Stratum Corneum Acidification in the Neonate

描述(申请人提供)：尽管角质层(SC)的酸性本质已经被认识了一个多世纪，但它的重要性和来源都鲜为人知。最近在成年动物身上的研究表明，酸性的SC pH对于正常的通透性屏障动态平衡和SC的完整性和凝聚力是必不可少的，而中性的SC pH会增加表皮中的细胞因子水平。在没有外源机制的情况下，表面pH达到酸性，如表面脂类、分泌腺产物和微生物产物，这些以前被认为是SC酸化的重要因素。最近的研究表明，三种内源性机制酸化成人表皮的SC：1)磷脂水解产生游离脂肪酸；2)非能量依赖的钠质子逆向转运体(NHE1)；3)组氨酸产生尿毒酸。然而，研究表明，新生儿的SC具有中性的PH值。在接下来的几周到几个月里，表面的pH值下降到成人的水平(pH=5.5)。与人类一样，我们最近在一个新生大鼠模型中表明，新生儿的表面pH值为6.5至7.0，并且表面pH值下降，以至于出生后5-6天的pH值为5.5(成人水平)。我们在之前的资金周期中的研究表明，PPARa、PPARd和LXR的激活剂在胎儿发育过程中刺激角质形成细胞分化、通透性屏障稳态和SC的发展。我们的初步研究进一步表明，局部应用LXR和PPARa配体可以加速新生大鼠SC的酸化。新生儿皮肤比成人皮肤更容易受到外界的侮辱，也更容易发炎。假设-新生儿的SC具有中性的pH，这是因为负责成年SC酸化的一个或多个内源机制：1)组氨酸转化为尿毒酸的组氨酸酶，2)sPLA2将磷脂代谢为游离脂肪酸，和/或3)NHE1将氢离子转移到细胞外空间，这些机制在新生哺乳动物的表皮中尚未完全发育。随着这些途径的进一步成熟，这些途径发展，SC最终酸化，这个过程可以通过激活PPARα、PPAR Delta和LXR来加速。在新生儿期，SC酸化的这种延迟导致功能异常，包括：a)通透性屏障动态平衡降低，b)SC的完整性和凝聚力受损，c)炎症的易感性增加，持续性炎症性皮肤病的发生阈值降低。目的：1)确定导致出生后SC酸化的机制(S)。2)确定中性pH对新生儿SC功能的不良影响。3)探讨通透性屏障动态平衡异常、SC完整性和凝聚力受损、SC pH中性新生动物炎症发生阈值降低的机制。4)确定PPARα、PPAR Delta和/或LXR的激活剂是否促进酸性SC的形成，这种酸化加速的机制，以及这种加速的功能后果。

DESCRIPTION (provided by applicant): Although the acidic nature of the stratum corneum (SC) has been appreciated for more than a century, both its importance and its origin are poorly understood. Recent studies in adult animals have demonstrated that an acidic SC pH is essential for normal permeability barrier homeostasis and SC integrity and cohesion, and that a neutral SC pH increases the levels of cytokines in the epidermis. An acidic surface pH is achieved in the absence of exogenous mechanisms, such as surface lipids, eccrine gland products, and microbial products, previously thought to be important for SC acidification. Recent studies have shown that three endogenous mechanisms acidify the SC of adult epidermis: 1) free fatty acid generation from phospholipid hydrolysis; 2) a non-energy-dependent, sodium-proton antiporter (NHE1); and 3) urocanic acid generation from histidine. However, studies have shown that the SC of newborn humans has a neutral pH. Over the next several weeks to months the surface pH decreases to adults levels (pH=5.5). As in humans, in a neonatal rat model we have recently shown that the surface pH of newborns is 6.5 to 7.0, and that the surface pH decreases such that by 5-6 days post birth the pH is 5.5 (adult levels). Our studies during the prior funding cycle have shown that activators of PPARa, PPARd, and LXR, stimulate keratinocyte differentiation, permeability barrier homeostasis, and the development of the SC during fetal development. Our preliminary studies have further shown that topical application of ligands of LXR and PPARa accelerates the acidification of the SC in newborn rats. Newborn skin is more susceptible to both external insults and to the development of inflammation than is adult skin. Hypothesis- The SC of newborns has a neutral pH, because one or more of the endogenous mechanisms that are responsible for SC acidification in adults; 1) histidase conversion of histidine to urocanic acid, 2) metabolism of phospholipids to free fatty acids by sPLA2, and/or 3) transport of hydrogen ions into the extracellular space by NHE1, are not yet fully developed in newborn mammal epidermis. With further maturation these pathways develop, and the SC ultimately acidifies, a process that can be accelerated by activation of PPAR alpha, PPAR delta, and LXR. In the neonatal period, this delay in SC acidification results in functional abnormalities, including; a) decreased permeability barrier homeostasis, b) compromised SC integrity and cohesion, and c) increased susceptibility to the development of inflammation with a decreased threshold for the development of persistent inflammatory dermatoses. Objectives- 1) To determine the mechanism(s) that lead to postnatal SC acidification. 2) To determine the adverse consequences of a neutral pH on SC function in the newborn. 3) To determine the mechanisms responsible for the a) abnormalities in permeability barrier homeostasis, b) compromised SC integrity and cohesion, and c) decreased threshold for the development of inflammation in newborn animals with a neutral SC pH. 4) To determine if activators of PPAR alpha, PPAR delta, and/or LXR accelerate the formation of an acidic SC, the mechanism for this acceleration of acidification, and the functional consequences of such an acceleration.