Source: University of Texas Medical Branch at Galveston     Released:
Thu 28-Jul-2005, 08:35 ET
Embargo expired: Mon 01-Aug-2005, 17:00 ET
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New Factor Implicated in Allergy and Asthma Attacks
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ALLERGY ASTHMA ROS REACTIVE OXYGEN SPECIES POLLEN
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Researchers have discovered strong evidence that the severe respiratory
inflammation involved in an allergy or asthma attack requires damage by
"reactive oxygen species" spawned by interactions between a single
pollen-carried enzyme and the cells that line airways.

Newswise - For a person with allergies or asthma, breathing in pollen
can be a very bad thing. Within minutes of inhalation by someone
sensitive to their effects, these tiny particles can trigger severe
inflammation of the respiratory passages, producing uncontrollable
sneezing, coughing, or extreme shortness of breath - symptoms
agonizingly familiar to those who suffer from allergy and asthma
attacks.

Scientists have long assumed that they know how pollen produces such
debilitating responses. They blame an overreaction by the body's
immune system, set off by proteins known as antigens, which are found
on the surface of pollen particles-an inappropriate activation of the
normal "antigen-mediated" immune response the body uses to defend
itself against viruses and bacteria.

Now, though, researchers at the University of Texas Medical Branch at
Galveston have discovered strong evidence that an additional factor is
necessary to cause the severe respiratory inflammation involved in an
allergy or asthma attack. This factor is the damage caused by
chemically hyperactive molecules known as "reactive oxygen
species," which are spawned by interactions between a single
pollen-carried enzyme and the cells that line airways. And, the
researchers say, if an effective way can be found to reduce that
damage-called "oxidative stress"-new and powerful allergy and
asthma therapies may result.

"There has been a lot of discussion about oxidative stress
exacerbating asthma and allergies, but this is the first direct
evidence that oxidative stress is required to induce a robust
inflammation, and the first demonstration that a source of that stress
is right there in the pollen itself," said UTMB associate professor
Istvan Boldogh, a lead author of a paper on the research that will be
published online August 1 in the Journal of Clinical Investigation.

Boldogh and the other lead authors -Attila Bacsi, Nilesh Dharajiya
and Barun Choudhury, along with UTMB researchers Tapas Hazra, Sankar
Mitra, Randall Goldblum and Sanjiv Sur and Rafeul Alam (formerly of
UTMB and now director of the Division of Allergy and Immunology at the
National Jewish Medical and Research Center in Denver)-worked for
nearly four years conducting extensive test-tube and lab-mouse
experiments to prove the paradigm-shifting "two-signal concept" in
detail. They zeroed in on a key enzyme known as NADPH oxidase, which
they identified in grains of pollen produced by ragweed and 38 other
plant pollens and molds linked to allergy and asthma attacks. Within
minutes of exposure, ragweed pollen or its extract containing NADPH
oxidase produce damaging reactive oxygen species in cell culture and,
in experiments with mice, in their lungs and airway lining fluid. The
resulting oxidative stress, Boldogh said, almost immediately prompted
the production of inflammatory immune signaling molecules and
accumulation of inflammatory cells, a downstream event common to lung
and other type of allergic inflammations. By contrast, ragweed pollen
extract from which NADPH oxidase had been removed produced no reactive
oxygen species, and resulted in a much smaller increase in numbers of
inflammatory immune cells.

"We showed that you need both oxidative stress and antigenic exposure
to get a robust allergy or asthma attack, and also that the first few
minutes of the exposure are critical," Boldogh said. "The antigen
exposure has to happen in parallel with oxidative stress, and having
both components in the pollen makes that possible." These two signals
play a vital role in inducing allergic inflammation.

These findings suggest that antioxidant substances may be useful in
forestalling allergy or asthma attacks. Sur and Boldogh predict that
this new paradigm showing how allergic inflammation is initiated may
lead to discovery of novel compounds that either specifically inhibit
pollen NADPH oxidases or those that prevent or inhibit oxidative stress
in the lungs induced by this enzyme.

Past studies reported contradictory results concerning the
effectiveness of antioxidants such as Vitamin C in reducing airway
inflammation. Those contradictions, Dharajiya pointed out, are resolved
by the evidence that pollen brings both NADPH oxidase and antigens into
the airways, making airway antioxidant levels the critical factor.
"The antioxidant has to be there when the person is exposed, and if
the antioxidant level is not sufficient, it won't eliminate this
oxidative insult."

Because antioxidant compounds are quickly metabolized in the lungs and
airways, it may be necessary to deliver them every few hours via an
inhaler. Boldogh and Sur suggested that it is now important to develop
longer-lived antioxidants. "If we can find an antioxidant with a
longer half-life, it could be really very effective in asthma and
allergy treatment and also prevention," Boldogh said.

This research was supported by a grant to Sur and Boldogh from the
National Heart Lung and Blood Institute, UTMB's National Institute of
Environmental Health Sciences Center (Sur, Alam, Boldogh), and National
Heart Lung and Blood Institute Proteomics Initiative (Sur).

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