Key Point

Researchers have identified a gene —Nrf2—that protects against the harmful effects of tobacco smoke and may play a role in the pathogenesis of emphysema.

BALTIMORE—The emphysema that occurs with COPD often has an inflammatory component, which is characterized by the accumulation of macrophages and neutrophils in the lungs. In fact, many patients with smoking-induced emphysema are deficient in the antiproteinase inhibitors produced by inflammatory cells. This deficiency contributes to the destruction of the alveolar extracellular matrix.

Researchers at Johns Hopkins University in Baltimore and the University of Tsukuba in Japan have recently identified a gene—nuclear factor, erythroid-derived 2, like 2 (Nrf2)—that appears to protect the lungs from the harmful effects of tobacco smoke. They also found that suppressing the gene in mice greatly increases the degree of alveolar inflammation that occurs in the lungs.¹

Two groups of mice were studied—wild-type mice and mice that had disruption of Nrf2 expression. When both groups were exposed to room air, they showed no differences in lung development at three days, 10 days, two months, or six months of age. Histology showed similar alveolar architecture between the groups.

INCREASED INFLAMMATION SEEN EARLY

When the mice were exposed to cigarette smoke for one and one-half to six months, alveolar destruction in the Nrf2-disrupted mice was much greater than in the wild-type mice. Furthermore, alveolar changes were apparent after only three months of smoke exposure in the Nrf2-disrupted mice. After six months of exposure to cigarette smoke, the wild-type mice had an increase of less than 10% in both mean linear intercept and alveolar diameter. Nrf2-disrupted mice, on the other hand, had increases of 26.1% and 33.1% in mean linear intercept and alveolar diameter, respectively.

Bronchoalveolar lavage also revealed a significant increase in the number of total inflammatory cells in the lungs of both groups of mice that were exposed to cigarette smoke, compared to mice that were breathing room air. However, the number of inflammatory cells was significantly higher in the Nrf2-disrupted mice. Macrophages were the predominant inflammatory cell type, comprising 87% to 90% of the total inflammatory cell population in both groups of mice exposed to cigarette smoke.

“We have shown that the response of Nrf2 is important for protection against pulmonary emphysema,” said Shyam Biswal, MD, Assistant Professor of Medicine at Johns Hopkins University. He explained that during chronic insult to the lungs by environmental pollutants such as cigarette smoke, Nrf2 may maintain the balance between antioxidant and oxidant as well as between antiproteinase and proteinase. “Thus,” he continued, “Nrf2 could be an important modifier gene in pulmonary diseases where inflammation and exposure to environmental pollutants are involved.”

Currently, there is a lack of evidence for the role of oxidative stress in the pathogenesis of emphysema as a result of smoking. However, the results of this study have illustrated a clear connection between defects on the transcription of Nrf2 and oxidative stress, increased apoptosis, inflammation, and worsened emphysema. “Most likely, there are differences in the response of Nrf2 in emphysema patients, which will be reflected as differences in levels of pulmonary antioxidants,” Dr. Biswal observed. For these patients, activators of Nrf2 can be used to increase the Nrf2 response. He and his colleagues are currently engaged in devising ways to measure the Nrf2 response in patients with emphysema and studying the gene’s status.

—Gale Jurasek

Reference
1. Rangasamy T, Cho CY, Thimmulappa RK, et al. Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke–induced emphysema in mice. J Clin Invest. 2004;114:1248-1259.

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