responsible for emphysema
In two studies, Yale researchers have demonstrated for the first time that two genes, Interleuken-13 (IL-13) and gamma-interferon, cause pulmonary emphysema.
Using "transgenic" mice that were genetically engineered to express these genes in the adult mouse lung, Dr. Jack A. Elias, section chief of pulmonary and critical care medicine at the School of Medicine, and a team of researchers have demonstrated that these genes, which are known to cause inflammation, also cause pulmonary emphysema similar to the kind seen in patients with chronic obstructive pulmonary disease (COPD).
The first study, published in the November issue of The Journal of Clinical Investigation, highlighted the potential importance of IL-13 in the development of emphysema and exaggerated mucus production seen in these disorders. Since IL-13 is also thought to contribute to asthma, this study also demonstrated that common mechanisms might underlie the development of both of these lung disorders.
The second study, published in the December issue of the Journal of Experimental Medicine, sheds light on the potential role of gamma-interferon in the development of COPD. Elias notes that the symptoms in the two transgenic systems can vary from one person to another.
"We saw different types of inflammation, differences in mucus production and different rates of emphysema development in the two different transgenic systems," says Elias. "These differences recapitulate, in many ways, the individual to individual differences seen in groups of patients with COPD, and may explain why only some patients have exaggerated mucus production, while others have rapidly progressive or slowly progressive disease."
Elias adds, "The results also provide a mechanistic explanation for the observation that asthmatics who smoke cigarettes have the most rapid rates of loss of lung function."
In the normal lung, there is a fine balance between proteins that degrade lung tissue -- called proteases -- and proteins that inhibit protease function -- called antiproteases. Researchers have assumed that emphysema develops when the activity of the proteases overwhelms the controlling capacity of the antiproteases.
"Pulmonary inflammation is a characteristic feature of lungs from patients with COPD, however, the way that inflammation causes emphysema has not been defined until now," says Elias, who is also the Waldemar Von Zedtwitz Professor of Medicine at Yale. "Our studies demonstrate that IL-13 and gamma interferon, gene products that regulate inflammation, can also trigger emphysema. The studies also demonstrated that IL-13 and gamma interferon caused impressive increases in two classes of proteases called matrix metalloproteinases (MMPs) and cathepsins. They also caused selective decreases in antiproteases."
In addition, the emphysema that was induced by IL-13 was blocked when the animals were given drugs that inhibited the MMPs or the cathepsins. Elias said the studies demonstrate for the first time the importance of these inflammatory pathways in the development of emphysema.
"They also provide knowledge of the molecular mechanisms involved in these responses," Elias says. "This provides researchers in academia and industry with knowledge of target molecules against which drugs can be developed in attempts to better treat these disorders."
COPD affects 16 million people in the United States alone and is the fourth leading cause of death worldwide. It is estimated that at least one million people will die from emphysema a year for the next 50 years in China alone. However, only 15% to 20% of cigarette smokers actually develop COPD. Elias says this suggests that differences in patient susceptibility are also important determinants of an individual's response to cigarette smoke exposure. The type of inflammation that is induced by cigarette smoke or infections may play an important role in determining the type of response to cigarettes that occurs.
The results of each study are the culmination of two and a half years of research, which was funded by the National Heart Lung and Blood Institute of the National Institutes of Health.
The research team included Elias, Tao Zheng, Zhou Zhu, Bing Ma and Zongde Wang, in the Section of Pulmonary and Critical Care Medicine at Yale; Robert J. Homer in the Department of Pathology at Yale; Richard J. Riese at Harvard University; Harold A. Chapman Jr. of the Cardiovascular Research Institute at the University of California at San Francisco; and Steven D. Shapiro at Washington University School of Medicine.
-- By Karen Peart
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