Sakurai Kaori, Chubachi Shotaro, Miyata Jun, Hamamoto Junko, Naganuma Tatsuro, Shimada Takashi, Otake Shiro, Nakayama Shingo, Irie Hidehiro, Tsutsumi Akihiro, Kameyama Naofumi, Hegab Ahmed E, Shimoda Masayuki, Terai Hideki, Yasuda Hiroyuki, Kanai Yae, Arita Makoto, Fukunaga Koichi
Division of Pulmonary Medicine, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
Division of Physiological Chemistry and Metabolism, Graduate School of Pharmaceutical Sciences, Keio University, Tokyo, Japan.
Front Immunol. 2025 Mar 19;16:1557790. doi: 10.3389/fimmu.2025.1557790. eCollection 2025.
Lung cancer is characterized by a poor prognosis and is a significant comorbidity of chronic obstructive pulmonary disease (COPD). Therefore, effective chemopreventive agents are warranted. We evaluated the effects of the cyclooxygenase-2 (COX-2) inhibitor celecoxib on the prevention of lung-carcinoma development using an intermittent smoking-induced lung-carcinoma mouse model. Additionally, we explored COX-2's role in lipid metabolism.
Male A/J mice were exposed to sham air or mainstream cigarette smoke for 20 weeks. Vehicle or celecoxib was administered via intragastric feeding once daily. Lung tissues were analyzed for tumor nodules and emphysema; the bronchoalveolar lavage fluid was collected for cell counting. COX-2 expression was measured using real-time polymerase chain reaction and western blotting; lipidomic analysis was conducted using liquid chromatography-tandem mass spectrometry. Cell proliferation and colony-forming assays were performed on LA-4 cells to assess the effects of prostaglandins and COX-2 inhibitors.
Intermittent smoking exposure increased lung adenomas, adenocarcinomas, and COX-2 expression. Lung adenomas were characterized by abundant COX-2-positive cells. Celecoxib reduced intermittent smoking-induced inflammation, emphysema, and cell counts in the bronchoalveolar lavage fluid and decreased the incidence of lung adenocarcinomas, whereas the total number of observed lung tumors was unchanged. Celecoxib markedly suppressed single-smoke-induced prostaglandin E2 (PGE) production in the airway. PGE increased LA-4 cell viability via the EP4 receptor and promoted colony formation.
Celecoxib effectively inhibited lung-carcinoma development, inflammation, and emphysema, demonstrating the potential for chemoprevention in smokers and patients with COPD. Further studies on EP4 inhibitors for the prevention of emphysema and lung cancer are warranted.
肺癌预后较差，是慢性阻塞性肺疾病（COPD）的一种重要合并症。因此，需要有效的化学预防药物。我们使用间歇性吸烟诱导的肺癌小鼠模型评估了环氧化酶-2（COX-2）抑制剂塞来昔布对预防肺癌发生的作用。此外，我们还探讨了COX-2在脂质代谢中的作用。
将雄性A/J小鼠暴露于假空气或主流香烟烟雾中20周。通过每日一次灌胃给予载体或塞来昔布。分析肺组织中的肿瘤结节和肺气肿情况；收集支气管肺泡灌洗液进行细胞计数。使用实时聚合酶链反应和蛋白质印迹法测量COX-2表达；使用液相色谱-串联质谱法进行脂质组学分析。对LA-4细胞进行细胞增殖和集落形成试验，以评估前列腺素和COX-2抑制剂的作用。
间歇性吸烟暴露增加了肺腺瘤、腺癌和COX-2表达。肺腺瘤的特征是有大量COX-2阳性细胞。塞来昔布减少了间歇性吸烟诱导的炎症、肺气肿和支气管肺泡灌洗液中的细胞计数，并降低了肺腺癌的发生率，而观察到的肺肿瘤总数未变。塞来昔布显著抑制了单次吸烟诱导的气道中前列腺素E2（PGE）的产生。PGE通过EP4受体增加LA-4细胞活力并促进集落形成。
塞来昔布有效抑制肺癌发生、炎症和肺气肿，表明其在吸烟者和COPD患者中具有化学预防潜力。有必要进一步研究EP4抑制剂对预防肺气肿和肺癌的作用。
