Environmental Factor, October 2008, National Institute of Environmental Health Sciences
UNC Researcher Discusses Causes and Treatment of Cystic Fibrosis
By Robin Arnette
NIEHS opened its 2008-2009 Distinguished Lecture Series on September 8 with a seminar about cystic fibrosis (CF), an inherited chronic disease that causes mucus to clog the lungs and other organs of the body. Richard Boucher, M.D., a specialist in the field of pulmonary pathophysiology, presented "Cystic Fibrosis: A Failure of Lung Defense Against the Environment." James Putney Jr., Ph.D., a principal investigator in the NIEHS Laboratory of Signal Transduction, hosted the talk in Rodbell Auditorium.
Boucher (http://www.med.unc.edu/marsicolunginstitute/about-us/faculty/boucher) is a William R. Kenan Professor of Medicine at the University of North Carolina at Chapel Hill (UNC-CH), director of the Cystic Fibrosis/Pulmonary Treatment and Research Center, and co-director of the Gene Therapy Center, both at UNC-CH. He said that CF was really a failure of the lung's defenses against outside invaders, and specifically, a breakdown of the two-phase system of mechanical clearance. He explained what occurs in normal lungs first. "Bacteria or viruses come into contact with a mucus layer that is designed to trap material and move it away from the airway surface," Boucher said. "They then encounter a watery pericellular environment that provides enough lubricant activity for the mucus - which contains the microbes - to move out of the lung effectively."
Boucher said that the pericellular layer contains cilia, hair-like cellular projections that move the mucus, but for them to work properly the mucus layer has to be well-hydrated and the airway epithelial cells have to secrete mucus glycoproteins called mucins. Boucher said that hydration is more important in mechanical clearance than cilia or mucins. He pointed out that because salt on the airway surface osmotically determines the amount of water, the lungs modulate hydration by absorbing salt. The lungs then use two mechanisms to secrete chloride and water to the surface - a calcium-activated channel mechanism and a cystic fibrosis transmembrane conductance regulator (CFTR)-chloride channel mechanism.
In CF patients, however, the CFTR protein is mutated. Since CFTR can't enter the plasma membrane in a CF patient's lungs, chloride and water can't be secreted, which leads to unrestrained absorption of salt from the surface. As a result, the mucus layer becomes more concentrated, and together with mucins, forms mucus plaques that stick to airway surfaces and obstruct airflow.
Boucher said these plaques contain 107 or 108 bacteria/ml of mucus, and that the biofilms the bacteria exist in prevent neutrophils or antimicrobial drugs from reaching the organisms and killing them. He explained, "This resistance leads to a chronic infection in CF patients. When CF kids get their first Pseudomonas infection during the first few months of life, they never eradicate it."
To examine how much liquid hydration occurs in normal and CF epithelial cells and how it is controlled, Boucher used a lung epithelial cell culture system developed by one of his collaborators. The system mimicked in vivo cells by displaying a counterclockwise rotational movement when liquid was present. Boucher's team determined that the airway surface liquid (ASL) compartment in normal cells had a height of 7.5-8 microns of liquid, which was about the height of the extended cilia. This height was maintained through the CFTR protein by the regulated release of ATP and its product adenosine, in a dual, redundant mechanism for hydrating the airway surface. In contrast, without a functioning CFTR, CF patients have to rely on the ATP system since the adenosine pathway needs CFTR. "ATP release gives CF patients enough fluid on the surface to move mucus, but this amount is less than normal," Boucher stated.
Boucher added that his and other CF investigators' work have yielded two promising therapies for CF sufferers - inhaling a hypertonic saline solution that draws water to the airway surface or taking a drug that turns off sodium absorption and initiates chloride secretion. Several studies have indicated that CF patients participating in either of these regimens increase their lung function and reduce the number of respiratory tract exacerbations.