BACKGROUND Previously, we showed that abnormal levels of bioactive lipids in bronchoalveolar lavage fluid (BALF) from infants with cystic fibrosis (CF) correlated with early structural lung damage. METHOD To extend these studies, BALF bioactive lipid measurement by mass spectrometry and chest computed tomography (CT, combined with the sensitive PRAGMA-CF scoring method) were performed longitudinally at 2-year intervals in a new cohort of CF children (n = 21, aged 1-5 yrs). RESULTS PRAGMA-CF, neutrophil elastase activity, and myeloperoxidase correlated with BALF lysolipids and isoprostanes, markers of oxidative stress, as well as prostaglandin E2 and combined ceramide precursors (Spearman's Rho > 0.5; P < 0.01 for all). Multiple protein agonists of inflammation and tissue remodeling, measured by Olink protein array, correlated positively (r = 0.44-0.79, p < 0.05) with PRAGMA-CF scores and bioactive lipid levels. Notably, levels of lysolipids, prostaglandin E2 and isoprostanes at first BALF predicted the evolution of PRAGMA-CF scores 2 years later. In wild-type differentiated primary bronchial epithelial cells, and in CFTR-inducible iCFBE cells, treatment with a lysolipid receptor agonist (VPC3114) enhanced shedding of pro-inflammatory and pro-fibrotic proteins. CONCLUSIONS Together, our findings suggest that bioactive lipids in BALF correlate with and possibly predict structural lung disease in CF children, which supports their use as biomarkers of disease progression and treatment efficacy. Furthermore, our data suggest a causative role of airway lysolipids and oxidative stress in the progression of early CF lung disease, unveiling potential therapeutic targets.

中文翻译：

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生物活性脂质的气道分布预测囊性纤维化肺病的早期进展

背景 此前，我们发现囊性纤维化 (CF) 婴儿的支气管肺泡灌洗液 (BALF) 中生物活性脂质水平异常与早期结构性肺损伤相关。方法 为了扩展这些研究，在一个新的 CF 儿童队列（n = 21， 1-5 岁）。结果 PRAGMA-CF、中性粒细胞弹性蛋白酶活性和髓过氧化物酶与 BALF 溶血脂和异前列腺素、氧化应激标志物以及前列腺素 E2 和联合神经酰胺前体相关（Spearman's Rho > 0.5；所有 P < 0.01）。炎症和组织重塑的多种蛋白质激动剂，通过 Olink 蛋白质阵列测量，与 PRAGMA-CF 评分和生物活性脂质水平呈正相关（r = 0.44-0.79，p < 0.05）。值得注意的是，第一次 BALF 中溶血脂、前列腺素 E2 和异前列腺素的水平预测了 2 年后 PRAGMA-CF 评分的演变。在野生型分化的原代支气管上皮细胞和 CFTR 诱导的 iCFBE 细胞中，溶血脂受体激动剂 (VPC3114) 处理增强了促炎和促纤维化蛋白的脱落。结论 总之，我们的研究结果表明 BALF 中的生物活性脂质与 CF 儿童的结构性肺病相关并可能预测它们，这支持将它们用作疾病进展和治疗效果的生物标志物。此外，我们的数据表明气道溶血脂和氧化应激在早期 CF 肺病进展中的致病作用，