Abnormalities In Barrier Function Research Articles

Targeting therapeutic approaches and highlighting the potential role of nanotechnology in atopic dermatitis.

Atopic dermatitis is a chronic as well as widespread skin disease which has significant influence on the life attributes of affected people and their families. Systemic immunosuppressive drugs can be utilised for effective care of disease, although they are often prescribed for rigorous disruption or disease that is complicated to manage. Therefore, topical applications of corticosteroids are considered the primary pharmacologic therapies for atopic dermatitis, and research recommends that these medications might be helpful in preventing disease flare-ups. However, topical medicine administration to deeper layers of skin is challenging because of the skin anatomic barrier that restricts deeper drug permeation, and also due to barrier function abnormalities in atopic dermatitis skin, which might result in systemic drug absorption, provoking systemic consequences. Hence, effective management of atopic dermatitis needs new, effective, safe and targeted treatments. Therefore, nanotechnology-based topical therapeutics have attracted much interest nowadays because of their tendency to increase drug diffusion and bioavailability along with enormous drug targeting potential to affected cells, and, thereby, reducing the adverse effects of medications. In this review, we mention different symptoms of atopic dermatitis, and provide an overview of the different triggering factors causing atopic dermatitis, with emphasis on its epidemiology, pathophysiology, clinical features and diagnostic, and preventive measures. This review discusses existing therapeutics for treating atopic dermatitis, and the newer approaches as well as the current classical pharmacotherapy of atopic dermatitis against new nanoparticle skin delivery systems. This review has also briefly summarised the recent patents and clinical status of therapeutic modalities for atopic dermatitis.

Impact of Genetically Predisposed Skin Barrier Function Abnormalities on the Onset and Course of Food Allergy in Children

The increase in the incidence of the food allergy (FA) occurs more rapidly than changes in the genome sequence. To investigate the impact of genetically predisposed skin barrier function abnormalities associated with filaggrin (FLG) genes polymorphism on the FA onset and course, we studied 53 children with skin FA symptoms. Genotyping was performed for FLG variants R501X and 2282del4. Results. The frequency of 2 variants in the study population was 0.018 for R501X and 0.075 for 2282del4. The combined allele frequency was 0.096. All patients were heterozygotes. Children with mutations showed significant odds ratio (OR) of 31.3 (95% CI 2.1; 452.0) in terms of early onset of the skin allergy symptoms — during 1st month of life. And had no influence on the FA clinical signs start after 12 months of age (OR 0.5 (0.05; 4.85), p < 0.05). Null mutations were clinically important risk factors for the persistent transepidermal water loss (TEWL). Conclusion. Genetically predisposed skin barrier function abnormalities have impact on early FA onset and are important for persistent TEWL.

As in Atopic Dermatitis, Nonlesional Skin in Allergic Contact Dermatitis Displays Abnormalities in Barrier Function and Ceramide Content

As in Atopic Dermatitis, Nonlesional Skin in Allergic Contact Dermatitis Displays Abnormalities in Barrier Function and Ceramide Content

Atopic dermatitis and skin barrier dysfunction

Atopic dermatitis is a chronic relapsing eczematous dermatosis, which usually starts in childhood, and various causes are intricately associated with the development of the disease. Recently, various abnormalities in barrier function have been identified as the cause of atopic dermatitis. Loss-of-function mutation of filaggrin, a significant constituent of skin barrier, has been revealed as a cause for atopic dermatitis, and factors like enhanced protease activity, and decreased synthesis of the lipid lamellae especially ceramides also plays an important role in barrier dysfunction. Not only these genetic causes but also environmental factors are associated in barrier dysfunction, such as soap or detergents which increases skin pH, or proteases of dust mites or cockroaches which enhances epidermal barrier breakdown. Lately, skin barrier dysfunction is also thought to play an important role in the early stage of other allergic diseases such as asthma. Therefore, comprehension of the function of skin barrier can provide help in understanding various allergic diseases. (Allergy Asthma Respir Dis 1(1):20-28, 2013)Allergy Asthma Respir Dis 1(1):20-28, 2013)

