MECHANISMS FOR CHRONIC UVR-INDUCED DAMAGE TO SKIN

紫外线引起的皮肤慢性损伤的机制

• 批准号: 6045349
• 负责人: IRENE KOCHEVAR
• 金额: $ 28.23万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-07-10 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6045349
• 关键词: cellular pathology; elastases; enzyme activity; enzyme inhibitors; fibrillin; fibroblasts; histology; human tissue; keratinocyte; laboratory mouse; laboratory rat; light adverse effect; neutrophil; skin disorder; solar radiation; ultraviolet radiation

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.

日光弹性增厚是光老化的一个标志，即累积的反应 皮肤对多年环境暴露在阳光下造成的伤害 紫外线照射(UVR)。在日光弹力增殖症中， 真皮的数量大大增加，看起来增厚并含有 大片无定形区域。尽管弹性蛋白增加了，但皮肤显示 弹性降低，弹性丧失。更多的合成和 退化是慢性日晒引起的皮肤重塑的一部分。 曝光。刺激原弹性蛋白合成的过程 成纤维细胞对UVR的反应还不是很清楚。这 应用程序解决慢性UVR暴露可能增加的机制 弹性蛋白的主要成分原弹性蛋白和纤维蛋白的合成 纤维。总体目标是确定关键控制点，以便制定 保护措施。 这个应用程序的具体目的是：1)检验假设 中性粒细胞产生的活性氧种(ROS)促进了糖尿病的发生。 长期接受紫外线照射治疗的小鼠皮肤中的日光弹力增生症。 2)检验以下假设：弹性蛋白酶活性增加对 慢性紫外线照射上调原弹性蛋白和纤维蛋白合成 皮肤成纤维细胞因此有助于日光弹力增生症的发展， 3)确定角质形成细胞或成纤维细胞吸收的UVR是否会诱导 真皮成纤维细胞合成原弹性蛋白和纤维蛋白。具体的 AIMS将使用在世代中存在缺陷的小鼠品系来解决 中性粒细胞释放ROS，或中性粒细胞弹性蛋白酶释放不足 或α-1蛋白水解酶抑制剂。弹性酶抑制剂也将用于 活着。人真皮成纤维细胞的体外实验 胶原蛋白凝胶或皮肤替代物将被用来定义 活体观察到的现象。