Hyperglycemia-activated 11ß-hydroxysteroid dehydrogenase type 1 increases endoplasmic reticulum stress and skin barrier dysfunction.

The diabetes mellitus (DM) skin shows skin barrier dysfunction and skin lipid abnormality, similar to conditions induced by systemic or local glucocorticoid excess and aged skin. Inactive glucocorticoid (GC) is converted into active glucocorticoid by 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1). Hyperglycemia in DM and excessive GC are known to increase endoplasmic reticulum (ER) stress. We hypothesized that hyperglycemia affects systemic GC homeostasis and that the action of skin 11ß-HSD1 and GC contributes to increased ER stress and barrier defects in DM. We compared 11ß-HSD1, active GC, and ER stress between hyperglycemic and normoglycemic conditions in normal human keratinocytes and db/db mice. 11ß-HSD1 and cortisol increased with time in keratinocyte culture under hyperglycemic conditions. 11ß-HSD1 siRNA-transfected cells did not induce cortisol elevation in hyperglycemic condition. The production of 11ß-HSD1 and cortisol was suppressed in cell culture treated with an ER stress-inhibitor. The 14-week-old db/db mice showed higher stratum corneum (SC) corticosterone, and skin 11ß-HSD1 levels than 8-week-old db/db mice. Topical 11ß-HSD1 inhibitor application in db/db mice decreased SC corticosterone levels and improved skin barrier function. Hyperglycemia in DM may affect systemic GC homeostasis, activate skin 11ß-HSD1, and induce local GC excess, which increases ER stress and adversely affects skin barrier function.

Increased Expression of 11ß-Hydroxysteroid Dehydrogenase Type 1 Contributes to Epidermal Permeability Barrier Dysfunction in Aged Skin.

Inactive cortisone is converted into active cortisol by 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1). Excessive levels of active glucocorticoids could deteriorate skin barrier function; barrier impairment is also observed in aged skin. In this study, we aimed to determine whether permeability barrier impairment in the aged skin could be related to increased 11ß-HSD1 expression. Aged humans (n = 10) showed increased cortisol in the stratum corneum (SC) and oral epithelium, compared to young subjects (n = 10). 11ß-HSD1 expression (as assessed via immunohistochemical staining) was higher in the aged murine skin. Aged hairless mice (56-week-old, n = 5) manifested greater transepidermal water loss, lower SC hydration, and higher levels of serum inflammatory cytokines than the young mice (8-week-old, n = 5). Aged 11ß-HSD1 knockout mice (n = 11), 11ß-HSD1 inhibitor (INHI)-treated aged wild type (WT) mice (n = 5) and young WT mice (n = 10) exhibited reduced SC corticosterone level. Corneodesmosome density was low in WT aged mice (n = 5), but high in aged 11ß-HSD1 knockout and aged INHI-treated WT mice. Aged mice exhibited lower SC lipid levels; this effect was reversed by INHI treatment. Therefore, upregulation of 11ß-HSD1 in the aged skin increases the active-glucocorticoid levels; this suppresses SC lipid biosynthesis, leading to impaired epidermal permeability barrier.

Reflux Esophagitis and Fatigue: Are They Related?

