By David N. Leff

Some years ago, the BBC produced a documentary film titled Death in the West. It updated the lives of those booted, Stetsoned cowboys, the Marlboro Men, who advertised that brand of cigarette in the 1960, and since.

A memorable shot in the movie shows one such aging veteran atop his horse, wheezing and gasping with emphysema, an oxygen canister strapped to the saddle — while smoking a cigarette.

Oxygen, as was discovered 20 years ago, is still the one and only drug for treating emphysema.

"Actually," observed cell biologist and physiologist Steven Shapiro, of Washington University, in St. Louis, "oxygen will improve the survival of patients with end-stage emphysema. Some individuals," he added, "are able to breathe easier when they're at rest; they need oxygen only during times of exertion. But as the disease progresses, many people must inhale it 24 hours a day."

Shapiro, who is testing potential new therapies in mice, pointed out, "The principal etiology of pulmonary emphysema is cigarette smoking." He cited two million as the number of Americans afflicted with the disease, but made the point that "emphysema is a major part of all the morbidity and mortality effects of chronic destructive pulmonary disease, or COPD, which is much more common. Some 14 million people in the U.S. suffer from COPD, already the fourth leading cause of death, and creeping up."

He observed COPD is a significant factor in mortality from the two leading causes of death, lung cancer and heart disease, but noted that emphysema is not directly linked to these other two diseases.

What seems to be trashing the lungs of smokers with emphysema is the onrush into their air passages of inflammatory macrophages — white blood cells of the immune system — which apparently release protein-eroding enzymes called metalloproteases. Their target is one protein in particular, elastin, the stretchable molecule that gives the lungs and bronchial tubes the flexibility they need for breathing, and swapping inhaled oxygen for outward-bound exhaled carbon dioxide.

"An interesting feature," Shapiro commented, "is that probably only 20 percent or so of smokers will get emphysema. The others will die of something else before emphysema does them in. It's an interesting problem that we don't understand.

"Wheezy patients gasping for air for years," Shapiro observed, "have a miserable quality of life, but emphysema really doesn't kill them immediately."

Irreversible, Haltable, Often Fatal

"If you stop smoking early on," he continued, "when you don't yet have much pulmonary destruction, you might be okay with mildly impaired lungs. That emphysema isn't going to improve, but you may be asymptomatic.

"After a certain point, even if you quit smoking, lung function keeps declining very gradually, and we still find these metalloelastase enzymes there. For a fairly severe emphysema, the average survival time is four years."

Shapiro is senior author of an article in today's Science, titled: "Requirement for macrophage elastase for cigarette smoke-induced emphysema in mice."

The mice in question are transgenic animals, engineered to lack the macrophage-recruited, elastin-degrading enzyme.

Shapiro and his co-authors turned these mice into heavy-smoking nicotine addicts by exposing them to concentrated smoke from two cigarettes a day, six days a week, for six months.

"We lined up five cigarettes," he recounted, "connected to syringes and a motor. We'd light a cigarette; the motor drives a 20-milliliter syringe. It takes the 20 ml of smoke, flips a switch, and exhausts it into a tubing that opens into little airtight chambers, where the mice are anxiously awaiting the cigarette smoke.

"After a couple of weeks," Shapiro went on, "they run right into the chamber; they're quite addicted. They love it."

At first the co-authors "were smoking the animals five days a week, but we felt bad for them on Monday, without their weekend of cigarette smoke," Shapiro said. "So now we give them six days a week.

"After about three months," Shapiro reported, "we could start to see inflammatory changes in the lungs of control mice, just like human smokers after a month or two. And in three to six months, the controls started to develop the lung destruction and air-space enlargement which looks very similar to human emphysema."

As for the equally heavy-smoking knockout mice, lacking the elastin protease, "It didn't touch 'em."

The group hasn't yet extended its experiment beyond six months to determine how long it would take for emphysema to kill the animals. It is now planning to do so.

"If these findings prove translatable to humans," Shapiro observed, "inhibiting the enzyme won't reverse the emphysema, but it would halt its progression."

Inhibitors Spark Clinical, Commercial Attention

Metalloproteinases are a focus of pharmaceutical interest for treating cancer. British Biotech P.L.C., of Oxford, U.K., Shapiro said, is conducting clinical trials of compounds that inhibit this class of enzyme.

Metalloelastase, he pointed out, "belongs to the same enzyme family, so compounds that inhibit it might be tried for emphysema. "Hopefully," he said, "we can convince British Biotech or some other interested company to give it a try."

In the European trials of metalloprotease inhibitors, Shapiro explained, "what they are using is hydroxamic acids — zinc chelators. These inactivate the zinc ion that is necessary for the enzymes to act."

Like his knockout mice, Shapiro suggested, some people may be born with a functioning gene that expresses the elastin protease. "When we look at patients," Shapiro pointed out, "even smokers have different levels of this enzyme. Whether some lack the inhibitor," he observed, "could lead to genetic testing and identification of populations at risk."

Might this encourage tobacco companies to say: "Aha! It isn't addiction; it's inherent. Your own body is doing the damage, not the cigarette smoke."?

"Right," Shapiro responded, "The gun doesn't kill you; it's the bullets." *