BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory dermatosis now increasingly linked to mutations that alter the structure and function of the stratum corneum. Activators of peroxisome proliferator-activated receptors (PPARs) alpha, beta/delta, and gamma and liver X receptor (LXR) regulate epidermal protein and lipid production, leading to superior barrier function. Additionally, some of these activators exhibit potent antihyperplastic and anti-inflammatory activity in irritant contact dermatitis and acute allergic contact dermatitis murine models. OBJECTIVE: We evaluated the efficacy of PPAR/LXR activation in a hapten (oxazolone [Ox])-induced AD-like model (Ox-AD) in hairless mice. METHODS: Ox-AD was established with 10 Ox challenges (every other day) on the flank. After the establishment of Ox-AD, twice-daily topical application with individual PPAR/LXR activators was then performed for 4 days, with continued Ox challenges every other day. The efficacy of topical PPAR/LXR activators to reduce parameters of Ox-AD was assessed physiologically, morphologically, and immunologically. RESULTS: Certain topical activators of PPARalpha, PPARbeta/delta, and LXR, but not activators of PPARgamma, reversed the clinical dermatosis, significantly improved barrier function, and increased stratum corneum hydration in Ox-AD mice. In addition, the same activators, but again not PPARgamma, largely reversed the immunologic abnormalities in Ox-AD mice, including the increased T(H)2 markers, such as tissue eosinophil/mast cell density, serum thymus and activation-related chemokine levels, the density of chemoattractant receptor-homologous molecule expressed on T(H)2-positive lymphocytes (but not serum IgE levels), and reduced IL-1alpha and TNF-alpha activation, despite ongoing hapten challenges. CONCLUSION: These results suggest that topical applications of certain activators/ligands of PPARalpha, PPARbeta/delta, and LXR could be useful for the treatment of AD in human subjects. Copyright 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.
BACKGROUND:Atopic dermatitis (AD) is a chronic inflammatory dermatosis now increasingly linked to mutations that alter the structure and function of the stratum corneum. Activators of peroxisome proliferator-activated receptors (PPARs) alpha, beta/delta, and gamma and liver X receptor (LXR) regulate epidermal protein and lipid production, leading to superior barrier function. Additionally, some of these activators exhibit potent antihyperplastic and anti-inflammatory activity in irritant contact dermatitis and acute allergic contact dermatitismurine models. OBJECTIVE: We evaluated the efficacy of PPAR/LXR activation in a hapten (oxazolone [Ox])-induced AD-like model (Ox-AD) in hairless mice. METHODS:Ox-AD was established with 10 Ox challenges (every other day) on the flank. After the establishment of Ox-AD, twice-daily topical application with individual PPAR/LXR activators was then performed for 4 days, with continued Ox challenges every other day. The efficacy of topical PPAR/LXR activators to reduce parameters of Ox-AD was assessed physiologically, morphologically, and immunologically. RESULTS: Certain topical activators of PPARalpha, PPARbeta/delta, and LXR, but not activators of PPARgamma, reversed the clinical dermatosis, significantly improved barrier function, and increased stratum corneum hydration in Ox-AD mice. In addition, the same activators, but again not PPARgamma, largely reversed the immunologic abnormalities in Ox-AD mice, including the increased T(H)2 markers, such as tissue eosinophil/mast cell density, serum thymus and activation-related chemokine levels, the density of chemoattractant receptor-homologous molecule expressed on T(H)2-positive lymphocytes (but not serum IgE levels), and reduced IL-1alpha and TNF-alpha activation, despite ongoing hapten challenges. CONCLUSION: These results suggest that topical applications of certain activators/ligands of PPARalpha, PPARbeta/delta, and LXR could be useful for the treatment of AD in human subjects. Copyright 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.
Authors: Peck Y Ong; Takaaki Ohtake; Corinne Brandt; Ian Strickland; Mark Boguniewicz; Tomas Ganz; Richard L Gallo; Donald Y M Leung Journal: N Engl J Med Date: 2002-10-10 Impact factor: 91.245
Authors: Mary Y Sheu; Ashley J Fowler; Jack Kao; Matthias Schmuth; Kristina Schoonjans; Johan Auwerx; Joachim W Fluhr; Mao-Qiang Man; Peter M Elias; Kenneth R Feingold Journal: J Invest Dermatol Date: 2002-01 Impact factor: 8.551
Authors: Yutaka Hatano; Mao-Qiang Man; Yoshikazu Uchida; Debra Crumrine; Tiffany C Scharschmidt; Esther G Kim; Theodora M Mauro; Kenneth R Feingold; Peter M Elias; Walter M Holleran Journal: J Invest Dermatol Date: 2009-01-29 Impact factor: 8.551
Authors: Sarah L Chamlin; Jack Kao; Ilona J Frieden; Mary Y Sheu; Ashley J Fowler; Joachim W Fluhr; Mary L Williams; Peter M Elias Journal: J Am Acad Dermatol Date: 2002-08 Impact factor: 11.527
Authors: Ashley J Fowler; Mary Y Sheu; Matthias Schmuth; Jack Kao; Joachim W Fluhr; Linda Rhein; Jon L Collins; Timothy M Willson; David J Mangelsdorf; Peter M Elias; Kenneth R Feingold Journal: J Invest Dermatol Date: 2003-02 Impact factor: 8.551