June 12, 2003 The biochemical components that cause a more severe form of cystic fibrosis have been identified by researchers at the University of California, San Diego (UCSD) School of Medicine. As reported in the June 12, 2003 issue of the journal Nature, severe cases of cystic fibrosis are caused when epithelial cells of sweat glands, intestine, lung and pancreas are unable to transport bicarbonate (which also serves as a buffer between acidity and alkalinity in the blood) across their cell membranes.
In addition, the researchers found that glutamate, an amino acid best known as a brain neurotransmitter, controls the movement of bicarbonate and another important chemical, chloride, into and out of epithelial cells. The two appear to act independently, but it is generally believed that their movement across cell membranes brings water to mucus that protects the cells, thus keeping the tissues lubricated and the mucus from becoming sticky and thick. However, scientists also believe that the contribution of these two chemicals to normal health is much more complex.
Previously, researchers thought that chloride was primarily involved in the cystic fibrosis disease. This, however, did not explain the variation seen in some patients with mild disease and others with a severe disorder.
A chronic, progressive, and frequently fatal disease of the body's glands responsible for either secretion or absorption of electrolyte solution, cystic fibrosis affects approximately 30,000 children and adults in the United States. On average, individuals with cystic fibrosis have a lifespan of 30 years. The disease primarily affects the respiratory and digestive systems, with the sweat glands and reproductive system also involved.
Although the disease doesn't follow the same pattern in all patients, the basic problem is the same, an abnormality in the glands, which produce or secrete salt solution and mucus. People with cystic fibrosis lose excessive amounts of salt when they sweat, risking the balance of minerals in the blood and subsequent heart rhythm. When mucus is thick, it accumulates in the intestines and lungs, resulting in malnutrition, poor growth, frequent respiratory infections, breathing difficulties, and eventually permanent lung damage.
While it is known that cystic fibrosis is caused by a mutation in a gene that creates the protein CFTR, the UCSD team decided to explore regulatory mechanisms that might account for the varying severity of the disease. In laboratory studies with human sweat gland tissue, they demonstrated that glutamate opens tiny holes, called CFTR ion pores, in epithelial cells. They also determined the extent to which chloride and bicarbonate chemicals can flow into or out of the gland cells. When CFTR was defective, the flow was restricted.
"We focused on glutamate because of its predominant role in regulating the neuronal channels and because glutamate receptors are widely distributed in epithelial cells, even though the functional significance of these receptors is almost unknown," said M.M. Reddy, Ph.D., the study's primary author and a research scientist in the UCSD Department of Pediatrics.
Reddy dissected the human sweat gland tissue and attached tiny pieces of sweat ducts to small glass tubes, which were connected to electrodes that measured electrical signals when different chemicals were applied. These experiments simulated the movement of chemicals through pores in cell membranes, thus allowing the scientists to determine when bicarbonate and/or chloride passed through the pores.
According to Reddy, CFTR forms a pore that was able to discriminate between chloride or bicarbonate, allowing one, or the other, or both to pass through the membrane under different conditions. This flexibility was previously unknown for any kind of pore.
When chloride availability was restricted and bicarbonate transport function was high, the resulting cystic fibrosis defect was mild. However, when bicarbonate ions were unable to move through pores, the defect was profoundly more severe.
Reddy said the new findings, "contribute to our understanding of how the movement of chloride and bicarbonate chemical substances across the cell membranes is controlled by the gland cells in the body, and may help in eventual therapy for severe forms of cystic fibrosis."
"Using this knowledge, our future efforts will be focused on how to correct or compensate for the abnormal functions of CFTR, with the hope to find a cure or reduce the severity of cystic fibrosis," he added.
In addition to Reddy, Paul Quinton, Ph.D., professor, UCSD Department of Pediatrics, contributed to the study, which was funded by the National Institutes of Health, the Cystic Fibrosis Foundation, the Gillette Company and the Texaco Foundation.
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