Cystic fibrosis from bench to bedside

Article Abstract:

In recent years, research workers have made great strides in understand both the physiological basis of cystic fibrosis and some of its complications. Cystic fibrosis is an inherited disorder. Studies using the techniques of molecular biology have found that the gene for cystic fibrosis provides the code for a protein, which serves as a transmembrane chloride conductance channel. Such a protein would permit chloride ions to cross the membrane of the cell in response to the physiological needs of the cell. Within the cells lining the airways of cystic fibrous patients, the abnormal protein causes a decrease in the secretion of chloride ions, along with a threefold increase in the flow of sodium ions into the cells. Osmotic pressure results in a flow of water, which accompanies the sodium that flows into the cells. The net effect is to remove water from the secretions in the airways, rendering them almost glue-like. Since it is known that the particular chloride channel affected in cystic fibrous is regulated by a cellular 'messenger' molecule called cyclic AMP, the physiological studies also indicate a point in the disease process at which medical intervention may prove useful. Indeed, in the August 22, 1991 issue of The New England Journal of Medicine, physiologists report the results of research on the chloride channels that may be useful for developing treatment regimens. However, research has also opened up other treatment options. The difficulty a cystic fibrous patient has in clearing his lungs of the viscous secretions also leaves the patient open to infection. There is some evidence that the same process that causes the changes in the lung secretions also makes the airways more hospitable to the bacteria Pseudomonas aeruginosa. Once established, infection with this organism is not cleared from the lungs. Furthermore, the inflammatory response of the patient actually exacerbates the already delicate condition of the lungs. However, as the physiological details are worked out, possibilities arise for helping the patient reduce the inflammatory response and increase the immune response. The findings of cystic fibrous research are exciting examples of how laboratory research is providing new possibilities for improved care and treatment of patients. (Consumer Summary produced by Reliance Medical Information, Inc.)

editorial

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Activation by extracellular nucleotides of chloride secretion in the airway epithelia of patients with cystic fibrosis

Article Abstract:

In recent years, researchers studying cystic fibrosis (CF) have learned that the disease results from a genetic mutation affecting a specific protein, which regulates the transport of ions across the cell membrane. The various effects of this genetic disorder may be traced directly to abnormalities of ion transport. For example, patients with cystic fibrosis fail to properly regulate the secretion of chloride ions in the delicate lining of the airways and, at the same time, absorb too many sodium ions. This is believed to result in too little water remaining in the mucous secretions, which then become viscous and interfere with normal breathing. Researchers have begun to search for substances that may help to normalize ion transport in patients with CF. In healthy people, chloride secretion can be stimulated by a group of substances called cyclic nucleotides such as cyclic AMP (cAMP). However, cAMP and related compounds have already been found to be ineffective in patients with cystic fibrosis. Other nucleotides now being evaluated for their ability to stimulate chloride ion secretion in the epithelial lining of the respiratory tract of patients with CF. Physiological measurements of chloride secretion were made in the nasal cavity, which is easier to study physiologically than mucosal linings further along the respiratory tract. When two types of triphosphate nucleotides, adenosine triphosphate (ATP) and uridine triphosphate (UTP), were applied to the mucosal lining, they were observed to stimulate chloride secretion in 12 patients with CF, as well as in nine healthy controls. The administration of pure adenosine and uridine did not have the same effect, suggesting that the stimulation of the chloride secretion required interaction with particular phosphate nucleotide receptors. The present study did not attempt to evaluate the use of these substances in treating the symptoms of cystic fibrosis. However, it does demonstrate that ATP and UTP produces desirable physiological effects; further evaluation of these substances for their therapeutic benefits should be conducted. (Consumer Summary produced by Reliance Medical Information, Inc.)

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Pulmonary epithelial sodium-channel dysfunction and excess airway liquid in pseudohypoaldosteronism

Article Abstract:

Pseudohypoaldosteronism appears to cause excess fluid in the lungs and respiratory system. Pseudohypoaldosteronism is characterized by abnormal sodium transport in the body. In a study of 9 patients with pseudohypoaldosteronism, mutations were found in the genes for parts of the sodium channel, which transports sodium across tissues. The patients had more than twice as much fluid in their respiratory system as a healthy person would have. Most had chest congestion, coughing and wheezing. This illustrates the role that sodium plays in keeping fluid levels in the respiratory system normal.

Abnormalities, Hyperaldosteronism, Airway (Medicine), Airway, Body fluids

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