Smoking Exposure Induces Human Lung Endothelial Cell Adaptation to Apoptotic Stress
Smoking Exposure Induces Human Lung Endothelial Cell Adaptation to Apoptotic Stress
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DOI：
10.1165/rcmb.2013-0023oc
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发表时间：
2014-03-01
影响因子：
6.4
通讯作者：
Petrache, Irina
中科院分区：
文献类型：
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作者：
Petrusca, Daniela N.;Van Demark, Mary;Petrache, Irina
长期吸烟是肺气肿的主要危险因素，肺气肿是慢性阻塞性肺疾病（COPD）的一个组成部分，其特征是肺泡壁的破坏。此外，吸烟与肺动脉重塑和肺动脉高压相关，即使在没有COPD的情况下，通过尚未解释的机制。在小鼠模型中，吸烟引起的细胞内和细胞旁神经酰胺升高与肺内皮细胞凋亡的诱导有关，但神经酰胺在人类细胞中的作用尚不清楚。我们对原代人肺微血管细胞中棕榈酰神经酰胺（Cer 16）的旁分泌增加（由外向内）进行了建模。在幼稚细胞，从非吸烟者中分离，Cer 16显着降低细胞增殖和诱导caspase-独立的凋亡通过线粒体膜去极化，凋亡诱导因子易位，和聚（ADP-核糖）聚合酶裂解。在这些细胞中，caspase-3被神经酰胺诱导的Akt磷酸化和诱导自噬微管相关蛋白-1轻链3脂化所抑制。相反，从吸烟者中分离的细胞表现出与缺乏p16 INK 4a表达和Akt过度磷酸化相关的基线增殖特征增加。这些细胞是耐铈16诱导的凋亡，尽管存在内质网应激反应和线粒体膜去极化。在吸烟者的细胞中，Akt通路的显著上调抑制了神经酰胺触发的细胞凋亡，并与鞘氨醇和高迁移率族蛋白1的升高相关，使细胞对自噬和存活的反应发生偏移。总之，细胞对神经酰胺的反应是由Akt信号传导和鞘脂代谢产物之间的复杂串扰调节的，并且通过先前的香烟烟雾暴露进行了深刻的修改，从而选择了抗癫痫表型。
Prolonged exposure to cigarette smoking is the main risk factor for emphysema, a component of chronic obstructive pulmonary diseases (COPDs) characterized by destruction of alveolar walls. Moreover, smoking is associated with pulmonary artery remodeling and pulmonary hypertension, even in the absence of COPD, through as yet unexplained mechanisms. In murine models, elevations of intraand paracellular ceramides in response to smoking have been implicated in the induction of lung endothelial cell apoptosis, but the role of ceramides in human cell counterparts is yet unknown. We modeled paracrine increases (outside-in) of palmitoyl ceramide (Cer16) in primary human lung microvascular cells. In naive cells, isolated from nonsmokers, Cer16 significantly reduced cellular proliferation and induced caspase-independent apoptosis via mitochondrial membrane depolarization, apoptosis-inducing factor translocation, and poly(ADP-ribose) polymerase cleavage. In these cells, caspase-3 was inhibited by ceramide-induced Akt phosphorylation, and by the induction of autophagic microtubule-associated protein-1 light-chain 3 lipidation. In contrast, cells isolated from smokers exhibited increased baseline proliferative features associated with lack of p16INK4a expression and Akt hyperphosphorylation. These cells were resistant to Cer16-induced apoptosis, despite presence of both endoplasmic reticulum stress response and mitochondrial membrane depolarization. In cells from smokers, the prominent up-regulation ofAkt pathways inhibited ceramide-triggered apoptosis, and was associated with elevated sphingosine and highmobility group box 1, skewing the cell's response toward autophagy and survival. In conclusion, the cell responses to ceramide are modulated by an intricate cross-talk between Akt signaling and sphingolipid metabolites, and profoundly modified by previous cigarette smoke exposure, which selects for an apoptosis-resistant phenotype.