MECHANISMS FOR CHRONIC UVR-INDUCED DAMAGE TO SKIN

日光性弹性组织变性是光老化的标志， 皮肤的伤害所造成的环境暴露于太阳能 紫外线照射（UVR）。在日光性弹性组织变性中， 真皮的数量大大增加，似乎变厚，并含有 大的无定形区域。尽管弹性蛋白增加，皮肤显示 弹性下降和丧失弹性。增加合成和 降解是皮肤重塑的一部分， exposure.参与刺激弹性蛋白原合成的过程， 成纤维细胞对UVR的反应还不完全清楚。这 本申请阐述了慢性UVR暴露可能增加 弹性蛋白由弹性蛋白原和弹性蛋白的主要成分合成 纤维总体目标是确定关键控制点，以制定 保护措施。 本申请的具体目的是：1）检验以下假设： 中性粒细胞产生的活性氧（ROS）增强了 长期用紫外线照射治疗的鼠皮肤日光性弹性组织变性。 2)为了验证弹性蛋白酶活性增加是对以下假设的响应： 慢性紫外线照射上调弹性蛋白原和弹性蛋白合成， 真皮成纤维细胞从而促进日光性弹性组织变性的发展， 和3）确定UVR是否被角质形成细胞或成纤维细胞吸收， 真皮成纤维细胞合成弹性蛋白原和弹性蛋白。具体 目的将使用小鼠品系，是缺乏在一代 或缺乏中性粒细胞弹性蛋白酶的释放 或α-1蛋白酶抑制剂。弹性蛋白酶抑制剂也将被用于 vivo.在体外实验中，使用人真皮成纤维细胞生长在收缩 将使用胶原凝胶或皮肤等同物来定义 在体内观察到的现象。

Solar elastosis is a hallmark of photoaging, the accumulated response of skin to injury caused by years of environmental exposure to solar ultraviolet irradiation (UVR). In solar elastosis, the elastic fibers in the dermis are greatly increased in amount and appear to be thickened and contain large amorphous areas. Despite this increase in elastin, the skin shows decreased elasticity and loss of resilience. Increased synthesis and degradation are part of the dermal remodeling resulting from chronic sun exposure. The processes involved in stimulating synthesis of tropoelastin by fibroblasts in response to UVR are only inadequately understood. This application addresses mechanisms whereby chronic UVR exposure may increase elastin by synthesis of tropoelastin and fibrillin, major components of elastin fibers. The overall goal is to identify key control points in order to devise protective measures. The Specific Aims of this application are: 1) to test the hypothesis that reactive oxygen species (ROS) produced by neutrophils enhance development of solar elastosis in murine skin that is chronically treated with UV irradiation. 2) to test the hypothesis that increased elastase activity in response to chronic UV irradiation up-regulates tropoelastin and fibrillin synthesis by dermal fibroblasts thereby contributing to the development of solar elastosis, and 3) to determine whether UVR absorbed by keratinocytes or fibroblasts induce the synthesis of tropoelastin and fibrillin by dermal fibroblasts. The Specific Aims will be addressed using mouse strains that are deficient in the generation of ROS by neutrophils, or are deficient in the release of neutrophil elastase or alpha-1 protease inhibitor. Elastase inhibitors will also be employed in vivo. In vitro experiments using human dermal fibroblasts grown in contracted collagen gels or skin equivalents will be used to define mechanisms for the phenomena observed in vivo.