Department of Pediatric Respiratory Sciences, Johns Hopkins University, Baltimore, MD 21287, USA.
J Immunol. 2011 Jan 1;186(1):602-13. doi: 10.4049/jimmunol.1002850. Epub 2010 Dec 6.
Ceramide accumulation mediates the pathogenesis of chronic obstructive lung diseases. Although an association between lack of cystic fibrosis transmembrane conductance regulator (CFTR) and ceramide accumulation has been described, it is unclear how membrane-CFTR may modulate ceramide signaling in lung injury and emphysema. Cftr(+/+) and Cftr(-/-) mice and cells were used to evaluate the CFTR-dependent ceramide signaling in lung injury. Lung tissue from control and chronic obstructive pulmonary disease patients was used to verify the role of CFTR-dependent ceramide signaling in pathogenesis of chronic emphysema. Our data reveal that CFTR expression inversely correlates with severity of emphysema and ceramide accumulation in chronic obstructive pulmonary disease subjects compared with control subjects. We found that chemical inhibition of de novo ceramide synthesis controls Pseudomonas aeruginosa-LPS-induced lung injury in Cftr(+/+) mice, whereas its efficacy was significantly lower in Cftr(-/-) mice, indicating that membrane-CFTR is required for controlling lipid-raft ceramide levels. Inhibition of membrane-ceramide release showed enhanced protective effect in controlling P. aeruginosa-LPS-induced lung injury in Cftr(-/-) mice compared with that in Cftr(+/+) mice, confirming our observation that CFTR regulates lipid-raft ceramide levels and signaling. Our results indicate that inhibition of de novo ceramide synthesis may be effective in disease states with low CFTR expression like emphysema and chronic lung injury but not in complete absence of lipid-raft CFTR as in ΔF508-cystic fibrosis. In contrast, inhibiting membrane-ceramide release has the potential of a more effective drug candidate for ΔF508-cystic fibrosis but may not be effectual in treating lung injury and emphysema. Our data demonstrate the critical role of membrane-localized CFTR in regulating ceramide accumulation and inflammatory signaling in lung injury and emphysema.
神经酰胺积累介导慢性阻塞性肺疾病的发病机制。虽然已经描述了囊性纤维化跨膜电导调节因子（CFTR）缺乏与神经酰胺积累之间的关联，但尚不清楚膜-CFTR 如何调节肺损伤和肺气肿中的神经酰胺信号。使用 Cftr(+/+)和 Cftr(-/-)小鼠和细胞来评估肺损伤中 CFTR 依赖性神经酰胺信号。使用对照和慢性阻塞性肺疾病患者的肺组织来验证 CFTR 依赖性神经酰胺信号在慢性肺气肿发病机制中的作用。我们的数据表明，与对照相比，CFTR 表达与慢性阻塞性肺疾病患者肺气肿和神经酰胺积累的严重程度呈负相关。我们发现，化学抑制从头合成神经酰胺可控制 Pseudomonas aeruginosa-LPS 诱导的 Cftr(+/+)小鼠的肺损伤，而在 Cftr(-/-)小鼠中的疗效明显降低，表明膜-CFTR 是控制脂筏神经酰胺水平所必需的。抑制膜神经酰胺释放显示在控制 Cftr(-/-)小鼠的 P. aeruginosa-LPS 诱导的肺损伤方面具有增强的保护作用与 Cftr(+/+)小鼠相比，证实了我们的观察结果，即 CFTR 调节脂筏神经酰胺水平和信号。我们的结果表明，抑制从头合成神经酰胺可能在 CFTR 表达低的疾病状态（如肺气肿和慢性肺损伤）中有效，但在完全缺乏脂筏 CFTR （如 ΔF508-囊性纤维化）的情况下则无效。相比之下，抑制膜神经酰胺释放可能是 ΔF508-囊性纤维化的更有效的候选药物，但可能对治疗肺损伤和肺气肿无效。我们的数据表明，膜定位的 CFTR 在调节肺损伤和肺气肿中的神经酰胺积累和炎症信号中起着关键作用。
