Dept. of Molecular Biology, University of Duisburg-Essen, Hufelandstrasse 55, D-45122 Essen, Germany.
Biochem Biophys Res Commun. 2010 Dec 17;403(3-4):368-74. doi: 10.1016/j.bbrc.2010.11.038. Epub 2010 Nov 13.
Cystic fibrosis is a hereditary metabolic disorder caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene and characterized by severe intestinal and pulmonary symptoms, in particular intestinal obstruction, pancreatic insufficiency, chronic pulmonary inflammation, and microbial lung infections. Recent studies have demonstrated an accumulation of ceramide in the lungs of cystic fibrosis patients and in several mouse models. These findings showed that pulmonary ceramide concentrations play an important role in pulmonary inflammation and infection. In this study we investigated whether ceramide concentrations are also altered in the trachea and the intestine of cystic fibrosis mice and whether an accumulation of ceramide in these organs has functional consequences that are typical of cystic fibrosis. Our findings demonstrate a marked accumulation of ceramide in tracheal and intestinal epithelial cells of cystic fibrosis mice. When acid sphingomyelinase activity is inhibited by treating cystic fibrosis mice with amitriptyline or by genetic heterozygosity of acid sphingomyelinase in cystic fibrosis mice, ceramide concentrations in the trachea and the intestine are normalized. Moreover, increased rates of cell death and increased cytokine concentrations in the trachea, the intestine, or both were normalized by the inhibition of acid sphingomyelinase activity and the concomitant normalization of ceramide concentrations. These findings suggest that ceramide plays a crucial role in inflammation and increased rates of cell death in several organs of cystic fibrosis mice.
囊性纤维化是一种遗传性代谢紊乱，由囊性纤维化跨膜电导调节因子（CFTR）基因突变引起，其特征为严重的肠道和肺部症状，特别是肠梗阻、胰腺功能不全、慢性肺部炎症和肺部微生物感染。最近的研究表明，囊性纤维化患者的肺部和几种小鼠模型中存在神经酰胺的积累。这些发现表明，肺部神经酰胺浓度在肺部炎症和感染中起着重要作用。在这项研究中，我们研究了囊性纤维化小鼠的气管和肠道中神经酰胺浓度是否也发生了改变，以及这些器官中神经酰胺的积累是否具有囊性纤维化的典型功能后果。我们的研究结果表明，囊性纤维化小鼠的气管和肠道上皮细胞中存在明显的神经酰胺积累。当通过用阿米替林治疗囊性纤维化小鼠或通过囊性纤维化小鼠中酸性鞘磷脂酶的遗传杂合性来抑制酸性鞘磷脂酶的活性时，气管和肠道中的神经酰胺浓度得到正常化。此外，通过抑制酸性鞘磷脂酶的活性和同时使神经酰胺浓度正常化，气管、肠道或两者中增加的细胞死亡率和细胞因子浓度得到正常化。这些发现表明，神经酰胺在囊性纤维化小鼠的几个器官的炎症和增加的细胞死亡率中起着关键作用。
