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Tonic toxins

POSTED 16 JUNE 2005
Toxic tonic for deadly lung diseases?
Cystic fibrosis is a deadly genetic disease that prevents the lungs from discharging mucus, a fluid that protects the lungs by removing a load of bacteria and pollutants. In explaining how CF is related to harmful algal blooms, we'll see how medicine can take advantage of toxins.

Bacteria seen through an electron microscope. An electron microscope view of Karenia brevis. This toxic alga causes red tide in Florida -- but also releases an anti-toxin that may be used to treat lung disease. Photo: NOAA

Karenia brevis, a Florida red tide organism, makes a toxin called brevetoxin that attacks the lungs, even at tiny concentrations. The economic consequences of emptying Gulf Coast beaches, combined with a desire to understand how the toxin affects the lungs, lead the National Institute for Environmental Health Sciences to sponsor a large, interdisciplinary look at the red tide. "The goal was to go from beach to bedside," says Daniel Baden, a professor of marine science at the University of North Carolina, Wilmington, who directed the program. "We started with the organism in the water, measured the amount of toxin, how much got aerosolized, what meteorological factors affect it moving shoreward, how much gets to the land, and how much gets into people, and to measure things at all times."

The toxin was shockingly potent -- causing symptoms at concentrations so low that the researchers had to invent a way to measure it, Baden told us. How low? Femtograms (quadrillionths) to picograms (trillionths of a gram) per cubic meter of air!

Those numbers alone indicate that brevetoxin has a precise target in biology, but there were other reasons to think Karenia brevis had medical significance:

The primary symptom of brevetoxin is constriction of the bronchia. The same phenomenon hinders inhalation in asthma and other lung diseases.

The toxin seemed most harmful to asthmatics and people with chronic obstructive pulmonary disease (COPD, often called emphysema). People with these conditions "tend to stay away from the beaches, because they are more susceptible," Baden said.

Many asthma drugs reduced the tightening of the bronchia.

Computer representation of bronchial branches in lungs.
Bronchoconstriction -- tightening of these tubes -- is a hallmark of asthma and other common lung diseases. Image: NIH

The beauty of blocking
But if toxin was causing symptoms, why didn't symptom severity correlate toxin levels? "When there was a lot of toxin, there might be little bronchoconstriction, or the opposite," Baden said. Could something be blocking the toxin? Yes. Andrea Bourdelais of UNC isolated an algal product that acted like an anti-toxin. This chemical, now called brevenal, "didn't have any lethal effects by itself," Baden said, "but when we added it to the toxin, we found that it was an antidote."

 Posted sign warns of infected shellfish Paralyzing warning: Harmful algal blooms are becoming more common on U.S. coasts. They may attack fish, shellfish, marine mammals, and swimmers. Photo: NOAA

Like all toxins, brevetoxin acts by binding to a receptor and interfering with a key signaling system. Brevenal, Baden explained, "blocks the neurotoxic effect, blocks the binding to the receptor, and that blocks the pulmonary effect."

Researchers next tested brevenal on the lungs of sheep. "We thought, guess what? This kind of looks like some of the drugs that are used to treat cystic fibrosis, it works in kind of the same way, let's try to apply it without any toxin present," said Baden.

Eventually, brevenal proved able to accelerate mucus removal, even at a dose 1 million times lower than the dose for amiloride, a primary cystic-fibrosis drug. In CF, remember, mucus accumulation is the primary cause of death.

Clearing out
Clearing mucus is critical to defending the airways from bacteria and pollutants. "We think the ability of these anti-toxins to improve the clearance of mucus may be due to a combination of increased movement of the cilia, the tiny hair-like structures that line the airways, and a thinning of mucus," Baden said. Serene coastline with red tide approachingBecause brevenal attaches to a different receptor than amiloride, Baden adds, "We believe brevenal has uncovered a new potential therapeutic site in the pulmonary system."

A (brownish) red tide occurs almost every summer along parts of Florida's Gulf Coast. Airborne toxins can cause lung disease among beachgoers. A new study has also blamed dolphin and manatee die-offs on this red tide. Photo: NOAA

As the discovery moves toward a possible treatment for lung disease, millions of people with asthma, COPD and cystic fibrosis may eventually benefit from research on a one-celled organism that used to concern only marine animals and beachgoers.

What other discoveries are credited to toxins?

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Megan Anderson, project assistant; Terry Devitt, editor; S.V. Medaris, designer/illustrator; David Tenenbaum, feature writer; Amy Toburen, content development executive

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