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Comparative Study
. 2008 Jan;128(1):79-86.
doi: 10.1038/sj.jid.5701011. Epub 2007 Aug 2.

Characterization of a Hapten-Induced, Murine Model With Multiple Features of Atopic Dermatitis: Structural, Immunologic, and Biochemical Changes Following Single Versus Multiple Oxazolone Challenges

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Free PMC article
Comparative Study

Characterization of a Hapten-Induced, Murine Model With Multiple Features of Atopic Dermatitis: Structural, Immunologic, and Biochemical Changes Following Single Versus Multiple Oxazolone Challenges

Mao-Qiang Man et al. J Invest Dermatol. .
Free PMC article

Abstract

Atopic dermatitis (AD) is a chronic dermatosis bearing clinical, histological, and immunologic similarities to chronic allergic contact dermatitis (ACD). AD shows a Th2 cell-dominant inflammatory infiltrate, elevated serum IgE levels, a permeability barrier abnormality, and Staphylococcus aureus colonization. Repeated hapten challenges reportedly produce a Th2-like hypersensitivity reaction (Th2-like HR). Here, 9-10 challenges with oxazolone (Ox) to hairless mice also produced a chronic Th2-like HR. Permeability barrier function and expression of differentiation proteins, filaggrin, loricrin, and involucrin, became abnormal. CRTH-positive Th2-dominant inflammatory infiltrate, with increased IL-4 expression, and a large increase in serum IgE levels were observed. The barrier abnormality was associated with decreased stratum corneum (SC) ceramide content and impaired lamellar body secretion, resulting in abnormal lamellar membranes, as in human AD. Furthermore, as in human AD, epidermal serine protease activity in SC increased and expression of two lamellar body-derived antimicrobial peptides, CRAMP and mBD3, declined after Ox challenges, paralleling the decrease of their human homologues in AD. Thus, multiple Ox challenges to normal murine skin produce a chronic Th2-like HR, with multiple features of human AD. Because of its reproducibility, predictability, and low cost, this model could prove useful for evaluating both pathogenic mechanisms and potential therapies for AD.

Conflict of interest statement

CONFLICT OF INTEREST

The authors state no conflict of interest.

Figures

Figure 1
Figure 1. Functional abnormalities emerge after multiple Ox Challenges
(a) SC hydration assessed as electrical capacitance, in absolute units. (b) Surface pH assessed with a flat surface electrode. (c) Permeability barrier function, assessed as changes in basal TEWL with an electrolytic water analyzer (as mg/cm2/hour). (d) Kinetics of permeability barrier recovery after acute barrier disruption by cellophane tape stripping (initial TEWL is increased to 20- to 30-fold above basal levels).
Figure 2
Figure 2. Repeated Ox challenges alter stratum corneum lipid content/distribution
Cohorts of hairless mice (n=5 each) were treated with vehicle alone, or Ox (1 or 10 applications). Lipids were extracted from isolated stratum corneum sheets with Bligh–Dyer solvents, fractionated, quantified, and the content of each fraction was expressed as μg/mg dry SC weight. Data were expressed as % change from vehicle-treated±SEM.
Figure 3
Figure 3. Repeat Ox-challenged SC displays entombed lamellar bodies, lamellar membrane disorganization, and corneocyte detachment
(a) Lamellar bodies (LBs) accumulate in the peripheral cytosol of granular cells in Ox-challenged mice (arrows), while (b) LB are more widely dispersed in preparation for secretion in vehicle (Veh)-treated mice. (c) Ox-challenged corneocytes (SC) focally detach from underlying stratum granulosum (SG) and lose contact between themselves (open arrows), sometimes leading to large cleavage planes (asterisk). Decreased quantities and poor organization of extracellular lamellar membranes are seen in Ox-challenged (d, single arrows) versus vehicle-treated (e, layered arrows) mice. Note entombed organelle remnants in corneocyte cytosol of Ox-challenged mice, indicating incomplete LB secretion (d, open arrows). (ac) Osmium tetroxide post-fixation; (d, e) ruthenium tetroxide post-fixation. Bars=1 μm (a–c); 0.1 μm (d, e).
Figure 4
Figure 4. Th2 immunophenotype predominates after repeated Ox challenges
(a) CRTH2 immunostaining of Th2 lymphocytes is virtually absent in dermis after (a) vehicle treatment alone or (b) one Ox challenge, but density of CRTH2-positive cells increases significantly after 10 challenges (c, arrows). Merged images with propidium iodide secondary staining in 5 μm frozen sections. Bar=40 μm.
Figure 5
Figure 5. Antimicrobial peptide expression declines after one Ox challenge, and remains reduced after 10 challenges
Immunofluorescent staining for (ac) cathelicidin-related antimicrobial peptide (CRAMP) and (df) mouse β-defensin 3 (mBD3). (a, d) With vehicle treatment; (b, e) with one Ox challenge; (c, f) with 10 Ox challenges. Propidium iodide counterstaining. Bars=20 μm.

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