Discovery Might Boost Cystic Fibrosis Therapy

The finding is important because it confirms a theory of how lungs protect themselves and may suggest better ways of treating cystic fibrosis, the most common lethal genetic illness among whites, the researchers say.

"We found that this rare disorder, which is called systemic pseudohypoaldosteronism, is in a sense the exact opposite of cystic fibrosis," said Dr. Michael R. Knowles, professor of medicine at the UNC-CH School of Medicine and director of the Cystic Fibrosis Therapeutics Development Center. "People with this illness are born without functioning sodium channels that remove salt and liquid coating the airways, and so there is too much liquid. On the other hand, airway cells in people with cystic fibrosis remove too much liquid so that the coating becomes too thick."

In cystic fibrosis, overly sticky lung secretions retard the countless microscopic hair-like structures called cilia that continuously sweep dust and bacteria out of the lungs in a natural cleansing mechanism, Knowles said. Infections and the resulting lung damage eventually kill young patients.

A report on the findings appears in Thursday's issue (July 15) of the New England Journal of Medicine.

Researchers studied in detail nine pseudohypoaldosteronism patients ranging in age from 1.5 years to 22 years in North Carolina, California and Israel.

They tested for mutations in lung surface cell sodium channel genes, estimated sodium transport rates in the airways and determined the volume and ion composition of airway surface liquids. They also reviewed clinical information about patients, collected laboratory data relevant to lung function and in three adults measured the lungs' ability to clear mucus and related liquids.

Physicians found their patients bore genetic mutations that prevented their sodium channels from functioning and that no sodium or liquid was absorbed from airway surfaces. They also discovered that patients had more than twice the normal volume of lung surface liquids.

The rate at which cilia cleared airway secretions was about four times as high as normal, laboratory analyses showed. The youngest patients suffered recurrent chest congestion, coughing and wheezing while those over age 5 displayed fewer respiratory symptoms.

"This work definitely has implications for cystic fibrosis treatment because it shows we somehow need to block sodium channels to prevent excessive removal of salt and water from the airway surface," Knowles said. "We should be able to do that eventually through drugs and later gene therapy. We are now looking at the possible benefits of having CF patients inhale saltwater in aerosol form."

Cystic fibrosis affects about 30,000 children and young adults in the United States. When two carriers of a defective gene known as CFTR produce children, on average one in four of their children will have the disease, two will be carriers like their parents and one will be disease-free.

Most children born with pseudohypoaldosteronism die within the first three days after birth because of loss of fluids through the kidneys. Those who survive usually become less sick over the years through some adaptive mechanism not yet understood that speeds up clearance of the liquids from the lung.

###Besides Knowles, who is the senior author, UNC-CH authors are Drs. Zhaoqing Zhou, Pierre Barker and Richard Boucher of the Cystic Fibrosis-Pulmonary Research and Treatment Center and Dr. William Bennett of the Center for Environmental Medicine.

Authors at other institutions are Drs. Eitan Kerem of Hebrew University Medical School in Jerusalem, Tzvi Bistritzerin of the Assaf Harofeh Medical Center in Zerifin, Israel, Aaron Hanukoglu of the Sackler School of Medicine in Tel Aviv, Israel, Thomas Hofmann of the JLU Children's Clinic in Giesen, Germany, Eithne MacLaughlin of the Children's Hospital of Los Angeles and the University of Southern California and Martin Nash and Lynne Quittell of Columbia-Presbyterian Medical Center in New York.

The National Institutes of Health and the Cystic Fibrosis Foundation supported the research.