Background Petrolatum is a common moisturizer often used in the prevention of skin infections after ambulatory surgeries and as a maintenance therapy of atopic dermatitis (AD). However, the molecular ...responses induced by petrolatum in the skin have never been assessed. Objective We sought to define the cutaneous molecular and structural effects induced by petrolatum. Methods Thirty-six healthy subjects and 13 patients with moderate AD (mean SCORAD score, 39) were studied by using RT-PCR, gene arrays, immunohistochemistry, and immunofluorescence performed on control skin, petrolatum-occluded skin, and skin occluded with a Finn chamber only. Results Significant upregulations of antimicrobial peptides (S100A8/fold change FCH, 13.04; S100A9/FCH, 11.28; CCL20/FCH, 8.36; PI3 elafin/FCH, 15.40; lipocalin 2/FCH, 6.94, human β-defensin 2 DEFB4A/FCH, 4.96; P < .001 for all) and innate immune genes ( IL6 , IL8 , and IL1B ; P < .01) were observed in petrolatum-occluded skin compared with expression in both control and occluded-only skin. Application of petrolatum also induced expression of key barrier differentiation markers (filaggrin and loricrin), increased stratum corneum thickness, and significantly reduced T-cell infiltrates in the setting of “normal-appearing” or nonlesional AD skin, which is known to harbor barrier and immune defects. Conclusions Petrolatum robustly modulates antimicrobials and epidermal differentiation barrier measures. These data shed light on the beneficial molecular responses of petrolatum in barrier-defective states, such as AD and postoperative wound care.
Background Atopic dermatitis (AD) is the most common inflammatory disease. Evolving disease models link changes in epidermal growth and differentiation to TH 2/TH 22 cytokine activation. However, ...these models have not been tested by in vivo suppression of T-cell cytokines. Cyclosporine (CsA) is an immunosuppressant that is highly effective for severe disease, but its mechanism in AD skin lesions has not been studied. Objective We sought to establish the ability of a systemic immunosuppressant to modulate immune and epidermal alterations that form the pathogenic disease phenotype and to correlate changes with clinical improvement. Methods CsA's effects on AD skin pathology were evaluated by using gene expression and immunohistochemistry studies in baseline, week 2, and week 12 lesional and nonlesional biopsy specimens from 19 patients treated with 5 mg/kg/d CsA for 12 weeks. Results After 2 and 12 weeks of treatment, we observed significant reductions of 51% and 72%, respectively, in SCORAD scores. Clinical improvements were associated with significant gene expression changes in lesional but also nonlesional skin, particularly reductions in levels of TH 2-, TH 22-, and some TH 17-related molecules (ie, IL-13, IL-22, CCL17, S100As, and elafin/peptidase inhibitor 3), and modulation of epidermal hyperplasia and differentiation measures. Conclusions This is the first study that establishes a relationship between cytokine activation and molecular epidermal alterations, as well as correlations between disease biomarkers in the skin and clinical improvement. The reversal of the molecular phenotype with CsA and the associated biomarkers can serve as a reference for the successful modulation of tissue inflammation with specific immune antagonists in future studies, contributing to the understanding of the specific cytokines involved in epidermal pathology.
Background Topical glucocorticosteroids are considered an efficient treatment option for atopic dermatitis (AD), but a global assessment of glucocorticosteroid responses on key disease circuits upon ...weeks to months of treatment is currently lacking. Objective We sought to assess short (4 weeks) and long-term (16 weeks) application of topical glucocorticosteroids on AD skin and define response biomarkers. Methods The effects of triamcinolone acetonide cream 0.025% were assessed based on gene expression and immunohistochemistry studies at baseline, 4 weeks, and 16 weeks in biopsy specimens from 15 patients with moderate-to-severe AD. Results At 16 weeks, only 3 patients were clinical responders (by using SCORAD50 criteria), but 6 patients qualified as responders based on histologic criteria. Baseline characteristics indicated more severe disease in nonresponders. While 3 of 15 patients experienced only transient benefit after 4 weeks, others showed progressive improvements toward 16 weeks. Topical glucocorticosteroid use in patients with AD resulted in improvements of the AD genomic signature of 25.6% at 4 weeks and 71.8% at 16 weeks, respectively, and even 123.9% in the histologic responder group. Cytokines (IL-12p40, IL-13, IL-22, CCL17, CCL18, peptidase inhibitor 3 PI3/elafin, and S100As) showed consistent decreases from baseline toward 16 weeks with corresponding improvements in epidermal disease hallmarks (keratin 16 and loricrin) in lesional skin from responders ( P < .05). Nonresponders largely showed lesser/nonsignificant reductions in key inflammatory and barrier markers (keratin 16, IL-13, IL-22, CCL17, CCL18, PI3/elafin, S100As, and loricrin). The combination of IL-21 and IFN-γ baseline expression closely predicted individual clinical glucocorticosteroid responses at 16 weeks of treatment. Conclusion Our study indicates that even low-potency glucocorticosteroids can broadly affect immune and barrier responses in patients with moderate-to-severe AD, associating higher baseline severity with increased steroid resistance in patients with AD.
Background Past studies of blood T-cell phenotyping in patients with atopic dermatitis (AD) have provided controversial results and were mostly performed before the identification of TH 9, TH 17, and ...TH 22 T-cell populations in human subjects. Objective We sought to quantify TH 1, TH 2, TH 9, TH 17, and TH 22 T-cell populations and corresponding CD8+ T-cell subsets in both cutaneous lymphocyte antigen (CLA)–positive and CLA− T-cell subsets in patients with AD and control subjects. Methods We studied 42 adults with severe AD (mean SCORAD score, 65) and 25 healthy subjects using an 11-color flow cytometric antibody panel. Frequencies of IFN-γ–, IL-22–, IL-13–, IL-17–, and IL-9–producing CD4+ and CD8+ T cells were compared in CLA− and CLA+ populations. Results We measured increased TH 2/TC 2/IL-13+ and TH 22/TC 22/IL-22+ populations ( P < .1) in patients with severe AD versus control subjects, with significant differences in CLA+ T-cell numbers ( P < .01). A significantly lower frequency of CLA+ IFN-γ–producing cells was observed in patients with AD, with no significant differences in CLA− T-cell numbers. The CLA+ TH 1/TH 2 and TC 1/TC 2 ratio was highly imbalanced in patients with AD (10 vs 3 P = .005 and 19 vs 7 P < .001, respectively). Positive correlations were found between frequencies of IL-13– and IL-22–producing CD4+ and CD8+ T cells ( r = 0.5 and 0.8, respectively; P < .0001), and frequencies of IL-13–producing CLA+ cells were also correlated with IgE levels and SCORAD scores. Patients with AD with skin infections had higher CD4+ IL-22+ and IL-17+ cell frequencies, which were highly significant among CLA− cells (IL-22: 3.7 vs 1.7 P < .001 and IL-17: 1.7 vs 0.6 P < .001), with less significant effects among CLA+ T cells (IL-22: 11 vs 7.5, P = .04). Conclusions Severe AD is accompanied by expansion of skin-homing TH 2/TC 2 and TH 22/TC 22 subsets with lower TH 1/TC 1 frequencies. These data create a critical basis for studying alterations in immune activation in adults and pediatric patients with AD.
PDF
