagonist or vehicle (veh) to opposing flanks of previously sensitized and subsequently challenged mice (3x=subacute allergic contact dermatitis (SACD)); (atopic dermatitis (AD)=10 hapten challenges). Dotted line indicates upper level of water loss in normal mice. Journal of Investigative Dermatology 2013 133, 469-478DOI: (10.1038/jid.2012.335) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions