By activating dozens of genes that combat free radicals and toxic pollutants in cigarette smoke, a naturally produced protein called Nrf2 can stand as a stalwart defender against emphysema, a new study suggests.
The finding indicates that variations in the gene encoding Nrf2 might partly explain why some smokers get emphysema while others don’t. Cigarette smoking accounts for most cases of the lung ailment, which is the fourth leading cause of death in the United States.
Cigarette smoke contains highly reactive free radicals—unstable molecules that destructively oxidize other molecules, including DNA. Fortunately, vitamins C and E and other antioxidant compounds continually clear oxidizing radicals from the body.
Past research showed that Nrf2 activates genes that encode antioxidant proteins. But its full role has been unclear.
In the new study, researchers compared mice that lacked the Nrf2 gene with others that had such a gene. After exposing both groups to cigarette smoke for 6 months, the scientists found that the lungs of mice lacking Nrf2 protein had more free radicals, inflammation, and dead cells.
The researchers identified 50 genes that were significantly more active in the mice that made the Nrf2 protein than in those that didn’t. One gene was 11 times as active in the mice with Nrf2. Thirteen of the Nrf2–activated genes encode antioxidant proteins, the scientists report in the November Journal of Clinical Investigation.
That suggests that a dearth of antioxidant proteins in the lungs leaves the mice “with less of a defense against oxidative stress [from free radicals] produced by the cigarette smoke,” says study coauthor Tirumalai Rangasamy, an immunologist at Johns Hopkins University Medical Institutions in Baltimore.
Mice lacking Nrf2 also showed less activity in genes encoding proteins that detoxify pollutants and that support cell survival and growth.
Study coauthor Shyam Biswal, a toxicologist at Johns Hopkins, points out that free radicals unchecked by antioxidants can cause an overabundance of protein-chopping enzymes called proteases. Lung damage caused by extra proteases in the mice without Nrf2 probably contributes to the death of lung cells, he says.
“There’s a maintenance program that’s active and effective in the normal human lung, even in significant smokers, and that’s what protects most people from emphysema,” says pulmonologist Norbert Voelkel of the University of Colorado Health Sciences Center in Denver.
People and mice have similar versions of Nrf2 protein. Whether Nrf2 protein regulates that maintenance program in people, as it seems to do in mice, remains to be seen, Voelkel says.
By identifying variations in the Nrf2 gene among smokers with or without disease, Biswal says, researchers might ascertain the protein’s role in people and perhaps even determine who is genetically predisposed to developing emphysema.