We propose to study the mechanism of action of a class of drugs, the thiazolidinediones (or TZDs), that have potential value for the treatment of a variety of tobacco-related diseases. Tobacco use is the leading cause of preventable death in the world. Although better known for its role in lung cancer and heart disease, cigarette smoke is also the leading cause of a more insidious, slowly crippling disorder: chronic obstructive pulmonary disease (COPD). This progressive disease (often commonly referred to as emphysema or chronic bronchitis) interferes with normal breathing and activity, gradually reducing endurance and quality of life, and often ultimately proving lethal. Over 200 million people worldwide have COPD, and more than 3 million people are estimated to die from it each year (representing 5% of all causes of death). COPD is not curable, but a variety of therapies, including prescription drugs, have been successfully developed to control its symptoms.
Although COPD is a disease of many facets, it is generally agreed that inflammation plays a key part in its origin and progression. Inflammation, probably initially triggered by cigarette smoke, activates an immune response in the lung, which release chemicals that both damage lung tissue and recruit additional immune cells, creating a self-reinforcing loop of lung damage and chronic inflammation. As a result, the lung air passages thicken and become less elastic, accumulate fluids and mucus, and the patient becomes increasing unable to draw in an adequate air supply on their own, often requiring oxygen supplementation. Current treatment involves use of drugs that open the airways, reduce the thickness of the mucus and counteract the inflammatory response.
TZDs are drugs first developed for the treatment of diabetes, but which were recently discovered to also have unexpected, potentially beneficial anti-inflammatory actions. TZDs appear to work in a different fashion from the anti-inflammatory drugs already used for COPD; as a result, TZDs appear to be a particularly promising new approach for the treatment for this disorder, either employed alone, or perhaps together with the anti-inflammatory agents already in use. Notably lung cancer and heart disease can also be caused or intensified by inflammation, and TZDs have shown some promise in the treatment of these diseases. Unfortunately, the precise mechanism of action of TZDs as anti-inflammatory agents is not fully understood, and undesirable side effects may limit the ability to use the current generation of TZDs for treatment of COPD and these other tobacco-related diseases.
We propose to better understand how tobacco use (and related signals) turn on the genes responsible for inflammation, and the method by which TZDs turn off this inflammatory gene expression pattern. Based on the work of ourselves and other researchers, we suggest that a family of interrelated regulators, called corepressors, function as switching devices that normally help turn off inflammatory gene expression, and that TZDs work by re-directing which corepressor family member (which switch) turns off which gene. We will investigate this concept in both model cells that are easy to study in the laboratory, and in cells obtained directly from lungs. We will also test if different TZDs differ in their ability to inhibit inflammation, with the idea of discovering the best drug for treatment of COPD (that is, the drug having the strongest anti-inflammatory effects but the least undesirable side effects).
By the end of this exploratory project, we hope to have a much better insight into how tobacco use causes inflammatory diseases such as COPD, and insights into better ways of treating these disorders. |