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Acid May be Key to Cystic Fibrosis Infections

Study identifies mechanism for deadly lung invasions

MONDAY, Nov. 19, 2001 (HealthDayNews) -- Drugs that neutralize acids may help protect patients with cystic fibrosis (CF) from the deadly lung infections that now cut their lives short, says a new study.

Researchers have found that cystic fibrosis, the most common lethal birth defect among whites, makes cells in the airway lining abnormally acidic. That creates a friendlier environment for harmful bacteria, which then are better able to infect the lungs and bring on disease.

But reversing the acidity with compounds called bases -- much the way an antacid soothes indigestion -- may pull up the welcome mat for these germs, say the researchers, whose findings appear in the Nov. 20 issue of the Proceedings of the National Academy of Sciences.

Christopher Taylor, a lung infection expert at the National Institute of Allergy and Infectious Diseases, calls the study "innovative."

"It's really an important finding. If it holds up, it could have major implications for the treatment" of CF, Taylor says.

Cystic fibrosis affects one in roughly 2,500 people in the United States. The disorder is linked to errors in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which controls a protein that monitors the sodium content in cells and the properties of mucus.

Patients with two mutant versions of CFTR suffer potentially crippling respiratory problems, including airways obstructed by overly-thick mucus and frequent infections. They often also have difficulty digesting food and absorbing nutrients.

While its effects on the body are well known, CF's biology has been less clear. The CFTR gene oversees the flow of charged atoms, or ions, across the cell's membrane, but why mutations in the gene make carriers more susceptible to infection has been a mystery. The new study sheds light on the puzzle.

Vojo Deretic, a microbiologist at the University of New Mexico in Albuquerque, and colleagues there and at the University of Michigan (where he formerly worked) sought to learn why CF patients are so often afflicted with a particular lung germ called Pseudomonas aeruginosa. The microbe, which rarely infects healthy people, is a leading cause of death among CF patients.

The finding about acidity hinges on tiny factories inside cells called trans-Golgi networks. These centers perform final assembly on protein molecules destined to become part of the cell's outer surface.

Deretic's group, including New Mexico researcher Jens Poschet, showed that the trans-Golgi networks in lung cells of CF patients have an overabundance of acid, which stops them from cobbling the right sugar molecules to proteins. The flaw prevents the networks from affixing a final sugar, like icing on protein cake, and this flaw, in turn, makes the cell walls especially sticky for bacteria like P. aeruginosa.

The error attracts not only P. aeruginosa but other dangerous microbes as well. Even influenza uses the unaltered site as a grip for infection, though it must first decapitate the normal sugar tip, Deretic says.

The researchers also found they could undermine this hospitality in the test tube by dosing lung cells with ammonia. P. aeruginosa laid atop the treated tissue lost about 20 percent of its sticking power, Deretic says.

Although that might not seem like much, Deretic says even small differences can have a major impact if they're consistent and prolonged. "If you could just enable the innate system to function properly, maybe these bugs would not get a foothold, and you might postpone the development of disease," he says.

Deretic cites recent theories about the eye disease macular degeneration, which develops over decades and which, if impeded early, might be partly or wholly avoidable.

One possible candidate drug is chloroquine, a long-time malaria medication with a well-known safety profile. Deretic says he and his colleagues now plan to conduct studies to see whether chloroquine and other basic compounds can help prevent bacterial infection in CF lung tissue.

What To Do: To learn more about CF, visit the Cystic Fibrosis Foundation or Cystic Fibrosis Research, Inc..

SOURCES: Interviews with Vojo Deretic, Ph.D., professor of molecular genetics and microbiology, University of New Mexico School of Medicine, Albuquerque; Christopher Taylor, Sc.D., lung infection expert, National Institute of Allergy and Infectious Diseases, Bethesda, Md.; Nov. 20, 2001, Proceedings of the National Academy of Sciences
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