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  • Title: Phenylbutyrate suppresses distinct skin reactions that are enhanced by blockade of epidermal growth factor receptor signaling.
    Author: Chung YL, Pui NN.
    Journal: J Dermatol Sci; 2011 Dec; 64(3):163-73. PubMed ID: 21924869.
    Abstract:
    BACKGROUND: Epidermal growth factor receptor inhibitors (EGFRIs) cause skin inflammation, and understanding the factors that mediate this reaction is fundamental for designing therapies for EGFRI-related cutaneous side effects. OBJECTIVE: We characterized EGFRI-enhanced skin reactions and evaluated the therapeutic efficacy of phenylbutyrate, a histone deacetylase inhibitor. METHODS: PD168393, an EGFRI, was applied topically to the ear skin of mice with or without mast cell deficiency. The skin was then irritated once or pre-sensitized and repeatedly challenged with 2,4-dinitrofluorobenzene (DNFB). The reaction pattern, the type and number of infiltrating cells, changes in protein, cytokine (TNF-α) and chemokine (CCL2) expression, and the immune response were analyzed. Phenylbutyrate, formulated as a gel for topical treatment or dissolved in water for intraperitoneal administration, was tested as a treatment. RESULTS: EGFRI rapidly upregulated the mast cell chemotactic factor, stem cell factor (SCF) and augmented DNFB-induced immediate contact dermatitis within hours of treatment in the presence of mast cells. Topical phenylbutyrate treatment suppressed EGFRI-induced SCF expression in the epithelium, inhibited DNFB-induced mast cell recruitment in the dermis, and ameliorated the EGFRI-enhanced acute skin reaction. EGFRI also enhanced the delayed-type DNFB-induced hypersensitive reaction that was mast-cell independent but was associated with T lymphocytes. Systemic phenylbutyrate administration suppressed EGFRI-enhanced delayed-type skin hypersensitivity by increasing the number and function of Foxp3(+) T regulatory suppressor cells, which inhibited T helper cell proliferation. CONCLUSIONS: Our data suggest that phenylbutyrate has dual beneficial therapeutic effects on EGFRI-enhanced acute (local inflammatory) and late (systemic immune) skin reactions.
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