Metabolomics screening identifies reduced L-carnitine to be associated with progressive emphysema
Metabolomics screening identifies reduced L-carnitine to be associated with progressive emphysema
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DOI：
10.1042/cs20150438
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发表时间：
2016-02-01
期刊：
影响因子：
6
通讯作者：
Yildirim, Ali Oender
中科院分区：
文献类型：
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作者：
Conlon, Thomas M.;Bartel, Joerg;Yildirim, Ali Oender
慢性阻塞性肺疾病（COPD）的特征是慢性支气管炎、小气道重塑和肺气肿。肺气肿是肺泡结构的破坏，导致气腔扩大和表面积减少，损害气体交换的能力。为了进一步了解进行性肺气肿的病理机制，我们使用基于MS的方法来定量肺气肿进展期间的肺、支气管肺泡灌洗液（BALF）和血清代谢组，在第28、56和161天建立的鼠猪胰弹性蛋白酶（PPE）模型中，与PBS对照相比。偏最小二乘（PLS）分析显示肺气肿进展过程中肺代谢组的变化更大，其次是BALF而不是血清。此外，我们首次证明肺气肿的进展与肺特异性L-肉碱的减少有关，L-肉碱是一种将长链脂肪酸转运到线粒体中进行随后的β-氧化的关键代谢物。在体外，刺激肺泡上皮II型（ATII）样LA 4细胞系与L-肉毒碱减少PPE和过氧化氢诱导的细胞凋亡。此外，与PBS治疗的对照组相比，PPE治疗的小鼠表现出肺功能受损（肺顺应性; 0.067 +/- 0.008 ml/cmH（2）O与0.035 +/- 0.005 ml/cmH（2）O（2）相比，P < 0.0001），补充L-肉碱后改善（0.051 +/- 0.006，P < 0.01），并与细胞凋亡减少相关。总之，我们的研究结果提供了一个新的见解的作用，左旋肉碱，重要的是，建议治疗途径慢性阻塞性肺疾病。
Chronic obstructive pulmonary disease (COPD) is characterized by chronic bronchitis, small airway remodelling and emphysema. Emphysema is the destruction of alveolar structures, leading to enlarged airspaces and reduced surface area impairing the ability for gaseous exchange. To further understand the pathological mechanisms underlying progressive emphysema, we used MS-based approaches to quantify the lung, bronchoalveolar lavage fluid (BALF) and serum metabolome during emphysema progression in the established murine porcine pancreatic elastase (PPE) model on days 28, 56 and 161, compared with PBS controls. Partial least squares (PLS) analysis revealed greater changes in the metabolome of lung followed by BALF rather than serum during emphysema progression. Furthermore, we demonstrate for the first time that emphysema progression is associated with a reduction in lung-specific L-carnitine, a metabolite critical for transporting long-chain fatty acids into the mitochondria for their subsequent beta-oxidation. In vitro, stimulation of the alveolar epithelial type II (ATII)-like LA4 cell line with L-carnitine diminished apoptosis induced by both PPE and H2O2. Moreover, PPE-treated mice demonstrated impaired lung function compared with PBS-treated controls (lung compliance; 0.067 +/- 0.008 ml/cmH(2)O compared with 0.035 +/- 0.005 ml/cmH(2)O(2), P < 0.0001), which improved following supplementation with L-carnitine (0.051 +/- 0.006, P < 0.01) and was associated with a reduction in apoptosis. In summary, our results provide a new insight into the role of L-carnitine and, importantly, suggest therapeutic avenues for COPD.