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Down-Regulated NF-E2–Related Factor 2 in Pulmonary Macrophages of Aged Smokers and Patients with Chronic Obstructive Pulmonary Disease
Abstract
Pulmonary macrophages are one of the sources of various antioxidant and detoxification enzymes for which NF-E2–related factor 2 (Nrf2) is a key transcriptional factor. Although Nrf2 deficiency reportedly induces severe emphysema in mice exposed to cigarette smoke (CS), no reports have studied Nrf2 regulation in chronic obstructive pulmonary disease (COPD). In this study, Nrf2 activation in response to CS was evaluated in human alveolar macrophages, and age-related differences in CS-induced Nrf2 regulation in mouse alveolar macrophages were determined. Furthermore, Nrf2 mRNA levels in human macrophages harvested by bronchoalveolar lavage or laser capture microdissection were measured. CS induced nuclear Nrf2 accumulation and up-regulation of Nrf2 target genes without substantial changes in Nrf2 mRNA levels in human alveolar macrophages. In humans, the Nrf2 mRNA level in lavaged macrophages of young subjects (n = 14) was independent of smoking status; however, the Nrf2 mRNA level was down-regulated in the lavaged macrophages of older current smokers (n = 14) compared with older nonsmokers (n = 9) (P < 0.001). Among older subjects, the macrophage Nrf2 mRNA level was inversely correlated with oxidized glutathione and carbonylated albumin levels in bronchoalveolar lavage fluid. In mice, aging suppressed the CS-induced up-regulation of Nrf2 target genes, as well as Nrf2, in alveolar macrophages. Furthermore, the Nrf2 mRNA level was decreased in laser capture microdissection–retrieved macrophages obtained from subjects with COPD (n = 10) compared with control subjects (n = 10) (P = 0.001). In conclusion, CS induces Nrf2 activation in macrophages, and Nrf2 expression is decreased in the macrophages of older current smokers and patients with COPD.
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“Experimental studies have illustrated an age-associated increase in ROS levels that corresponds with decreased antioxidative responses in AM (111, 112).”
From Aging and Lung Disease (2020) · cites this paper as [112]
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Metadata
- Authors
- Suzuki, M., Betsuyaku, T., Ito, Y., Nagai, K., Nasuhara, Y., Kaga, K., Kondo, S., & Nishimura, M.
- Affiliations
- Hokkaido University (JP)
- First Department of Medicine and
- Venue
- American Journal of Respiratory Cell and Molecular Biology
- Publisher
- Oxford University Press (OUP)
- Published
- 2008-12-01
- Volume
- 39
- Issue
- 6
- Pages
- 673-682
- ISSN
- 1044-1549 (ISSN-L)
- 1535-4989
- OpenAlex
- W2095835362
- Cited by
- 286
- References
- 38
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 13 · 2023: 11 · 2022: 14 · 2021: 20 · 2020: 23 · 2019: 14 · 2018: 11 · 2017: 18 · 2016: 22 · 2015: 12 · 2014: 17 · 2013: 23 · 2012: 17
- FWCI
- 7.81
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Respiratory Cell and Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Chronic Obstructive Pulmonary Disease (COPD) Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heme Oxygenase-1 and Carbon Monoxide
- Keywords
- Nrf2, lung macrophages, alveolar macrophages, chronic obstructive pulmonary disease, cigarette smoke, aging, Nrf2 target genes, glutathione disulfide, oxidative stress, antioxidant defense, emphysema
- MeSH terms
- Adult, Aged, Aging, Animals, Bronchoalveolar Lavage Fluid, Female, Humans, Immunohistochemistry, Lung, Male, Mice, Inbred C57BL, Mice, Inbred ICR, Middle Aged, RNA, Messenger, Smoking, Biomarkers, Down-Regulation, Macrophages, Alveolar, Oxidative Stress, Pulmonary Disease, Chronic Obstructive, NF-E2-Related Factor 2, Mice
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