Smoking Mice Lead To Emphysema Breakthrough

September 22, 1997

St. Louis, Sept. 26, 1997 -- With the help of some heavy-smoking mice, researchers at Washington University School of Medicine in St. Louis have discovered that lungs lacking a certain enzyme are apparently immune to emphysema. The discovery, described in the Sept. 26, 1997, issue of Science, throws serious doubt on conventional theories of the disease, and researchers are already using the finding to search for potential new drugs.

Steven D. Shapiro, M.D., associate professor of medicine and of cell biology and physiology at the School of Medicine, and colleagues found that mice genetically engineered to lack an enzyme called macrophage elastase showed no signs of emphysema even after inhaling the smoke of two unfiltered cigarettes a day, six days a week for six months. Such heavy smoking invariably causes emphysema-like symptoms in normal mice. "There hasn't been a new drug for emphysema in 20 years, and that was oxygen," Shapiro says. "Blocking this enzyme or related enzymes might give us a way to halt the disease."

Emphysema, almost always caused by smoking, robs lungs of their elasticity and leaves patients gasping for air. The lungs actually become overinflated, leaving no room for deep breaths. About 2 million Americans suffer from the disease.

Before this study, most researchers assumed that emphysema was caused by neutrophils, white blood cells that destroy foreign invaders and, occasionally, cause inflammation. According to the most widely-accepted scenario, neutrophils mount a counter-attack against smoke by congregating in the lungs and releasing inflammatory enzymes. The enzymes eventually break down elastic fibers in the lungs, causing a new case of emphysema.

But the prevailing theory had a shortcoming: lungs with emphysema don't have many neutrophils. Instead, they are full of macrophages, immune-system cells that eat bacteria and other intruders. Few thought macrophages played a role in emphysema because the cells seemed incapable of destroying sturdy lung tissue. But recent experiments by Shapiro and others showed that macrophages did indeed produce an enzyme -- macrophage elastase -- that could be up to the task.

To find out if macrophage elastase causes emphysema, Shapiro and others created a strain of mice that lacked the enzyme. He calls them "mighty mice" and estimates their value at tens of thousands of dollars apiece. "We could speculate for years about the function of this enzyme," he says. "These mice helped us pin it down."

Researchers put both the mighty mice and normal mice into smoking chambers twice a day, six days a week. The mice didn't actually have cigarettes in their mouths, but they got enough passive smoke to become quite fond of their routine. "After a while, they just started running into the chambers," Shapiro says. "They loved it." To Shapiro's knowledge, his is the first smoking chamber ever designed for mice.

Six months later, all of the normal mice had inflamed, over-inflated lungs ? the hallmarks of emphysema. The mighty mice, however, appeared completely healthy. "This enzyme clearly plays a primary role in the development of the disease in mice and probably in humans," Shapiro says.

Macrophage elastase is a member of a family of enzymes that is currently attracting intense scientific interest. Many researchers believe that members of this family, called metalloproteinases, play a major role in a host of disorders including tooth decay, atherosclerosis, arthritis ? and, now, emphysema. Pharmaceutical companies are now trying to develop metalloproteinase inhibitors that may be able to effectively prevent many of these disorders. Shapiro is currently determining whether a metalloproteinase inhibitor can block emphysema in normal, heavy-smoking mice.

Shapiro notes that a drug that blocks macrophage elastase would, at best, only prevent damage caused by emphysema. Such a drug could not repair already-damaged lungs. There is still no "cure" for emphysema on the horizon, and the best way to avoid the disease is to not smoke, he says.

One important question remains largely unanswered: What are metalloproteinases good for? They apparently help remodel tissues during growth and wound healing, but their role in healthy adults is unclear, Shapiro says. "Before we give people drugs to block these enzymes, we really need to know what the enzymes do," he explains. Other strains of "mighty mice" will undoubtedly be the stars of future experiments to answer these questions, he says.

The study was funded by an American Lung Association Career Investigator Award and grants from the National Institutes of Health, the Alana A. and Edith Wolff Charitable Trust, and the Marc and Marjorie Seldin Endowed Fund for Pulmonary Research.

Washington University School of Medicine

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