Platelet Activating Factor and Epidermal Cytotoxicity

摘要 不同刺激导致角质形成细胞产生细胞因子和细胞毒性的信号和过程 目前还没有很好地理解。此外，由诸如紫外线辐射的药剂引起的慢性刺激导致 恶性肿瘤近年来的研究表明，紫外线B辐射（UVB）对人体有一定的损伤作用 角质形成细胞（HK）部分通过诱导氧化应激和细胞因子的产生。严重的UVB损伤 角质形成细胞也可导致细胞凋亡或程序性细胞死亡。我们小组和其他人以前的研究 已经表明，角质形成细胞损伤，特别是通过导致氧化应激的试剂导致的角质形成细胞损伤， 产生甘油磷酸胆碱（GPC），其可作为血小板活化因子（PAF）的激动剂，或 过氧化物酶体增殖物激活受体γ（PPARs）系统。长期目标是 正在进行的研究建议是阐明这些氧化的GPCs在急性UVB诱导的 光反应三个具体的目的是为了测试假设，UVB介导的氧化损伤 导致产生新的ox-GPCs，其激活PAF-R和PPAR？系统。 这些新型脂质增加细胞因子的产生，调节细胞凋亡，并诱导角质形成细胞增殖： 1）。这些ox-GPCs对急性UVB介导的炎症、细胞因子产生、DNA合成和细胞因子水平的影响。 将在PAF-R和表皮PPAR <$缺陷的小鼠中评估损伤/凋亡和增殖; 2）质量 光谱方法将用于结构表征响应UVB产生的ox-GPC; 和3）将确定这些ox-GPC在人类急性UVB光响应中的作用。我们 预期这些使用新的体外和体内模型系统和新方法的研究将产生 在急性UVB诱导的具有PAF-R-和PPAR-激动作用的ox-GPCs的表征中， 角质细胞细胞因子产生、细胞毒性和增殖。这些信息将有助于 了解氧化应激可能参与皮肤病理生理学的机制。 由于这些介质将在其他器官系统中响应氧化应激而产生，这些研究 应该提供重要的见解和工具，研究ox-GPCs在人类病理生理学的影响。

Abstract The signals and processes by which diverse stimuli lead to keratinocyte cytokine production and cytotoxicity are presently not well understood. Moreover, chronic stimulation by agents such as ultraviolet radiation leads to malignancy. Recent studies have demonstrated that ultraviolet B radiation (UVB) damages human keratinocytes (HK) in part by inducing oxidative stress and cytokine production. Severe UVB damage to the keratinocyte can also result in apoptosis, or programmed cell death. Previous studies by our group and others have indicated that keratinocyte damage, especially via agents that result in oxidative stress results in the production of glycerophosphocholines (GPC) that can act as agonists for the Platelet-activating Factor (PAF) or the peroxisome proliferator activated receptor gamma (PPAR¿) systems. The long-term objective of this ongoing research proposal is to elucidate the role of these oxidized GPCs in the acute UVB-induced photoresponse. Three specific aims are designed to test the hypothesis that UVB-mediated oxidative damage to the keratinocyte results in the production of novel ox-GPCs that activate the PAF-R and PPAR¿ systems. These novel lipids augment cytokine production, modulate apoptosis, and induce keratinocyte proliferation: 1). The effect of these ox-GPCs on acute UVB-mediated inflammation, cytokine production, DNA damage/apoptosis and proliferation will be assessed in mice deficient in PAF-R and epidermal PPAR¿; 2) Mass spectrometric methodologies will be used to structurally characterize ox-GPCs produced in response to UVB; and 3) The role of these ox-GPCs in the acute UVB photoresponse in humans will be determined. We anticipate that these studies using novel in vitro and in vivo model systems and novel methodologies will result in the characterization of ox-GPCs with PAF-R- and PPAR¿- agonistic effects in acute UVB-induced keratinocyte cytokine production, cytotoxicity, and proliferation. This information will aid in the understanding of the mechanism(s) by which oxidative stress can be involved in cutaneous pathophysiology. Since these mediators would be produced in response to oxidative stress in other organ systems, these studies should provide important insights into and tools to study the impact of ox-GPCs in human pathophysiology.