Acute Acidification of Stratum Corneum Membrane Domains Using Polyhydroxyl Acids Improves Lipid Processing and Inhibits Degradation of Corneodesmosomes

Neutralization of the normally acidic stratum corneum (SC) has deleterious consequences for permeability barrier homeostasis and SC integrity/cohesion attributable to serine proteases (SPs) activation leading to deactivation/degradation of lipid-processing enzymes and corneodesmosomes (CD). As an elevated pH compromises SC structure and function, we asked here whether SC hyperacidification would improve the structure and function. We lowered the pH of mouse SC using two polyhydroxyl acids (PHA), lactobionic acid (LBA), or gluconolactone (GL). Applications of the PHA reduced the pH at all levels of SC of hairless mouse, with further selective acidification of SC membrane domains, as shown by fluorescence lifetime imaging. Hyperacidification improved permeability barrier homeostasis, attributable to increased activities of two key membrane-localized, ceramide-generating hydrolytic enzymes (beta-glucocerebrosidase and acidic sphingomyelinase), which correlated with accelerated extracellular maturation of SC lamellar membranes. Hyperacidification generated "supernormal" SC integrity/cohesion, attributable to an SP-dependent decreased degradation of desmoglein-1 (DSG1) and the induction of DSG3 expression in lower SC. As SC hyperacidification improves the structure and function, even of normal epidermis, these studies lay the groundwork for an assessment of the potential utility of SC acidification as a therapeutic strategy for inflammatory dermatoses, characterized by abnormalities in barrier function, cohesion, and surface pH.

Skin barrier function.

Like other inflammatory dermatoses, the pathogenesis of atopic dermatitis (AD) has been largely attributed to abnormalities in adaptive immunity. T helper (Th) cell types 1 and 2 cell dysregulation, IgE production, mast cell hyperactivity, and dendritic cell signaling are thought to account for the chronic, pruritic, and inflammatory dermatosis that characterizes AD. Not surprisingly, therapy has been directed toward ameliorating Th2-mediated inflammation and pruritus. Here, we review emerging evidence that inflammation in AD occurs downstream to inherited and acquired insults to the barrier. Therapy based upon this new view of pathogenesis should emphasize approaches that correct the primary abnormality in barrier function, which drives downstream inflammation and allows unrestricted antigen access.

Characterization of stratification and tight junction formation in cultured human urothelial cells

The urothelium is composed of stratified transitional epithelium of 3 cell types: basal, intermediate, and superficial. It has been proposed that urothelial cells acquire their mature characteristics through differentiation. The most differentiated, superficial cells develop tight junctions (TJs) that restrict urine movement and abnormalities in barrier function may be involved in syndromes such as interstitial cystitis. To further our understanding of urothelial differentiation, we used cells from normal human ureter and examined the zonula occludens (ZOs), “undercoat” scaffolding proteins in the cytosol that interact with claudins and actin filaments. Cell monolayers were stratified and differentiated using Ca and fetal bovine serum (FBS) and the process was studied using impedance, videomicroscopy, and confocal immunohistochemistry. With addition of Ca and FBS, impedance quickly increased by 2.5 fold. Withdrawal of the supplements returned impedance to baseline, suggesting the formation of tight junctions, rather than increased cell proliferation and immunohistochemistry demonstrated the appearance of ZO‐1 at cell junctions minutes after supplement addition. Observation by videomicroscopy suggested that cell division continued to occur after the cells had differentiated. Taken together, these studies increase our understanding of urothelial development.Supported by DK66119 (JM)

Depletion of stratum corneum intercellular lipid lamellae and barrier function abnormalities after long-term topical corticosteroids

Depletion of stratum corneum intercellular lipid lamellae and barrier function abnormalities after long-term topical corticosteroids

