Linoleic acid-derived lipid mediators increase in a female-dominated subphenotype of COPD
Linoleic acid-derived lipid mediators increase in a female-dominated subphenotype of COPD
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DOI：
10.1183/13993003.01080-2015
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发表时间：
2016-06-01
影响因子：
24.3
通讯作者：
Wheelock, Craig E.
中科院分区：
文献类型：
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作者：
Balgoma, David;Yang, Mingxing;Wheelock, Craig E.
慢性阻塞性肺疾病(COPD)是导致死亡的主要原因；然而，炎症介质在其病理生物学中的作用尚不清楚。为探讨慢性阻塞性肺疾病(COPD)患者性别对血脂介质水平的影响，对114例慢性阻塞性肺疾病(COPD)患者和健康非吸烟者、吸烟者和COPD患者(全球慢性阻塞性肺疾病倡议I-II/A-B期)的支气管肺泡灌洗液(BALF)和血清进行检测。通过液-质联用分析了细胞色素P450、脂氧合酶和环氧合酶途径所产生的94种脂类介质。多元模拟发现BALF中有一个9-脂组分，用于区分COPD女性吸烟者和健康女性吸烟者(p=6x10(-6))。在相应的男性人群中没有观察到差异(p=1.0)。这些发现在独立队列中重复，准确率为92%(p=0.005)。最强的驱动因素是亚油酸(白毒素)的细胞色素P450衍生环氧化物产物及其相应的可溶性环氧化物水解酶(SEH)衍生产物(白毒素)。这些物种与肺功能(r=0.87；p=0.0009)和推测参与其生物合成的酶的基因水平(r=0.96p=0.003)相关。白毒素水平与杯状细胞丰度相关(r=0.72；p=0.028)。这些发现提示，杯状细胞相关的细胞色素P450和sEH活性导致白毒素-二醇水平升高的机制，这可能在女性为主的疾病亚型的慢性阻塞性肺疾病的临床表现中起作用。
Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality; however, the role of inflammatory mediators in its pathobiology remains unclear. The aim of this study was to investigate the influence of gender in COPD on lipid mediator levels.Bronchoalveolar lavage fluid (BALF) and serum were obtained from healthy never-smokers, smokers and COPD patients (Global Initiative for Chronic Obstructive Lung Disease stage I-II/A-B) (n=114). 94 lipid mediators derived from the cytochrome-P450, lipoxygenase, and cyclooxygenase pathways were analysed by liquid chromatography-mass spectrometry.Multivariate modelling identified a 9-lipid panel in BALF that classified female smokers with COPD from healthy female smokers (p=6x10(-6)). No differences were observed for the corresponding male population (p=1.0). These findings were replicated in an independent cohort with 92% accuracy (p=0.005). The strongest drivers were the cytochrome P450-derived epoxide products of linoleic acid (leukotoxins) and their corresponding soluble epoxide hydrolase (sEH)-derived products (leukotoxindiols). These species correlated with lung function (r=0.87; p=0.0009) and mRNA levels of enzymes putatively involved in their biosynthesis (r=0.96; p=0.003). Leukotoxin levels correlated with goblet cell abundance (r=0.72; p=0.028).These findings suggest a mechanism by which goblet cell-associated cytochrome-P450 and sEH activity produce elevated leukotoxin-diol levels, which play a putative role in the clinical manifestations of COPD in a female-dominated disease sub-phenotype.