Drug shields lungs from smoking damage

JOHNS HOPKINS (US) — A common blood pressure medicine appears to help prevent the lung damage associated with cigarette smoke, according to a study with mice.

Administering the drug, losartan (also known by the brand name Cozaar) to mice improved or prevented lung tissue breakdown, airway wall thickening, inflammation, and lung overexpansion associated with two months of exposure to cigarette smoke.


“The results … suggest that losartan or similar drugs could serve as an effective treatment for smoking-related lung diseases in humans,” says senior investigator Enid Neptune, assistant professor of medicine at Johns Hopkins University.

“And because these drugs are already approved for use in the United States as safe and effective treatments for hypertension, incorporating them into our treatment regimen for COPD would be quite rapid.”

The next step, the researchers say, is a clinical trial of the drug in people with smoking-related chronic obstructive pulmonary disease (COPD), the long-term consequence of smoking. At present, there is no known treatment to prevent or repair the lung damage resulting from COPD.

Existing medication

COPD is the third-leading cause of death in the United States, mostly in people with either chronic bronchitis or emphysema, or both; some 12 million Americans have been diagnosed with COPD.

The mouse study, published in the Journal of Clinical Investigation, is considered a breakthrough, the research team says, because it is the first to show that a drug already in clinical use can prevent most the serious consequences of smoking in an animal test model, by preserving both lung structure and function.

In smoking-related COPD, breathing becomes difficult and progressively worsens, as the small airways and airspaces that conduct oxygen through the lungs and into the bloodstream become damaged. Airway walls thicken and are more readily obstructed by mucus, and the airspaces lose their elasticity.

“It is very exciting that an existing medication has proven capable in an animal model of not only treating the problems of COPD, but also disrupting the biological pathway that precipitated them,” says pulmonologist Robert A. Wise, who is piloting the clinical studies.

“If our tests in people prove successful, we could help restore lung health to millions of people who have suffered from tobacco addiction.”

Wise says existing remedies for smoking-related COPD consist mainly of providing relief of symptoms, such as shortness of breath, coughing, and mucus production. Drugs that lower blood pressure also help, and surgery can be done to remove damaged portions of the lung or transplant new lungs.

Wise and Neptune began their investigation of losartan after a Johns Hopkins colleague, Harry (Hal) Dietz, discovered it could potentially treat Marfan syndrome, which results from a single genetic mutation and weakens arteries, affecting all major organs, including the lungs.

The pulmonary researchers wanted to know if the medication had the same reparative effects on the lungs in other more complex and common respiratory diseases, such as COPD.

Previous research on losartan, by Dietz and others, had shown that the drug blocked the action of a key signaling protein called transforming growth factor beta, or TGF-beta.

Neptune’s research showed that TGF-beta levels were elevated in lung tissue samples from smokers with COPD and in the lung tissue of mice with Marfan syndrome. Neptune and Dietz had also shown in 2003 that TGF-beta neutralizing antibodies prevented developmental emphysema in Marfan mice.

Early tests

In the new experiments, the team first confirmed elevated levels of TGF-beta in the lungs of mice exposed to cigarette smoke and in lung tissue samples of smokers with COPD.

Biochemical analyses showed that smoke-exposed mice had a fourfold increase in TGF-beta signaling in their lungs than mice exposed to indoor air only; in people, TGF-beta signaling in the COPD sufferers’ lungs was 25 percent greater than in those of nearly a dozen smokers without COPD.

While continuing exposure to tobacco smoke, the researchers treated some mice with either a low or high dose of losartan. Another set of smoke-exposed mice was given a neutralizing antibody to TGF-beta signaling, the same treatment that had been used in Marfan mice.

Researchers found major improvements in more than a half-dozen measures of lung damage. In untreated mice exposed to smoke, airway wall thickness had doubled. The thickening was 50 percent less in mice treated with either dose of losartan or with TGF-beta antibodies.

Losartan-treated mice showed no signs of lung overexpansion and no signs of increased collagen deposition, a gauge of TGF-beta activity, and had normal levels of elastin-metabolizing enzymes and protein fragments in their air sac walls. Measures of oxidative stress, inflammation and cell death were also better in mice given the blood pressure medication.

Funding support for the mouse study was provided by the National Heart, Lung and Blood Institute (NHLBI), one of the National Institutes of Health, and by the Grace Anne Dorney Fund for Tobacco-related Research.

Funding for the clinical trial is from NHLBI and the drug’s manufacturer, Merck & Co.

More news from Johns Hopkins University: http://releases.jhu.edu