Stratum Corneum Acidification in the Neonate

描述（由申请人提供）：尽管角质层（SC）的酸性已经被人们认识了一个多世纪，但人们对它的重要性和起源都知之甚少。最近对成年动物的研究表明，酸性SC pH对正常的渗透性屏障稳态和SC完整性和内聚是必不可少的，中性SC pH增加表皮细胞因子的水平。酸性表面pH值是在缺乏外源机制的情况下实现的，如表面脂质、分泌腺产物和微生物产物，这些之前被认为是SC酸化的重要因素。最近的研究表明，成年表皮SC酸化的内源性机制有三种：1)磷脂水解产生游离脂肪酸；2)非能量依赖的钠质子反转运体（NHE1）；3)组氨酸生成尿酸。然而，研究表明，新生儿的SC具有中性pH值。在接下来的几周到几个月内，表面pH值降低到成人的水平（pH=5.5）。与人类一样，我们最近在一个新生大鼠模型中发现，新生儿的表面pH值为6.5至7.0，并且表面pH值下降到出生后5-6天的pH值为5.5（成人水平）。在之前的资助周期中，我们的研究表明，PPARa、PPARd和LXR的激活剂在胎儿发育过程中刺激角化细胞分化、通透性屏障稳态和SC的发育。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。新生儿的皮肤比成人的皮肤更容易受到外界的伤害和炎症的发展。假设-新生儿的SC具有中性pH值，因为一种或多种内源性机制负责成人SC酸化；1)组氨酸转化为尿尿酸的组氨酸酶，2)磷脂通过sPLA2代谢为游离脂肪酸，以及/或3)氢离子通过NHE1转运到细胞外空间，这些在新生哺乳动物表皮中尚未完全发育。随着这些途径的进一步成熟，SC最终会酸化，这一过程可以通过激活PPAR α、PPAR δ和LXR来加速。在新生儿期，SC酸化的延迟会导致功能异常，包括；a)渗透性屏障稳态降低，b) SC完整性和内聚性受损，c)炎症发展的易感性增加，持续性炎症性皮肤病发展的阈值降低。目的- 1)确定导致出生后SC酸化的机制。2)确定中性pH对新生儿SC功能的不良影响。3)确定a)渗透性屏障稳态异常，b) SC完整性和内聚性受损，c)中性SC ph下新生动物炎症发展阈值降低的机制。4)确定PPAR α， PPAR δ和/或LXR的激活剂是否加速酸性SC的形成，这种加速酸化的机制，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.