Experimental drug fends off emphysema in mice

A compound that revs up the production of homegrown antioxidant proteins in the body prevents emphysema from developing in mice exposed to cigarette smoke for six months, a new study finds. The study is the latest in a series to hint at big things for the experimental drug CDDO-imidazole, or CDDO-Im. Separately, scientists are testing a similar drug against cancer in people.

The new findings appear online Dec. 22 in Proceedings of the National Academy of Sciences.

Even though the study focuses on emphysema in mice, the researchers suggest the drug could work in people by delaying or preventing chronic obstructive pulmonary disease, which encompasses emphysema and chronic bronchitis and is the fourth most common cause of death in the United States.

CDDO-Im jump-starts a molecule called Nrf2 that in turn switches on a host of genes that encode antioxidants in the body, studies of human cells and in animals suggest. Shyam Biswal, a pulmonary toxicologist at Johns Hopkins University in Baltimore, says these antioxidants seem to counteract the damage caused by exposure to inhalation of cigarette smoke.

Cigarette smoke assaults lung tissue by introducing highly reactive compounds of oxygen and nitrogen that go by several names — free radicals, oxidants or reactive oxygen species. Long-term smoking and the accumulation of free radicals lead to inflammation and cell death, destroying lung tissues that normally orchestrate oxygen exchange via the blood.

To test whether CDDO-Im could prevent this damage, Biswal and his colleagues exposed mice to cigarette smoke for six months. Some of these mice had normal complements of Nrf2 protein, others lacked it. Both sets of mice showed lung damage akin to emphysema after six months, with the animals lacking Nrf2 exhibiting worse symptoms.

The researchers also tested two other groups of smoke-exposed mice that made Nrf2 or not. Some of these animals received ordinary food while others ate food containing CDDO-Im. Mice with normal Nrf2 complements that received the drug in food fended off emphysema, despite six months of breathing smoke, which caused extensive oxidative damage in the lung tissue of the other mice.

A separate analysis showed the mice free of emphysema had higher lung levels of glutathione, a homemade antioxidant. The researchers chose to analyze glutathione because it is a major antioxidant whose synthesis is regulated by Nrf2, Biswal says.

When the researchers analyzed the heart tissue of mice in these tests they found that the drug also prevented right ventricle damage in animals that had the winning combination of a normal complement of Nrf2 and CDDO-Im in their chow.

Recruiting homemade antioxidants is a better approach than trying to consume them, such as by taking vitamins C and E, says Biswal. “For every oxidant molecule, to destroy it you will need another antioxidant molecule,” he says. The best way to achieve that is to target Nrf2, which he calls a “master regulator” of genes encoding antioxidants.

“Nrf2 will turn on all the different antioxidant pathways in the cells, thereby providing a robust antioxidant defense that in turn protects against lung destruction and cardiac dysfunction,” Biswal concludes.

“This is very exciting,” says biochemist Irfan Rahman of the University of Rochester, in New York. CDDO-Im has the effect of freeing up Nrf2 to switch on genes that encode antioxidant enzymes, he says. These compounds efficiently neutralize free radicals, a process he likens to detoxifying and “fine-tuning” the body.

Whether these results in mice will be replicated in people taking CDDO-Im remains unclear, he says. “It may not work anyway, but we have to try,” Rahman says. “It might be protective.”

CDDO-Im is a synthetic compound derived from oleanolic acid, a substance found in plants. After showing promise against cancer in animal tests, a related drug called RTA 402 (CDDO-Me) is being tested in cancer patients.

Biswal says the CDDO drug family holds promise for ex-smokers, whose health risk lingers even after they quit. More than four-fifths of emphysema cases are attributable to smoking.