Alice Macgowan

Epidermal barrier dysfunction in atopic dermatitis.

Atopic dermatitis (AD) is a multifactorial, heterogenous disease that arises as a result of the interaction between both environmental and genetic factors. Changes in at least three groups of genes encoding structural proteins, epidermal proteases, and protease inhibitors predispose to a defective epidermal barrier and increase the risk of developing AD. Loss-of-function mutations found within the FLG gene encoding the structural protein, filaggrin, represent the most significant genetic factor predisposing to AD identified to date. Enhanced protease activity and decreased synthesis of the lipid lamellae lead to exacerbated breakdown of the epidermal barrier. Environmental factors, including the use of soap and detergents, exacerbate epidermal barrier breakdown, attributed to the elevation of stratum corneum pH. A sustained increase in pH enhances the activity of degradatory proteases and decreases the activity of the lipid synthesis enzymes. The strong association between both genetic barrier defects and environmental insults to the barrier with AD suggests that epidermal barrier dysfunction is a primary event in the development of this disease. Our understanding of gene-environment interactions should lead to a better use of some topical products, avoidance of others, and the increased use and development of products that can repair the skin barrier.

The activation of the retinoic acid response element is inhibited in an animal model of congenital diaphragmatic hernia.

Defects very similar to those seen in infants born with congenital diaphragmatic hernias can be induced in rodents by the administration of the teratogen nitrofen. There is an interest in understanding the biochemical mechanisms of nitrofen’s actions in hopes of gaining insights into the etiology of congenital diaphragmatic hernia. In this study, we test the hypothesis that nitrofen is acting to perturb the retinoid signaling pathway by utilizing genetically engineered mice that have the lacZ reporter gene linked to a retinoic acid response element (RARE). We demonstrate a pronounced suppression of RARE-lacZ expression by nitrofen in vitro (by approximately 64%) and in vivo (by approximately 43%).