Ceramide-Induced Destruction In Emphysema

摘要 这一应用将检验这样一种假设，即抑制鞘氨醇-1磷酸(S1P)的产生和 慢性香烟烟雾暴露对肺内皮细胞的信号转导是肺气肿的关键事件 发病机制。我们认为，抑制S1P产生的上游鞘磷脂代谢将产生 双重效应：失去保护性的、有利于生存的S1P产生和信号，加上积累的 细胞毒性鞘磷脂代谢物，如神经酰胺，可导致细胞死亡。我们将初步测试这一范例 在肺内皮细胞中，因为它们的丢失被认为是肺气肿发病的关键因素。尽管有一个 大量数据强调S1P对血管系统的有益影响，但人们对其知之甚少 CS所致肺损伤和肺气肿的调控及意义及S1P的作用机制 防止或解除上游鞘脂代谢物引发的各种类型的细胞损伤。这些 新发现的细胞应激反应、损伤和死亡存在于肺气肿中，包括 线粒体受损，吞噬线粒体的不适当清除，以及一种新的细胞死亡形式--坏死性下垂。我们 假设CS减少S1P的产生及其S1P受体1依赖的信号，导致 坏死性下垂诱导的棕榈酰神经酰胺在肺内的蓄积和促生存信号的减少 内皮细胞，最终导致肺气肿。我们将使用CS的翻译方法来检验这一假设 小鼠暴露于原代人类肺细胞。我们的工作将在CS和CS之间提供机械联系， 稳态和条件性S1P水平与细胞损伤，将揭示新的治疗靶点 限制这种常见疾病对肺的破坏。

Abstract This application will test the hypothesis that inhibition of sphingosine-1 phosphate (S1P) production and signaling in lung endothelial cells by chronic cigarette smoke (CS) exposure is a critical event in emphysema pathogenesis. We propose that inhibition of sphingolipid metabolism upstream of S1P production will have a dual effect: loss of protective, pro-survival S1P production and signaling, coupled with accumulation of cytotoxic sphingolipid metabolites such as ceramide that cause cell death. We will test this paradigm primarily in lung endothelial cells, since their loss is known to be a key element of emphysema pathogenesis. Despite an abundance of data highlighting the beneficial effects of S1P on the vasculature, little is known about its regulation and importance in CS-induced lung injury and emphysema and the mechanisms by which S1P prevents or disengages various types of cell injury triggered by upstream sphingolipid metabolites. These newly uncovered cell stress responses, injury, and death are present in emphysema lungs and include mitochondria damage, inappropriate clearance by mitophagy, and a new form of cell death, necroptosis. We hypothesize that CS decreases S1P production and its S1P receptor 1-dependent signaling, leading to accumulation of necroptosis-inducing palmitoyl-ceramide and to decreased pro-survival signaling in lung endothelial cells, culminating in emphysema. We will test this hypothesis using a translational approach of CS exposure in mice coupled with primary human lung cells. Our work will provide a mechanistic link between CS, the steady and conditional state levels of S1P and cellular injury and will reveal novel therapeutic targets to limit lung destruction in this common disease.