Enzyme May Play Unexpected Role In Asthma

Asthma is on the rise in the United States and causes at least 5,000 deaths a year. Although the subject of intense study, the condition remains poorly understood at the fundamental level. Dr. Rothenberg and his colleagues used mouse models of asthma along with "gene chip" technology to probe the underpinnings of asthma. "We've identified nearly 300 mouse genes, which we call asthma signature genes, that appear to be involved in asthma pathogenesis," notes Dr. Rothenberg. "This gives us an unprecedented insight into the orchestration of the large number of genes that give rise to asthma."

The findings, published in the current issue of Journal of Clinical Investigation, appear to apply in humans as well, says Dr. Rothenberg. If confirmed through further study, the new knowledge could lead to asthma treatments tailored to an individual patient's disease.

"NIAID has long supported both basic research into asthma and the translation of such basic knowledge into more effective treatment and prevention strategies," says NIAID Director Anthony S. Fauci, M.D. "This finding is an important step towards understanding the pathogenesis of asthma, and it provides new leads to interventions that could reduce the burden of this debilitating and sometimes deadly disease."

In their quest to identify the critical genes involved in asthma, Dr. Rothenberg and his colleagues induced asthma in mice, then analyzed lung tissue with gene chips to see which genes were most active following the attacks. Two strains of asthmatic mice were evaluated following two different methods of asthma induction. A set of 496 genes was activated in the lungs of one mouse strain, while 527 genes "turned on" in the lungs of the second strain. Of these, 291 were same in both groups. The investigators called the shared genes "asthma signature genes."

The large number of genes involved in asthma--more than 6 percent of the mouse genome--same as some surprise, say lead authors Nives Zimmerman, M.D., and Nina King, Ph.D. Even more surprising, according to Dr. Rothenberg, was strong expression of genes involved in amino acid metabolism, in particular the gene encoding the enzyme arginase. Previously, arginase was thought to be limited primarily to the liver, where it helps process the amino acid arginine. "We've learned that arginase is involved in asthma regardless of the specific allergen used to induce the attack," says Dr. Rothenberg.

To learn whether arginase plays a role in human asthma as well, the scientists analyzed fluid and tissue samples from the lungs of asthmatic people and from non-asthmatic control subjects. No arginase was detected in the control samples, but significant amounts were found in the asthmatic lung. Importantly, arginase appears to be the molecule that "kicks off" the chain of action leading ultimately to asthmatic symptoms. Thus, it makes an attractive target for drug intervention. "We hope to come up with a treatment for asthma by targeting arginase," says Dr. Rothenberg.

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NIAID is a component of the National Institutes of Health (NIH), which is an agency of the Department of Health and Human Services. NIAID supports basic and applied research to prevent, diagnose, and treat infectious and immune-mediated illnesses, including HIV/AIDS and other sexually transmitted diseases, illness from potential agents of bioterrorism, tuberculosis, malaria, autoimmune disorders, asthma and allergies.

Reference: N Zimmerman et al. Dissection of experimental asthma with DNA microarray analysis identifies arginase in asthma pathogenesis. The Journal of Clinical Investigation. 111:1863-74 (2003). doi: 10.1172/JCI200317912.

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