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Aging Enhances Susceptibility to Cigarette Smoke–Induced Inflammation through Bronchiolar Chemokines

¹ First Department of Medicine, Hokkaido University School of Medicine, Sapporo; and ² Teijin Institute for Biomedical Research, Teijin Pharma Ltd., Tokyo, Japan

Correspondence and requests for reprints should be addressed to Tomoko Betsuyaku, M.D., Ph.D., First Department of Medicine, Hokkaido University School of Medicine, N-15, W-7, Kita-ku, Sapporo, Japan 060-8638. E-mail: bytomoko{at}med.hokudai.ac.jp

Cigarette smoking and aging are major risk factors for chronic obstructive pulmonary disease. An unsolved question is whether elderly lungs are particularly vulnerable to cigarette smoke (CS) exposure. In this study, we used a mouse model to test the hypothesis that aging increases the susceptibility to CS-induced pulmonary inflammation. We subjected 9-week-old and 69-week-old C57BL/6J mice to CS (whole-body exposure, 90 min/d), and evaluated neutrophil infiltration in the lungs, the levels of keratinocyte-derived chemokine (KC) and macrophage inflammatory protein (MIP)-2 in bronchoalveolar lavage fluid, and mRNA expression in bronchiolar epithelium retrieved by laser capture microdissection. The 69-week-old mice showed a greater number of neutrophils and higher levels of bronchiolar KC and MIP-2 expression than 9-week-old mice after 9 days of CS exposure. Furthermore, single CS exposure induced the rapid up-regulation of KC and MIP-2 in bronchiolar epithelium in both 9-week-old and 69-week-old mice, and the much higher levels in 69-week-old mice were associated with greater nuclear translocation of NF-B. In contrast, no age-related differences were observed in the bronchiolar expression of NF-E2–related factor 2–regulated antioxidant and detoxification genes, heme oxygenase-1, reduced nicotinamide adenine dinucleotide phosphate quinone reductase 1, and glutamate-cysteine ligase, modifier unit, or antioxidant activity in bronchoalveolar lavage fluid, regardless of CS exposure. In summary, aging increases susceptibility to CS-induced inflammation in a mouse model, and robust mRNA up-regulation and nuclear translocation of NF-B in bronchiolar epithelium may be involved.

Key Words: age • smoking • neutrophil • chemokine • bronchiolar epithelium

CLINICAL RELEVANCE This research shows, for the first time, that acute cigarette smoke (CS) exposure provokes enhanced keratinocyte-derived chemokine and macrophage inflammatory protein-2 expression in bronchiolar epithelium accompanying vigorous neutrophilic responses in the lungs of aged mice. These results will assist in elucidating the mechanisms through which elderly lungs become more vulnerable to CS.