Investigation of molecular action mechanism and prevention effect of Celecoxib on pulmonary emphysema and lung cancer

塞来昔布治疗肺气肿及肺癌的分子作用机制及预防效果研究

• 批准号: 19K17681
• 负责人: 中山 真吾
• 金额: $ 2.66万
• 依托单位: Keio University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Early-Career Scientists
• 财政年份: 2019
• 资助国家: 日本
• 起止时间: 2019-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-19K17681/
• 关键词: Celecoxib; 喫煙誘導肺癌発生抑制; Chemoprevention

我々はCOPD前向きコホート解析で肺気腫が肺癌発症リスク因子である事を明らかにしており,肺気腫進行と肺癌発生に共通病態があると考えた.共通病態では慢性炎症,酸化ストレス,遺伝子異常等が言われている.我々は末梢血好中球リンパ球比という炎症性マーカーがCOPD重症度や増悪と関連する事を明らかにしており,慢性炎症に注目した.また,少量発癌物質投与後,間歇的喫煙曝露で肺内慢性炎症や気腫病変が増悪し,肺腺腫・肺腺癌が高率発生する喫煙誘導肺気腫・肺癌マウスモデルを確立した.過去に喫煙誘導肺気腫ラットモデルへの抗炎症薬のCOX-2阻害薬Celecoxib投与での肺気腫予防報告やヒト肺腺癌切除検体で前癌病変や浸潤癌でもCOX-2発現が認められた報告がある.これらより我々のモデルでCelecoxib投与が喫煙誘導肺癌も予防するか検討した.上記モデルにCelecoxibを投与した処,BAL液のマクロファージ,好中球等炎症細胞数が溶媒群に比して有意に減少した.組織学的に肺気腫が溶媒群に比して有意に改善した.腫瘍数や大きさに差はなかったが,肺腺癌数は有意に減少した.Celecoxibの肺腺癌数減少機序には腺腫の癌化,および,正常粘膜から直接発生のde novo経路の2通りを考慮したが,組織学的に肺腺腫と肺腺癌両者の要素を持つ結節を認めた為前者を想定した.Celecoxib投与による腫瘍発生抑制,縮小効果はないが,肺腺腫から肺腺癌への移行抑制が示唆された.両群で全肺ホモジネートのqPCRとWestern blotを施行し,COX-2のmRNA,蛋白質を比較すると喫煙曝露で発現は共に亢進したが,Celecoxib有無で差はなかった.これらよりCelecoxibは下流シグナルや代謝産物に影響していると推察された.今後はCelecoxibの肺気腫および肺癌への分子学的作用機序の検討を進めていく予定である.

COPD is a progressive disease, and lung cancer is a common disease. Common pathologies include chronic inflammation, acidification, genetic abnormalities, etc. The severity of COPD is related to chronic inflammation. After administration of small amounts of carcinogenic substances, intermittent smoke exposure increased chronic inflammation and edema in the lungs, and increased incidence of lung adenocarcinoma and lung cancer. In the past, the anti-inflammatory COX-2 inhibitor of smoke-induced lung cancer has been reported to prevent lung cancer and to detect COX-2 expression in lung adenocarcinoma resection. Celecoxib administration and prevention of smoke-induced lung cancer. In addition, the number of inflammatory cells in BAL fluid decreased significantly when Celecoxib was administered. Histological changes in lung tissue were significantly improved compared to vehicle group. The number of lung adenocarcinomas decreased significantly.Celecoxib decreased the number of lung adenocarcinomas. The mechanism of decrease in the number of lung adenocarcinomas was carcinogenesis. The normal mucosa was directly developed. The two channels of de novo pathway were considered. Histological factors of lung adenocarcinomas were identified.Celecoxib inhibited the development of lung adenocarcinomas. Lung cancer is the most common form of cancer. qPCR and Western blot analysis of COX-2 mRNA and protein were performed in the whole lung tissue of mice. The effect of Celecoxib on the production of its metabolites was investigated. In the future, the molecular mechanism of action of Celecoxib in lung cancer should be further investigated.