Why some don't get emphysema

Nrf2—a protein involved in protecting against oxidative stress—is critical in the protection of the lungs in mice against the inflammation and destruction typical of emphysema, a team of researchers at Johns Hopkins University Bloomberg School of Public Health report in the November 1 issue of the Journal of Clinical Investigation. The finding could explain why only a tiny fraction of heavy cigarette smokers develop severe forms of the disease, according to Shyam Biswal and colleagues, since while all humans have Nrf2, the genetically determined responsiveness of the Nrf2 pathway may act as a major determinant of susceptibility to tobacco smoke–induced emphysema.Biswal and colleagues subjected Nrf2-deficient mice as well as wildtype ICR strain mice to chronic cigarette smoke by burning cigarettes using a smoking machine. The authors found a dramatic increase in alveolar destruction in the lungs of Nrf2-deficient mice when compared with wildtype mice after 6 months of exposure. Alveolar enlargement was detected in the lungs of the deficient mice as early as 3 months after exposure to smoke, suggesting an earlier onset of emphysema in these mice. By contrast, 6 months of exposure of wildtype mice to smoke resulted in an increase of less than 10% in the mean alveolar diameter, "highlighting an intrinsic resistance of [wildtype] mice to cigarette smoke–induced pulmonary emphysema," the authors write. In another set of experiments, the researchers found that Nrf2-disrupted mice displayed higher degrees of both alveolar apoptosis and oxidative stress as well as higher numbers of inflammatory cells in the bronchi and alveoli. They then demonstrated that Nrf2 is activated in the lungs of mice in response to cigarette smoke. It then translocates to the nucleus, where it binds with the antioxidant response element present in the target genes to carry out their transcriptional induction. Finally, by using microarray analyses, the scientists identified about 50 Nrf2-dependet antioxidant and cytoprotective genes, which had been activated in the lungs of wildtype but not Nrf2-deficient mice.Nrf2 "seems to be the master regulator of dozens of antioxidant genes and complicated circuit of several pathways," Biswal wrote The Scientist in an E-mail, adding that "the response of Nrf2 is an important modifier of emphysema." What remains to be determined, he said, is how the response of Nrf2 that regulates antioxidant/oxidant balance crosstalks and maintains the antiproteinase/proteinase balance.Biswal said that the team thinks that concerted action of all antioxidant genes is responsible for the added protection but that the mechanism is unknown. "Better understanding of the mechanism by which Nrf2 inhibits a plethora of process ranging from tissue destruction to inflammation in lungs may help in devising strategies aimed at intervening emphysema and other lung diseases where environmental pollutants and inflammation play an important role," he said. "The Nrf2 nuclear transcription pathway regulates a number of critical antioxidant pathways, including extracellular superoxide dismutase [SOD3], which is normally highly expressed in lung airways and is a primary defense against inhaled oxidants," said James Crapo, at the National Jewish Medical and Research Center in Denver. Crapo, who was not involved in the study, wrote The Scientist in an E-mail that it "opens new opportunities to understand the genetic factors involved in emphysema and points to new targets to create specific therapies for those individuals at greatest risk to develop the disease." The paper "sheds light on how [oxidative stress and apoptosis] may be linked and uncovers an important protein [Nrf2] that appears to be important in protecting the cells against oxidative stress," Steven Shapiro, at the Harvard School of Public Health, wrote The Scientist in an E-mail. "As we put the pieces together, a better understanding of chronic obstructive pulmonary disease is emerging that could lead to effective therapy." But Shapiro, who was not involved in the study, noted that "the main limitation is that while we believe that mice replicate basic human pathobiology, it remains to be seen whether these findings will translate to human disease and allow for the development of effective therapy."Sekhar Reddy, who is based at Johns Hopkins University but was not involved in the study, said in an E-mail that "the study points to an important role for Nrf2-dependent gene expression, especially antioxidant enzyme [AOE] induction, in inhibiting the development of emphysema in a mouse model."Still, Reddy said, "it remains to be seen whether supplementation with antioxidants or antioxidant enzymes, and genetic complementation studies (overexpression of Nrf2 in the lungs during the progression of emphysema) will provide protection. A detailed analysis of perturbations in Nrf2-dependent antioxidant signaling, especially the expression and polymorphisms of Nrf2 and its downstream target genes, such as AOEs, in clinically relevant human samples may provide new therapeutic avenues in the treatment of emphysema."

Why some don't get emphysema

finds that Nrf2 protects against inflammation and destruction of lungs

Nov 2, 2004

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