Protein Linked to Asthma

[Angel]

A protein previously linked to the development of type 2 diabetes and atherosclerosis may also be associated with asthma, a new study suggests.

Called aP2, the protein has no useful function in the body. It only appears during the course of disease, and seems to cause adverse effects on blood sugar levels and fatty acid metabolism. It previously has been found in fat cells and macrophages (a type of immune cell) in people with obesity, diabetes and heart disease.

Now, for the first time, a team of Australian and American researchers has found aP2 in the lining of the human lung, where it appears to regulate the inflammation associated with asthma.

This suggests there's a link between the metabolic and immune systems. "The exciting thing about this study is that perhaps the way all of these diseases are connected is through the inflammatory responses controlled by this boring little protein," said study co-author Dr. Gokhan S. Hotamisligil, of the Harvard School of Public Health in Boston.

The report is published in the July 13 online issue of the Journal of Clinical Investigation.

To study the effects of aP2, the researchers created genetically engineered mice that could not produce the protein. "They're metabolic supermice," Hotamisligil said. "We cannot make them obese, diabetic or atherosclerotic. They don't develop fatty liver disease, and they don't develop asthma." In mice with an animal model of asthma, the researchers found that aP2 regulated the infiltration of inflammatory molecules into the lungs.

Hotamisligil said that pharmaceutical companies have developed aP2-blocking drugs. "They work very well in animal models and produce the same effects we've seen in genetically engineered mice," he said. "But all the work is pre-clinical."

Although the drugs were specifically developed to treat diabetes and atherosclerosis, Hotamisligil said the new study may spur the development of versions that could be used to treat asthma. "It's easy to test asthma drugs, because you can administer them locally into the airways," he said. And because the linings of the lungs only have 1/10,000th as much aP2 as fat cells do, in theory, it would require much less medication to inhibit the protein, he added.

Human trials of aP2-blocking drugs probably won't be held for another three or four years, Hotamisligil said. Meanwhile, he and his colleagues are investigating lifestyle interventions that may help reduce aP2 levels. For clues, they're studying human subjects who carry a rare genetic mutation that makes them produce 50 percent to 60 percent less aP2 than normal. Results of the study could be published within a year, Hotamisligil said.

For now, he said, weight control may be the best strategy for countering the ill effects of aP2. "The most important implication of this research is that it demonstrates a direct link between the pathways that lead to obesity and diabetes and asthma," he said. "aP2 tends to go along with your weight and the state of your glucose metabolism. So, if you're overweight and have asthma, losing weight might help your asthma."

A growing body of research suggests that the obesity and asthma epidemics are related. In March, researchers from the University of New Mexico School of Medicine published research showing an increased risk of asthma in overweight women whose fat cells produce high levels of a hormone called leptin.

The new study linking aP2 with asthma is "important," said Dr. Clifford Bassett, of Long Island College Hospital in Brooklyn, and a spokesman for the American Academy of Allergy, Asthma and Immunology. But he cautioned that it's only "one piece of the puzzle as we move forward in our understanding of asthma as an inflammatory disease."

"The take-home message is that aP2 was important in acting locally in the lung," Bassett added. "This research may lead to future therapy to regulate or control excessive inflammation in the airway that can be associated with other forms of respiratory problems: rhinitis as well as asthma. But it's obviously preliminary data, and we need to wait for further data based upon clinical trials of drugs that work on this protein."