Division BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Netherlands.
Division BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Netherlands.
Biochim Biophys Acta Biomembr. 2019 Jul 1;1861(7):1317-1328. doi: 10.1016/j.bbamem.2019.04.005. Epub 2019 Apr 13.
The intercellular lipid matrix of the stratum corneum (SC), which consist mainly of ceramides (CERs), free fatty acids and cholesterol, is fundamental to the skin barrier function. These lipids assemble into two lamellar phases, known as the long and short periodicity phases (LPP and SPP respectively). The LPP is unique in the SC and is considered important for the skin barrier function. Alterations in CER composition, as well as impaired skin barrier function, are commonly observed in diseased skin, yet the understanding of this relationship remains insufficient. In this study, we have investigated the influence of non-hydroxy and α-hydroxy sphingosine-based CERs and their phytosphingosine counterparts on the permeability and lipid organization of model membranes, which were adjusted in composition to enhance formation of the LPP. The permeability was compared by diffusion studies using ethyl-p-aminobenzoate as a model drug, and the lipid organization was characterized by X-ray diffraction and infrared spectroscopy. Both the sphingosine- and phytosphingosine-based CER models formed the LPP, while the latter exhibited a longer LPP repeat distance. The ethyl-p-aminobenzoate flux across the sphingosine-based CER models was higher when compared to the phytosphingosine counterparts, contrary to the fact that the α-hydroxy phytosphingosine-based CER model had the lowest chain packing density. The unanticipated low permeability of the α-hydroxy phytosphingosine-based model is probably associated with a stronger headgroup hydrogen bonding network. Our findings indicate that the increased level of sphingosine-based CERs at the expense of phytosphingosine-based CERs, as observed in the diseased skin, may contribute to the barrier function impairment.
角质层（SC）的细胞间脂质基质主要由神经酰胺（CERs）、游离脂肪酸和胆固醇组成，是皮肤屏障功能的基础。这些脂质组装成两个层状相，分别称为长周期相和短周期相（LPP 和 SPP）。LPP 在 SC 中是独特的，被认为对皮肤屏障功能很重要。在患病皮肤中，通常观察到 CER 组成的改变以及皮肤屏障功能受损，但对这种关系的理解仍然不足。在这项研究中，我们研究了非羟基和α-羟基神经鞘氨醇基 CER 及其植物鞘氨醇对应物对模型膜渗透性和脂质组织的影响，这些模型膜的组成进行了调整以增强 LPP 的形成。通过使用乙基对氨基苯甲酸酯作为模型药物的扩散研究比较了渗透性，并且通过 X 射线衍射和红外光谱对脂质组织进行了表征。基于神经鞘氨醇和植物鞘氨醇的 CER 模型都形成了 LPP，而后者表现出更长的 LPP 重复距离。与植物鞘氨醇对应物相比，乙基对氨基苯甲酸酯穿过基于神经鞘氨醇的 CER 模型的通量更高，这与 α-羟基植物鞘氨醇基 CER 模型具有最低的链堆积密度的事实相反。出乎意料的是，α-羟基植物鞘氨醇基模型的低渗透性可能与更强的头基氢键网络有关。我们的发现表明，在患病皮肤中观察到的以神经鞘氨醇为基础的 CER 水平增加而以植物鞘氨醇为基础的 CER 水平降低，可能导致屏障功能受损。
