Lactosylceramide-accumulation in lipid-rafts mediate aberrant-autophagy, inflammation and apoptosis in cigarette smoke induced emphysema
Lactosylceramide-accumulation in lipid-rafts mediate aberrant-autophagy, inflammation and apoptosis in cigarette smoke induced emphysema
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DOI：
10.1007/s10495-015-1098-0
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发表时间：
2015-05-01
期刊：
影响因子：
7.2
通讯作者：
Vij, Neeraj
中科院分区：
文献类型：
--
作者：
Bodas, Manish;Min, Taehong;Vij, Neeraj
已知神经酰胺积累与慢性炎症性肺部疾病的发病机制有关，包括香烟烟雾诱发的肺气肿（CS-肺气肿），但引发肺气肿进展的确切鞘脂代谢物仍然不明确。我们在此评估了鞘脂乳糖神经酰胺 (LacCer) 作为 CS 肺气肿发病机制的潜在机制的新作用。我们评估了暴露于 CS 的小鼠肺部以及 COPD 受试者周围肺组织中 LacCer 的表达以及 LacCer 依赖性炎症、细胞凋亡和自噬反应，然后通过实验分析来验证 LacCer 在 CS 肺气肿中的作用。我们观察到，与非肺气肿对照相比，人类 COPD 肺部的 LacCer 积累显着升高，并且肺气肿的严重程度不断增加。此外，严重 COPD 受试者肺组织中缺陷自噬标记物 p62 的表达增加表明 LacCer 诱导的异常自噬可能导致 CS 肺气肿的发病机制。我们证实，CS 提取物治疗可显着诱导支气管上皮细胞 (BEAS2B) 和巨噬细胞 (Raw264.7) 中 LacCer 的积累，作为启动异常自噬（p62 积累）和细胞凋亡的机制，而 LacCer 合酶的药理学抑制剂可挽救这种机制。此外，我们证实，CS 暴露会诱导小鼠肺部 LacCer 积累，而 LacCer 合酶抑制剂可以控制这种积累。我们提出 LacCer 积累作为 COPD 肺气肿严重程度的新预测因子，并为 LacCer 合酶抑制剂在 CS 诱导的 COPD 肺气肿中的治疗功效提供证据。
Ceramide-accumulation is known to be involved in the pathogenesis of chronic inflammatory lung diseases including cigarette smoke-induced emphysema (CS-emphysema) but the exact sphingolipid metabolite that initiates emphysema progression remains ambiguous. We evaluated here a novel role for the sphingolipid, lactosylceramide (LacCer), as a potential mechanism for pathogenesis of CS-emphysema. We assessed the expression of LacCer, and LacCer-dependent inflammatory, apoptosis and autophagy responses in lungs of mice exposed to CS, as well as peripheral lung tissues from COPD subjects followed by experimental analysis to verify the role of LacCer in CS-emphysema. We observed significantly elevated LacCer-accumulation in human COPD lungs with increasing severity of emphysema over non-emphysema controls. Moreover, increased expression of defective-autophagy marker, p62, in lung tissues of severe COPD subjects suggest that LacCer induced aberrant-autophagy may contribute to the pathogenesis of CS-emphysema. We verified that CS-extract treatment significantly induces LacCer-accumulation in both bronchial-epithelial cells (BEAS2B) and macrophages (Raw264.7) as a mechanism to initiate aberrant-autophagy (p62-accumulation) and apoptosis that was rescued by pharmacological inhibitor of LacCer-synthase. Further, we corroborated that CS exposure induces LacCer-accumulation in murine lungs that can be controlled by LacCer-synthase inhibitor. We propose LacCer-accumulation as a novel prognosticator of COPD-emphysema severity, and provide evidence on the therapeutic efficacy of LacCer-synthase inhibitor in CS induced COPD-emphysema.