Study probes aspirin drug's link to allergic reactions
Investigators in the Center for Lung Research have discovered that an aspirin-like drug makes allergic and asthmatic reactions worse in mice.
The findings, reported in the American Journal of Respiratory and Critical Care Medicine, suggest that the cyclooxygenase enzymes — the targets of aspirin — have an important role in allergy development, opening another avenue for research into the underlying causes of allergy and asthma.
Allergies afflict about 25 percent of the U.S. population and asthma is on the rise, but the causes of these conditions are largely unknown.
Other researchers hypothesized that the enzyme cyclooxygenase-2 participates in the development of allergic disease.
The Vanderbilt investigators used a mouse model for allergic airway disease to test this hypothesis. They gave mice an aspirin-like drug called indomethacin during the time that the mice were developing allergies. The researchers expected the indomethacin, which blocks both cyclooxygenase-1 and cyclooxygenase-2, to reduce allergy and airway responsiveness, a marker for asthma. Instead, indomethacin made allergy and asthma worse.
“These were totally unexpected findings,” said Dr. R. Stokes Peebles, assistant professor of Medicine and lead investigator of the research. “They show that cyclooxygenase has a very important role in the allergic process, and potentially also in asthma.”
Sorting out the implications of the work and defining the enzyme’s role will require further investigation, Peebles said.
Peebles was cautious about inferring that aspirin and related drugs will make allergy or asthma worse in human beings.
“In the mouse, we can definitively say that nonsteroidal anti-inflammatory drugs are not good with regard to the allergic response,” Peebles said. “The studies suggest that cyclooxygenase and its products are playing a role in allergy development, and we’re very interested in investigating that role in human beings.”
Peebles developed the mouse model for allergic airway disease in collaboration with Dr. James R. Sheller, associate professor of Medicine, and Dr. Barney S. Graham, professor of Medicine and assistant professor of Microbiology and Immunology.
To cause an allergic response in mice, the investigators expose the mice to an aerosol containing the allergen ovalbumin, a protein from the chicken egg.
“The mice become sensitized to the ovalbumin just like we might become sensitized to ragweed or tree pollen,” Peebles said.
To assess the allergic response of the mice following sensitization, the investigators measure airway responsiveness and collect lung lavage fluid. They use the lavage fluid to determine the amounts of various molecular markers for allergy. In the present studies, the researchers compared the responses of mice that received the drug indomethacin before and during the sensitization procedure to the responses of mice that did not receive any drug.
“The mice that were treated with indomethacin were more allergic,” Peebles said. The indomethacin-treated mice had increased airway responsiveness and increased levels of several molecular markers of allergy: IgE, interleukin-5 and interleukin-13.
“There is clearly an effect of this medicine on the allergic process,” Peebles said.
He noted that because the mice receive indomethacin before they are ever exposed to allergen, the drug’s negative effects cannot simply be extended to an adult who already has allergies or asthma.
In future studies, Peebles hopes to determine which of the cyclooxygenase products are contributing to or protecting against allergy sensitization.
“If we can figure out the specific mediators that are involved in developing the allergic response, it will suggest ways to intervene to prevent that response,” Peebles said.
In addition to Sheller and Graham, other collaborators were Dr. Ryszard Dworski, research assistant professor of Medicine, Dr. Robert D. Collins, John L. Shapiro Professor of Pathology, and research assistants Kasia Jarzecka and Daphne B. Mitchell. The work was supported by the National Institutes of Health.