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Probing the genetic basis of emphysema

Yale Medicine Magazine, 2001 - Spring


In separate studies, Yale researchers have demonstrated that the genes that code for 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, Jack A. Elias, M.D., section chief of pulmonary and critical care medicine, and a team of researchers including Zhou Zhu, M.D., Ph.D.; Tao Zheng, M.D.; Chun Guen Lee, M.D.; Bing Ma, M.S.; and Qingsheng Chen, M.D., 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). COPD affects 16 million people in the United States alone and is the fourth leading cause of death worldwide.

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 in the 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, shed light on the potential role of gamma-interferon in the development of COPD. Elias notes that the symptoms in the two transgenic systems used in the studies 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,” said 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,” said Elias. “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 and cathepsins. They also caused selective decreases in antiproteases.