BARRIER FUNCTION REGULATES EPIDERMAL LIPID AND DNA-SYNTHESIS

The stratum corneum, the permeability barrier between the internal Mil ieu and the environment, is composed of fibrous protein-enriched corne ocytes and a lipid-enriched intercellular matrix. The lipids are a mix ture of sphingolipids, cholesterol and free fatty acids, which form in tercellular membrane bilayers. Lipid synthesis occurs in the keratinoc ytes in all nucleated layers of the epidermis, and the newly synthesiz ed lipids are delivered by lamellar bodies to the interstices of the s tratum corneum during epidermal differentiation. Disruption of barrier function by topical acetone treatment results in an increase in the s ynthesis of free fatty acids, sphingolipids and cholesterol in the liv ing layers of the epidermis, leading to barrier repair. Cholesterol an d sphingolipid synthesis are regulated by the rate-limiting enzymes HM G CoA reductase and serine palmitoyl transferase (SPT), respectively. Acute barrier disruption leads to an increase in both enzymes, but wit h a different time curve: increase in HMG CoA reductase activity begin s at 1 . 5 h, whereas the increase in SPT activity occurs 6 h after ba rrier impairment. Topical application of HMG CoA reductase or SPT inhi bitors after acetone treatment delays barrier repair, providing furthe r evidence for a role of cholesterol and sphingolipids in epidermal ba rrier function. Repeated application of lovastatin to untreated skin r esults in disturbed barrier function accompanied by increased DNA synt hesis and epidermal hyperplasia. Therefore, we have examined the speci fic relationship between barrier function and epidermal DNA synthesis. After acute and chronic disturbances not only lipid, but also DNA syn thesis, is stimulated. Thus, stimulation of DNA synthesis leading to e pidermal hyperplasia may be a second mechanism by which the epidermis repairs defects in barrier function. The link between barrier function and both lipid and DNA synthesis is supported further by occlusion st udies. Artificial barrier repair by latex occlusion prevents an increa se in both lipid and DNA synthesis. In addition, increased epidermal l ipid and DNA synthesis in essential fatty-acid deficiency can be rever sed by topical applications of the n-6 unsaturated fatty acids, linole ic or columbinic acid. These studies may be of relevance in understand ing the pathogenesis of hyperproliferative skin diseases, such as icht hyosis, psoriasis, atopic dermatitis, and irritant contact dermatitis.