Research Uncovers New Treatment Target For Cystic Fibrosis Patients’ Lung Infection
- Date:
- February 6, 2002
- Source:
- University Of North Carolina At Chapel Hill
- Summary:
- In experiments that could lead to an important advance in treating cystic fibrosis, the most common lethal genetic illness among whites, U.S. and European scientists have discovered that the chief bacteria infecting CF patients’ lungs can live without oxygen.
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CHAPEL HILL – In experiments that could lead to an important advance in treating cystic fibrosis, the most common lethal genetic illness among whites, U.S. and European scientists have discovered that the chief bacteria infecting CF patients’ lungs can live without oxygen.
The discovery, reported today (Jan. 30), suggests drugs now used to treat CF infections don’t work as well as doctors and patients wish since they are only poorly directed at the target, researchers say. Lung infections are the leading cause of illness and death in such patients.
A report on the study is the cover article in the February issue of the Journal of Clinical Investigation. U.S. authors are Drs. Ute Schwab, Robert Tarran, James R. Yankaskas, Scott Randell and Richard C. Boucher Jr. of the University of North Carolina at Chapel Hill and Dr. Keith C. Meyer of the University of Wisconsin. European authors include Drs. Dieter Worlitzsch, Martina Ulrich, Gerd Doring and others at the University of Tubingen in Germany, along with Swiss and French researchers.
Boucher, director of the Cystic Fibrosis/ Pulmonary Research and Treatment Center at the UNC School of Medicine, and one of two senior authors, called the paper “very important because before long it should change and improve treatment for children and young adults born with this very serious illness.
“Our initial work was designed to answer the question of whether the debilitating lung infections cystic fibrosis patients suffer occur deep in the cells lining the airways or are localized on cell surfaces in the sticky mucous overlying those cells,” he said. “Using electron microscopy and several sensitive techniques, we found, not surprisingly, that the infections were in the mucous.”
Researchers then reasoned that the most common bacterium infecting CF patients, Pseudomonas aeruginosa, thrived in that sticky, oxygen-rich environment in the airways, but that turned out not to be true, said Boucher, Kenan professor of medicine. Bacteria proliferated there all right, but it was only because they underwent a transformation to adapt to mucous containing little or no oxygen.
“Because of incorrect genetic instructions, cells lining the airways remove too much salt and water from the secretions, and when they do that, they work very hard,” Schwab said. “That strenuous effort consumes most of the oxygen in the mucous, and we found Pseudomonas swam into these very low-oxygen zones and, to our surprise, grew very well there.”
Adapting to their new, stressful environment, the bacteria, which normally require oxygen just as most living things do, generated protective sugar coatings around themselves and formed protective networks known as biofilms, she said.
“In the past, we’ve had a problem with antibiotic therapy for cystic fibrosis in that antibiotics that were very promising in the laboratory did not work very well in patients,” Boucher said. “This research may explain part of that failure.
“More importantly, our experiments suggest that there are enzymes at work in these bacteria infecting people that we haven’t targeted at all yet in our therapies,” Boucher said. “This would represent a new strategy that is catching scientists’ attention around the world.”
Using the new approach, researchers would create antibiotics to disrupt specific enzymes critical for maintaining Pseudomonas in the oxygen-depleted mucous layer. The enzymes allow the bacteria to produce, store and transfer a complex internal fuel known as ATP that keeps cells running.
In cystic fibrosis patients, Pseudomonas has adapted one or more ways of making ATP in the absence of oxygen, and those methods involve bacterial enzymes not yet attacked by drug therapy, Boucher said.
“This discovery is like finding creatures that not only live and breathe on land but also on the bottom of the ocean in an environment without oxygen,” he said.
UNC is renowned for its basic and clinical research on cystic fibrosis. Among the center’s previous contributions has been developing the first animal model for studying the illness. Its scientists also determined that the defective cystic fibrosis gene did not die out among humans over thousands of years because -- when inherited from only one parent -- it helped protect people from cholera. They also developed the most effective treatment so far and have been pioneers in gene therapy for the disease.
In 1998, UNC scientists found that cystic fibrosis depleted the seven millionths-of-a-meter-thick liquid layer lubricating the lung’s internal surfaces so that overly thick mucous trapped bacteria without being swept clear by tiny beating hairs known as cilia. Last year, their research showed that too little salt in the lungs contributed to the stickiness and chronic infections.
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Materials provided by University Of North Carolina At Chapel Hill. Note: Content may be edited for style and length.
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