Division of Pulmonary and Critical Care Medicine, Department of Medicine, Indianapolis, Indiana, USA.
PLoS One. 2013 May 14;8(5):e62968. doi: 10.1371/journal.pone.0062968. Print 2013.
Increases in ceramide levels have been implicated in the pathogenesis of both acute or chronic lung injury models. However, the role of individual ceramide species, or of the enzymes that are responsible for their synthesis, in lung health and disease has not been clarified. We now show that C24- and C16-ceramides are the most abundant lung ceramide species, paralleled by high expression of their synthetic enzymes, ceramide synthase 2 (CerS2) and CerS5, respectively. Furthermore, the ceramide species synthesis in the lung is homeostatically regulated, since mice lacking very long acyl chain C24-ceramides due to genetic deficiency of CerS2 displayed a ten-fold increase in C16-ceramides and C16-dihydroceramides along with elevation of acid sphingomyelinase and CerS5 activities. Despite relatively preserved total lung ceramide levels, inhibition of de novo sphingolipid synthesis at the level of CerS2 was associated with significant airflow obstruction, airway inflammation, and increased lung volumes. Our results suggest that ceramide species homeostasis is crucial for lung health and that CerS2 dysfunction may predispose to inflammatory airway and airspace diseases.
在急性或慢性肺损伤模型的发病机制中，神经酰胺水平的升高被认为与其相关。然而，特定神经酰胺种类的作用，或负责其合成的酶在肺健康和疾病中的作用尚未阐明。我们现在表明，C24-和 C16-神经酰胺是肺中最丰富的神经酰胺种类，与其合成酶神经酰胺合酶 2（CerS2）和 CerS5 的高表达相平行。此外，由于 CerS2 基因缺陷导致非常长链酰基 C24-神经酰胺缺乏的小鼠，肺中神经酰胺种类的合成受到体内平衡调节，其 C16-神经酰胺和 C16-二氢神经酰胺增加十倍，同时酸性鞘磷脂酶和 CerS5 活性升高。尽管总肺神经酰胺水平相对保持不变，但 CerS2 水平的从头合成的抑制与明显的气流阻塞、气道炎症和肺容积增加有关。我们的结果表明，神经酰胺种类的体内平衡对肺健康至关重要，CerS2 功能障碍可能使气道和肺泡疾病易感性增加。
