This year marks the 50th anniversary of the US Surgeon General’s first ever report, which implicated smoking as the primary cause of emphysema and other chronic diseases. Despite decades of research, emphysema—a form of chronic obstructive pulmonary disease (COPD), which ranks among the third leading cause of death in the US—remains incurable.
But a new study provides a glimmer of hope. In a paper published online yesterday in the Journal of Clinical Investigation, researchers show that a compound belonging to the class of drugs known as thiazolidinediones (TZDs) can reverse smoking-induced lung damage in mice. What makes the discovery even more intriguing is that TZDs activate a protein called PPAR-gamma, which acts on DNA, and two of these drugs—namely, Takeda’s Actos (pioglitazone) and GlaxoSmithKline’s Avandia (rosiglitazone)—have been used clinically to treat type 2 diabetes.
At first glance, type 2 diabetes and emphysema might appear to have little in common. But in the last decade several studies have suggested that smoking triggers heightened lung inflammatory responses through pathways that are normally held in check by PPAR-gamma, which is perhaps best known for its crucial role in the development of fat cells and regulation of metabolism.
In the new study, led by David Corry and Farrah Kheradmand at Baylor College of Medicine in Houston, the researchers investigated the genetic changes induced by tobacco smoke, and discovered that levels of PPAR-gamma mRNA were depleted in a subset of immune cells from the lungs of smokers with emphysema and mice exposed to cigarette smoke. What’s more, emphysema-associated lung damage began to heal in animals that had ongoing exposure to smoke when they received ciglitazone, an experimental antidiabetic medicine belonging to the TZD class drug that activates PPAR-gamma.
“The fact that they’ve shown evidence of reversal is pretty exciting,” says Paul Noble, a pulmonologist at Cedars-Sinai Medical Center in Los Angeles. “Most of us think that, in a disease like emphysema, you pretty much have permanent lung damage.”
“It’s a lovely piece of work,” says Fernando Martinez, a pulmonologist at the University of Michigan in Ann Arbor who wasn’t involved in the study. “I’m sure this will create some stir, because this is a class of drugs that are available and have a well-known, albeit storied, adverse event profile,” he adds, referring to the cardiovascular risks and other adverse side effects associated with the medications. “This is something that should be tried in a human study with very careful controls and attention to safety.”
Kheradmand acknowledges that her team has no clear understanding of how cigarette smoke influences the levels of PPAR-gamma. Nevertheless, her team is now examining data from smokers with diabetes who received TZD therapy to determine whether their lung function improved. “I think the other big question that needs to be answered is, how does PPAR-gamma allow the lung to heal,” says Keradmand. “I hope this will open a whole new way of looking at cigarette smoke’s effects within the lung.”
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