Proksch E, Holleran W M, Menon G K, Elias P M, Feingold K R
Dermatology Service, Veterans Administration Medical Center, San Francisco, CA.
Br J Dermatol. 1993 May;128(5):473-82. doi: 10.1111/j.1365-2133.1993.tb00222.x.
The stratum corneum, the permeability barrier between the internal milieu and the environment, is composed of fibrous protein-enriched corneocytes and a lipid-enriched intercellular matrix. The lipids are a mixture of sphingolipids, cholesterol and free fatty acids, which form intercellular membrane bilayers. Lipid synthesis occurs in the keratinocytes in all nucleated layers of the epidermis, and the newly synthesized lipids are delivered by lamellar bodies to the interstices of the stratum corneum during epidermal differentiation. Disruption of barrier function by topical acetone treatment results in an increase in the synthesis of free fatty acids, sphingolipids and cholesterol in the living layers of the epidermis, leading to barrier repair. Cholesterol and sphingolipid synthesis are regulated by the rate-limiting enzymes HMG CoA reductase and serine palmitoyl transferase (SPT), respectively. Acute barrier disruption leads to an increase in both enzymes, but with a different time curve: increase in HMG CoA reductase activity begins at 1.5 h, whereas the increase in SPT activity occurs 6 h after barrier impairment. Topical application of HMG CoA reductase or SPT inhibitors after acetone treatment delays barrier repair, providing further evidence for a role of cholesterol and sphingolipids in epidermal barrier function. Repeated application of lovastatin to untreated skin results in disturbed barrier function accompanied by increased DNA synthesis and epidermal hyperplasia. Therefore, we have examined the specific relationship between barrier function and epidermal DNA synthesis. After acute and chronic disturbances not only lipid, but also DNA synthesis, is stimulated. Thus, stimulation of DNA synthesis leading to epidermal 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 studies. Artificial barrier repair by latex occlusion prevents an increase in both lipid and DNA synthesis. In addition, increased epidermal lipid and DNA synthesis in essential fatty-acid deficiency can be reversed by topical applications of the n-6 unsaturated fatty acids, linoleic or columbinic acid. These studies may be of relevance in understanding the pathogenesis of hyperproliferative skin diseases, such as ichthyosis, psoriasis, atopic dermatitis, and irritant contact dermatitis.
角质层作为内部环境与外界环境之间的渗透屏障，由富含纤维蛋白的角质形成细胞和富含脂质的细胞间基质组成。脂质是鞘脂、胆固醇和游离脂肪酸的混合物，它们形成细胞间膜双层结构。脂质合成发生在表皮所有有核层的角质形成细胞中，在表皮分化过程中，新合成的脂质通过板层小体输送到角质层的间隙中。局部用丙酮处理破坏屏障功能会导致表皮活层中游离脂肪酸、鞘脂和胆固醇的合成增加，从而促进屏障修复。胆固醇和鞘脂的合成分别由限速酶HMG CoA还原酶和丝氨酸棕榈酰转移酶（SPT）调节。急性屏障破坏会导致这两种酶的活性增加，但时间曲线不同：HMG CoA还原酶活性在1.5小时开始增加，而SPT活性在屏障受损6小时后增加。丙酮处理后局部应用HMG CoA还原酶或SPT抑制剂会延迟屏障修复，这进一步证明了胆固醇和鞘脂在表皮屏障功能中的作用。对未处理的皮肤反复应用洛伐他汀会导致屏障功能紊乱，同时伴有DNA合成增加和表皮增生。因此，我们研究了屏障功能与表皮DNA合成之间的特定关系。急性和慢性干扰后，不仅脂质合成，而且DNA合成都会受到刺激。因此，导致表皮增生的DNA合成刺激可能是表皮修复屏障功能缺陷的第二种机制。封闭研究进一步支持了屏障功能与脂质和DNA合成之间的联系。通过乳胶封闭进行人工屏障修复可防止脂质和DNA合成增加。此外，局部应用n-6不饱和脂肪酸亚油酸或羽扇豆酸可逆转必需脂肪酸缺乏时表皮脂质和DNA合成的增加。这些研究可能有助于理解鱼鳞病、银屑病、特应性皮炎和刺激性接触性皮炎等过度增殖性皮肤病的发病机制。
