Division of Physiological Chemistry 2, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
Respiratory Medicine Unit, Dept of Medicine Solna and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
Eur Respir J. 2016 Jun;47(6):1645-56. doi: 10.1183/13993003.01080-2015. Epub 2016 Mar 10.
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=6×10(-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 (leukotoxin-diols). 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.
慢性阻塞性肺疾病（COPD）是主要的死亡原因；然而，炎症介质在其病理生物学中的作用仍不清楚。本研究旨在探讨性别在 COPD 中的作用对脂质介质水平的影响。支气管肺泡灌洗液（BALF）和血清取自健康不吸烟者、吸烟者和 COPD 患者（全球慢性阻塞性肺疾病倡议阶段 I-II/A-B）（n=114）。通过液相色谱-质谱法分析了来源于细胞色素 P450、脂氧合酶和环氧化酶途径的 94 种脂质介质。多变量建模确定了 BALF 中的 9 种脂质谱，可将患有 COPD 的女性吸烟者与健康女性吸烟者区分开（p=6×10(-6)）。对于相应的男性人群，没有观察到差异（p=1.0）。这些发现用 92%准确性的独立队列进行了复制（p=0.005）。最强的驱动因素是来自亚油酸的细胞色素 P450 衍生的环氧化物产物（白细胞毒素）及其相应的可溶性环氧化物水解酶（sEH）衍生产物（白细胞毒素二醇）。这些物质与肺功能（r=0.87；p=0.0009）和酶的 mRNA 水平相关，这些酶推测参与它们的生物合成（r=0.96；p=0.003）。白细胞毒素水平与杯状细胞丰度相关（r=0.72；p=0.028）。这些发现表明，杯状细胞相关的细胞色素 P450 和 sEH 活性产生升高的白细胞毒素二醇水平的机制，在以女性为主的疾病亚表型中，可能在 COPD 的临床表现中发挥作用。
