Sakurai Kaori, Nakayama Shingo, Chubachi Shotaro, Otake Shiro, Shimada Takashi, Irie Hidehiro, Tsutsumi Akihiro, Kameyama Naofumi, Hegab Ahmed E, Shimoda Masayuki, Hamamoto Junko, Terai Hideki, Yasuda Hiroyuki, Kanai Yae, Fukunaga Koichi
Division of Pulmonary Medicine, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
Medical Education Center, School of Medicine, International University of Health and Welfare, 4-3 Kozunomori, Narita, Chiba, 286-8686, Japan.
BMC Pulm Med. 2025 May 26;25(1):262. doi: 10.1186/s12890-025-03730-w.
The prognosis of lung cancer complicated by chronic obstructive pulmonary disease is poor, and effective prophylactic agents have not been established. Given that inflammation is a shared pathogenic mechanism of both diseases, we aimed to evaluate the efficacy of roflumilast, a novel anti-inflammatory drug, in preventing emphysema and lung cancer using a smoking-induced lung cancer mouse model.
Male A/J mice were exposed to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, a potent carcinogen, and intermittent mainstream cigarette smoke for 20 weeks. Roflumilast or vehicle was administered via intragastric gavage once daily. Lung tissues were assessed for tumor nodules and emphysema, and bronchoalveolar lavage fluid was collected for cell counting. Emphysema severity and concentrations of inflammatory cytokines (IL-6, IL-1β, and TNF-α) were assessed. RAW 264.7 macrophage cells were used to assess cellular responses to cigarette smoke extract.
Roflumilast attenuated the increase in total cells and macrophages in bronchoalveolar lavage fluid induced by intermittent smoking exposure and significantly suppressed smoking-induced expressions of IL-6, IL-1β, and TNF-α. Roflumilast also reduced emphysematous changes and the number of lung tumors. In vitro, roflumilast attenuated cigarette smoke extract-induced expression of IL-6, IL-1β, and TNF-α in RAW 264.7 cells.
This study highlights the potential use of roflumilast as a chemopreventive agent for patients with chronic obstructive pulmonary disease who are at risk of lung cancer and underscores its relevance for future clinical application and research on phosphodiesterase-4 inhibitors.
肺癌合并慢性阻塞性肺疾病的预后较差，且尚未确立有效的预防药物。鉴于炎症是这两种疾病共有的致病机制，我们旨在使用吸烟诱导的肺癌小鼠模型评估新型抗炎药物罗氟司特在预防肺气肿和肺癌方面的疗效。
雄性A/J小鼠暴露于强效致癌物4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮和间歇性主流香烟烟雾中20周。罗氟司特或赋形剂通过灌胃每天给药一次。评估肺组织中的肿瘤结节和肺气肿情况，并收集支气管肺泡灌洗液进行细胞计数。评估肺气肿严重程度和炎性细胞因子（IL-6、IL-1β和TNF-α）的浓度。使用RAW 264.7巨噬细胞评估细胞对香烟烟雾提取物的反应。
罗氟司特减轻了间歇性吸烟暴露诱导的支气管肺泡灌洗液中总细胞和巨噬细胞的增加，并显著抑制了吸烟诱导的IL-6、IL-1β和TNF-α的表达。罗氟司特还减少了肺气肿变化和肺肿瘤数量。在体外，罗氟司特减弱了香烟烟雾提取物诱导的RAW 264.7细胞中IL-6、IL-1β和TNF-α的表达。
本研究强调了罗氟司特作为慢性阻塞性肺疾病且有肺癌风险患者化学预防剂的潜在用途，并强调了其在未来临床应用和磷酸二酯酶-4抑制剂研究中的相关性。
