臭氧(O3)是直接威胁呼吸系统的主要空气污染物,肺脂肪酸代谢紊乱是肺部炎症性疾病的重要分子事件。肝激酶B1(LKB1)和核苷酸结合域富含亮氨酸的重复蛋白3(NLRP3)炎症小体不仅调节炎症,还与脂肪酸代谢密切相关。然而,LKB1和NLRP3炎性体在肺脂肪酸代谢中的作用及机制,这可能会导致臭氧引起的肺部炎症,仍不清楚,缺乏预防O3诱导的肺部炎症损伤的有效策略。为了探索这些,小鼠暴露于1.00ppmO3(3小时/天,5days),肺部炎症是由气道高反应性决定的,组织病理学检查,支气管肺泡灌洗液(BALF)中的总细胞和细胞因子。采用靶向脂肪酸代谢组学技术检测肺组织中、长脂肪酸。然后,利用LKB1过表达腺病毒和NLRP3基因敲除(NLRP3-/-)小鼠探讨O3诱导肺脂肪酸代谢紊乱的机制。结果表明,O3暴露引起肺部炎症损伤和肺中长链脂肪酸代谢紊乱,尤其是降低二高-γ-亚麻酸(DGLA)。同时,LKB1表达降低,O3暴露后,小鼠肺部的NLRP3炎性体被激活。此外,LKB1过表达减轻O3诱导的肺部炎症并抑制NLRP3炎性体的活化。我们发现,与O3暴露后的宽型小鼠相比,NLRP3-/-小鼠的肺脂肪酸代谢紊乱得到了改善。此外,在暴露于O3之前气管内施用DGLA可显着减轻O3诱导的肺部炎症损伤。一起来看,这些发现表明脂肪酸代谢紊乱与O3诱导的肺部炎症有关,受LKB1介导的NLRP3通路调节,DGLA补充剂可能是改善臭氧相关肺部炎症损伤的有效预防策略。
Ozone (O3) is a major air pollutant that directly threatens the respiratory system, lung fatty acid metabolism disorder is an important molecular event in pulmonary inflammatory diseases. Liver kinase B1 (LKB1) and nucleotide-binding domain leucine-rich repeat-containing protein 3 (NLRP3) inflammasome not only regulate inflammation, but also have close relationship with fatty acid metabolism. However, the role and mechanism of LKB1 and NLRP3 inflammasome in lung fatty acid metabolism, which may contribute to ozone-induced lung inflammation, remain unclear, and effective strategy for preventing O3-induced pulmonary inflammatory injury is lacking. To explore these, mice were exposed to 1.00 ppm O3 (3 h/d, 5 days), and pulmonary inflammation was determined by airway hyperresponsiveness, histopathological examination, total cells and cytokines in bronchoalveolar lavage fluid (BALF). Targeted fatty acids metabolomics was used to detect medium and long fatty acid in lung tissue. Then, using LKB1-overexpressing adenovirus and NLRP3 knockout (NLRP3-/-) mice to explore the mechanism of O3-induced lung fatty acid metabolism disorder. Results demonstrated that O3 exposure caused pulmonary inflammatory injury and lung medium and long chain fatty acids metabolism disorder, especially decreased dihomo-γ-linolenic acid (DGLA). Meanwhile, LKB1 expression was decreased, and NLRP3 inflammasome was activated in lung of mice after O3 exposure. Additionally, LKB1 overexpression alleviated O3-induced lung inflammation and inhibited the activation of NLRP3 inflammasome. And we found that pulmonary fatty acid metabolism disorder was ameliorated of NLRP3 -/- mice compared with those in wide type mice after O3 exposure. Furthermore, administrating DGLA intratracheally prior to O3 exposure significantly attenuated O3-induced pulmonary inflammatory injury. Taken together, these findings suggest that fatty acids metabolism disorder is involved in O3-induced pulmonary inflammation, which is regulated by LKB1-mediated NLRP3 pathway, DGLA supplement could be a useful preventive strategy to ameliorate ozone-associated lung inflammatory injury.