TY - JOUR
T1 - Intermittent exposure to cigarette smoke increases lung tumors and the severity of emphysema more than continuous exposure
AU - Kameyama, Naofumi
AU - Chubachi, Shotaro
AU - Hegab, Ahmed E.
AU - Yasuda, Hiroyuki
AU - Kagawa, Shizuko
AU - Tsutsumi, Akihiro
AU - Fukunaga, Koichi
AU - Shimoda, Masayuki
AU - Kanai, Yae
AU - Soejima, Kenzo
AU - Betsuyaku, Tomoko
N1 - Funding Information:
This work was supported by Japan Society for the Promotion of Science Grant-in-Aid for Young Scientists 17K16063 (S.C.), Grant-in-Aid for Scientific Research B 05-045-0215 (T.B.), and GlaxoSmithKline research grant 2016 A-34 (S.C.).
Publisher Copyright:
Copyright © 2018 by the American Thoracic Society.
PY - 2018/8
Y1 - 2018/8
N2 - Lung cancer and chronic obstructive pulmonary disease are leading causes of morbidity and mortality worldwide, and cigarette smoking is a main risk factor for both. The presence of emphysema, an irreversible lung disease, further raises the risk of lung cancer in patients with chronic obstructive pulmonary disease. The mechanisms involved in smoke-induced tumorigenesis and emphysema are not fully understood, attributable to a lack of appropriate animal models. Here, we optimized a model of cigarette smoke (CS)–induced lung cancer and emphysema in A/J mice treated with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, a potent carcinogen. We investigated whether variations in CS exposure patterns with the same total amount and duration of exposure affect tumorigenesis and/or development of emphysema. Continuous CS exposure for 3 months significantly suppressed 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone–induced development of adenomas and adenocarcinomas; however, emphysema independently developed during this period. Surprisingly, intermittent CS exposure increased the severity of emphysema and resulted in a higher incidence of adenocarcinomas. Furthermore, intermittent CS exposure elicited a marked increase in M2-polarized macrophages within and near the developed tumors. By employing a CS exposure protocol with repeated cycles of cessation and relapse, we provide evidence that intermittent CS exposure enhances tumorigenesis and emphysema progression more than that of continuous CS exposure.
AB - Lung cancer and chronic obstructive pulmonary disease are leading causes of morbidity and mortality worldwide, and cigarette smoking is a main risk factor for both. The presence of emphysema, an irreversible lung disease, further raises the risk of lung cancer in patients with chronic obstructive pulmonary disease. The mechanisms involved in smoke-induced tumorigenesis and emphysema are not fully understood, attributable to a lack of appropriate animal models. Here, we optimized a model of cigarette smoke (CS)–induced lung cancer and emphysema in A/J mice treated with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, a potent carcinogen. We investigated whether variations in CS exposure patterns with the same total amount and duration of exposure affect tumorigenesis and/or development of emphysema. Continuous CS exposure for 3 months significantly suppressed 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone–induced development of adenomas and adenocarcinomas; however, emphysema independently developed during this period. Surprisingly, intermittent CS exposure increased the severity of emphysema and resulted in a higher incidence of adenocarcinomas. Furthermore, intermittent CS exposure elicited a marked increase in M2-polarized macrophages within and near the developed tumors. By employing a CS exposure protocol with repeated cycles of cessation and relapse, we provide evidence that intermittent CS exposure enhances tumorigenesis and emphysema progression more than that of continuous CS exposure.
KW - Cigarette smoke
KW - Emphysema
KW - Lung cancer
KW - M2 macrophage
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U2 - 10.1165/rcmb.2017-0375OC
DO - 10.1165/rcmb.2017-0375OC
M3 - Article
C2 - 29443539
AN - SCOPUS:85051065943
VL - 59
SP - 179
EP - 188
JO - American Journal of Respiratory Cell and Molecular Biology
JF - American Journal of Respiratory Cell and Molecular Biology
SN - 1044-1549
IS - 2
ER -