Depletion of stratum corneum intercellular lipid lamellae and barrier function abnormalities after long-term topical corticosteroids

The intercellular lipid lamellae of the stratum corneum (SC) is believed to provide the permeability barrier of the epidermis. Previous functional studies have demonstrated an increase in the transepidermal water loss (TEWL) after long-term use of topical corticosteroids (TCS): however, direct morphological confirmation of this barrier abnormality is still lacking. The aim of this study was to determine whether any abnormality could be detected in the structure of the SC intercellular lipid lamellae in patients after long-term TCS. Atrophic skin and untreated normal skin of 10 patients after long-term TCS were examined by transmission electron microscopy using ruthenium tetroxide-fixed tissue for the multilamellar lipid sheets of SC, and oil red O stain for neutral lipids of the SC. Layers of the SC were evaluated by 0.1% methylene blue stain after alkaline expansion, and TEWL was measured by Evaporimeter EP1. The TCS-treated atrophic skin had fewer layers of horny cells, mean 9.4 layers, than the normal control skin, 18 layers (P < 0.001) and increased TEWL of 21.3 g/m2 compared with the control skin TEWL of 6.7 g/m2 (P < 0.01). The mean neutral lipid content of the SC was also significantly lower (P < 0.001). Moreover, ultrastructural studies revealed a marked decrease in both the numbers of intercellular lipid lamellae of SC and membrane-coating granules of stratum granulosum in the atrophic skin. These results suggest that the diminution in the SC intercellular lipid lamellae and SC cell layers play an important part in the pathogenesis of barrier dysfunction after long-term use of TCS.

Structural Basis for the Barrier Abnormality Following Inhibition of HMG CoA Reductase in Murine Epidermis

Recent studies have shown that increased epidermal 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG CoA) reductase activity is crucial for the barrier recovery response that follows solvent-induced barrier perturbation. Upregulation of this enzyme leads to increased cholesterologenesis, formation and secretion of cholesterol-enriched lamellar bodies, and barrier repair. Topical lovastatin-induced inhibition of HMG CoA reductase activity both delays the acute barrier-repair response, as well as leading to a chronic barrier abnormality when applied repeatedly to intact skin. Presently, we assessed the effects of repeated topical applications of two different specific inhibitors of HMG CoA reductase on barrier function, the lamellar body-secretory system, and stratum corneum intercellular domains, with functional and morphologic parameters. Once-daily applications of lovastatin or fluindostatin (XU62-320; Sandoz) for 4-8 d to intact hairless mouse epidermis produced a progressive abnormality in barrier function (transepidermal water loss greater than 2.0-5.0 in treated versus less than 0.25 mg/cm2/h for weakly active analogues or vehicle controls). The barrier defect was preceded by alterations in lamellar body internal structure and a partial failure of lamellar body secretion into the stratum corneum interstices, further confirmed by enzyme cytochemistry. Moreover, the deposition of abnormal lamellar body contents resulted in the formation of clefts in the intercellular spaces at the stratum granulosum-stratum corneum interface, resulting in increased permeability through these domains shown by lanthanum perfusion. Applications of irritants, even when producing a barrier abnormality, did not alter the lamellar body secretory system. Co-applications of cholesterol with the inhibitors reversed both the barrier abnormality and the abnormalities in the lamellar body secretory system that occur with the inhibitor alone. Finally, membrane bilayer structures in the mid-to-outer stratum corneum of inhibitor-treated specimens appeared normal, but the intercellular domains displayed enormously expanded lacunae. However, because similar dilatations also occurred in vehicle-treated samples, they can be attributed to the vehicle alone. These studies provide further evidence that the inhibitor-induced defect in barrier function a) is initiated by inhibition of HMG CoA reductase; b) can be attributed to defects in both lamellar body structure and deposition with resultant abnormalities in intercellular membrane domains in the lower stratum corneum; and c) is further enhanced by permissive effects of the vehicle on the permeability of the outer stratum corneum.