Mice smoke out key emphysema enzyme.

With every breath of life-giving air, elastic fibers in the lungs help those organs expand and contract. For the 2 million people suffering from emphysema, a disease usually induced by smoking, this essential routine doesn't come easily.

From a variety of evidence, emphysema investigators have theorized that the destruction typical of this disease results when large numbers of immune cells migrate to the lungs and release enzymes that degrade elastin, the major protein in the elastic fibers there.

Now, by creating mice that lack one such enzyme and showing that they resist smoke-induced emphysema, scientists have garnered strong support for this explanation of the disease.

"The hypothesis has lasted 30 years, and now we're able, with modern genetic manipulation, to confirm it directly in mammals," says Steven D. Shapiro of Washington University School of Medicine's Barnes-Jewish Hospital in St. Louis.

The results, reported in the Sept. 26 Science, also add a subtle twist to the old hypothesis. They highlight different immune cells, ones called macrophages, from those on which emphysema researchers had previously focused their studies.

Shapiro's experiments on the genetically engineered mice are "the first to suggest in an animal model that the presence of macrophages is essential to the development of smoke-induced emphysema," says Gordon L. Snider of the Boston Veterans Affairs Medical Center, who has studied the disease for decades.

Shapiro and his colleagues verified that they could induce emphysema in mice by placing the animals in a smoking chamber where the rodents were exposed to the equivalent of two nonfiltered cigarettes a day, 6 days a week, for up to 6 months.

When the scientists examined the lungs of the animals, they found all the characteristic signs of emphysema. "Early on, there's a recruitment of inflammatory cells, predominantly macrophages, and that's followed by a gradual destruction [of lung tissue] and enlargement of the air spaces," says Shapiro.

The researchers then used the smoking chamber to test mice genetically engineered to lack the macrophage enzyme called MME. This enzyme breaks down several proteins, including elastin. The mutant mice did not suffer the lung destruction observed in the unaltered mice.

Another finding surprised Shapiro and his colleagues. They had assumed that the macrophages lacking MME still rushed into the lungs. The scientists found few immune cells in the lungs of the mutant mice, however.

To explain the absence of macrophages, Shapiro suggests that cigarette smoke signals the few immune cells normally patrolling the lungs to release MME. This enzyme, in addition to destroying elastin, somehow attracts more macrophages. Consequently, macrophages without MME do not recruit additional immune cells to the lungs.

Until recently, most research on emphysema centered on elastin-destroying enzymes made by immune cells called neutrophils, even though macrophages make up 90 percent of the immune cells in the lungs, notes Snider.

To investigate the relative contributions of the two classes of immune cells, Shapiro's group is now exposing to cigarette smoke a group of mice engineered to lack an elastin-destroying enzyme made by neutrophils.

Compounds that inhibit enzymes similar to MME and the neutrophil enzymes are under development to treat cancer and may be adapted for the treatment of emphysema, adds Shapiro. He speculates that cigarette makers may one day add such protective compounds to their product.