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. 2011 Sep;131(9):1845-52.
doi: 10.1038/jid.2011.144. Epub 2011 Jun 2.

Efficacy of Combined Peroxisome Proliferator-Activated Receptor-α Ligand and Glucocorticoid Therapy in a Murine Model of Atopic Dermatitis

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Free PMC article

Efficacy of Combined Peroxisome Proliferator-Activated Receptor-α Ligand and Glucocorticoid Therapy in a Murine Model of Atopic Dermatitis

Yutaka Hatano et al. J Invest Dermatol. .
Free PMC article

Abstract

Although topical glucocorticoids (GCs) show potent anti-inflammatory activity in inflamed skin, they can also exert numerous harmful effects on epidermal structure and function. In contrast, topical applications of ligands of peroxisome proliferator-activated receptor-α (PPARα) not only reduce inflammation but also improve cutaneous barrier homeostasis. Therefore, we examined whether sequential topical GCs followed by topical Wy14643 (a ligand of PPARα) might be more effective than either alone for atopic dermatitis (AD) in a hapten (oxazolone (Ox))-induced murine model with multiple features of AD (Ox-AD). Despite expected anti-inflammatory benefits, topical GC alone induced (i) epidermal thinning; (ii) reduced expression of involucrin, loricrin, and filaggrin; and (iii) allowed outside-to-inside penetration of an epicutaneous tracer. Although Wy14643 alone yielded significant therapeutic benefits in mice with mild or moderate Ox-AD, it was less effective in severe Ox-AD. Yet, topical application of Wy14643 after GC was not only significantly effective comparable with GC alone, but it also prevented GC-induced structural and functional abnormalities in permeability barrier homeostasis. Moreover, rebound flares were largely absent after sequential treatment with GC and Wy14643. Together, these results show that GC and PPARα ligand therapy together is not only effective but also prevents development of GC-induced side effects, including rebound flares, in murine AD.

Conflict of interest statement

Conflict of Interest

The authors state no conflict of interest.

Figures

Figure 1
Figure 1. Effects of treatment with a topical glucocorticoid (GC) and/or a PPARα activator on transepidermal water loss (TEWL) and the infiltration of CD3-positive cells
Transepidermal water loss [(a) and (b)] was measured as described in the text. In (b) and (c), Ox-AD mice in which TEWL was more than 25 g/m2/h on day 1 were used for the experiments. * p<0.05 vs. day 1. Numbers of CD3-positive cells on day 5 are shown in (c). n = 8 (four mice) in (a), n=6–10 (three to five mice) in (b) and n=40–80 (three to four mice) in (c). Abbreviation of label of each experimental group is according to the description in Table 1.
Figure 2
Figure 2. Morphological changes in the epidermis
Skin samples were collected on experimental day 5 and were stained with hematoxylin and eosin as shown in (a). Bars =20 µm. Epidermal thickness was measured as described in the text and is shown in (b). n= 30–60 (three to four mice). Abbreviation of label of each experimental group is according to the description in Table 1.
Figure 3
Figure 3. Assessment of outside-to-inside permeability-barrier function
The results of a quantitative penetration assay with Evans blue [(a); n=8 (four mice)] and electron micrographs [(b), (c) and (d)] are shown. See text for details. (b) Ox+veh, (c) Ox+GC,GC and (d) Ox+GC,Wy. Block arrows indicate electron-dense material, namely, lanthanum nitrate, that has penetrated intercorneocyte spaces at the stratum corneum and stratum granulosum interface. Bars = 0.5 µm. Abbreviation of label for each experimental group is according to the description in Table 1.
Figure 4
Figure 4. Recovery of permeability barrier function
On experimental day 5, the permeability barrier was disrupted by tape stripping as described in the text. Transepidermal water loss (TEWL) was examined before and after tape stripping, at each indicated time point, as described in the text. The horizontal dotted line indicates the mean values in normal control mice. The p-values in (a) refer to differences between Ox+GC,GC and Ox+GC,Wy. n = 10 (five mice). Abbreviation of label of each experimental group is according to the description in Table 1.
Figure 5
Figure 5. Rebound of dermatitis after discontinuation of therapy
The every other day skin challenge with Ox alone was continued (day 5 and day 7) on the same area without GC nor Wy treatment. (a) Clinical appearance of mice on experimental day 9. (b) Alteration of transepidermal water loss (TEWL) (c) Density of CD3-positive cells in skin samples collected on day 9. The p-values refer to results from Ox+GC,GC and Ox+GC,Wy. n = 12 (six mice) in (b), n = 24 (three mice) for GC, GC in (c) and n = 26 (three mice) for GC,Wy in (c). Abbreviation of label of each experimental group is according to the description in Table 1.

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