Gastroesophageal reflux disease (GERD) is a chronic, recurrent disease. Reflux esophagitis can interfere with sleep via acid reflux, which can cause daytime sleepiness or fatigue. However, little is known about the association between reflux esophagitis and fatigue. OBJECTIVES: We evaluated the association between fatigue and reflux esophagitis in subjects seen at health check-ups. METHODS: Consecutive patients who were scheduled for screening endoscopies were enrolled prospectively at the Comprehensive Medical Examination Center of St. Vincent Hospital and Eunpyeong St. Mary's Hospital, Korea. Three validated questionnaires were used to assess fatigue, daytime hypersomnolence, anxiety, and depression: the Multidimensional Fatigue Inventory-Korean version (MFI-K), Epworth Sleepiness Scale (ESS), and Hospital Anxiety and Depression Scale (HADS). RESULTS: We investigated 497 consecutive eligible subjects. The reflux esophagitis and symptomatic GERD groups comprised 103 (20.7%) and 92 (18.5%) subjects, respectively. The MFI-K total, ESS, HADS-anxiety, and HADS-depression scores did not differ between the esophagitis and non-esophagitis groups (50.0 ± 11.5 vs. 49.7 ± 10.9, p = 0.661; 6.2 ± 2.8 vs. 6.1 ± 3.1, p = 0.987; 5.8 ± 3.1 vs. 5.2 ± 3.2, p = 0.060; 6.2 ± 3.6 vs. 6.0 ± 3.3, p = 0.561). However, the MFI-K total, ESS, HADS-anxiety, and HADS-depression scores were higher in the symptomatic group than in the non-symptomatic group (54.7 ± 12.7 vs. 48.6 ± 10.3, p < 0.001; 7.1 ± 3.5 vs. 5.9 ± 2.9, p = 0.002; 6.4 ± 3.3 vs. 5.1 ± 3.1, p < 0.001; 7.5 ± 4.0 vs. 5.7 ± 3.1, p < 0.001). Multiple regression analysis showed that the MFI-K total was correlated with GERD symptoms (p = 0.021), women (p = 0.001), anxiety (p < 0.001), and depression (p < 0.001). CONCLUSION: There was no statistically significant association in which reflux esophagitis could cause daytime sleepiness, fatigue, anxiety, or depression. However, fatigue was associated with GERD symptoms, women, anxiety, and depression. Further studies should clarify the association between fatigue and reflux esophagitis.

Role of 11ß-hydroxysteroid dehydrogenase type 1 in the development of atopic dermatitis.

Glucocorticoids (GCs) are potent anti-inflammatory drugs, the secretion of which is mediated and controlled by the hypothalamic-pituitary-adrenal axis. However, they are also secreted de novo by peripheral tissues for local use. Several tissues express 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1), including the skin. The inactive GC cortisone is converted by 11ß-HSD1 to active GC cortisol, which is responsible for delayed wound healing during a systemic excess of GC. However, the role of 11ß-HSD1 in inflammation is unclear. We assessed whether 11ß-HSD1 affects the development of atopic dermatitis (AD) in vitro and in vivo. The expression of 11ß-HSD1 in the epidermis of AD lesions was higher than that in the epidermis of healthy controls. Knockdown of 11ß-HSD1 in human epidermal keratinocytes increased the production of thymic stromal lymphopoietin. In an oxazolone-induced mouse model of AD, localized inhibition of 11ß-HSD1 aggravated the development of AD and increased serum cytokine levels associated with AD. Mice with whole-body knockout (KO) of 11ß-HSD1 developed significantly worse AD upon induction by oxazolone. We propose that 11ß-HSD1 is a major factor affecting AD pathophysiology via suppression of atopic inflammation due to the modulation of active GC in the skin.

Clinical characteristics and genetic variation in atopic dermatitis patients with and without allergic contact dermatitis.

In patients with atopic dermatitis (AD), the risk of contact sensitization may be higher as the disrupted skin barrier may increase the penetration of contact allergens. Therefore, it is necessary to screen for concurrent allergic contact dermatitis (ACD) in AD patients. To identify the clinical characteristics and genetic variation in AD patients with concurrent ACD. In total, 281 AD subjects who underwent patch testing were included. Subjects with a positive result were classified as "AD with ACD", while the others were classified as "AD only". Clinical characteristics and prevalence of genetic variants (FLG 3321delA, FLG K4022X, KLK7, SPINK5, DEFB1, KDR, IL5RA, IL9, and IL12RB1) were compared between the two groups. Seventy-one subjects (25.3%) were found to have AD and ACD. Female sex, older age, late onset, self-reported personal or family history of ACD, and presence of prurigo nodularis were associated with concurrent ACD in AD patients. Age was useful for predicting concurrent ACD based on the receiver operating characteristic curve. However, no differences in the frequency of genetic variants were identified between the two groups. A personal or family history of ACD, late onset, and prurigo nodularis support a suspicion of concurrent ACD, although these correlations were less apparent after correcting for age and sex. Patch testing for AD in males >20 years and females >14 years may aid diagnosis of concurrent ACD with high sensitivity and specificity.