Curing CF: New Questions, New Answers About CF Pathophysiology

Condensed from the talk by Jeffrey Wine, Ph.D.

Fall 1994

Gene therapy holds much promise in the treatment of cystic fibrosis but we must pay more attention to the infrastructure on which gene therapy will be built, said Dr. Jeffrey Wine, Professor in the Department of Molecular and Cellular Physiology and Director of the Cystic Fibrosis Research Laboratory at Stanford University. Rather than rely solely on CF genetic research, we must also develop a better understanding of the fundamentals of CF gene expression. In addition, we must understand the details of the cellular mechanisms that keep normal lungs sterile, and investigate what happens if CFTR operates in the wrong cells.

Dr. Wine believes that chloride conductance in CF is crucial to understanding why CF patients suffer to varying degrees from lung and pancreatic problems. The vas deferens is an example of an organ so sensitive to chloride conductance that a small loss can lead to blockage and degeneration even while allowing normal lung and pancreatic function.

The CF mouse strongly supports the attention on chloride conductance because all mouse organs that have an auxiliary mechanism of non-CFTR-mediated chloride secretion are spared the effects of CF. Thus, the mouse has the same intestinal problems as humans, but its pancreas, lungs and reproductive tract have calcium-mediated chloride channels and operate normally.

We are also at a better stage of understanding the pathology in the lungs concerning chloride conductance. We now know that most CFTR expresses itself in a type of cell called a serous cell that produces many natural antibiotics. Serous cells also secrete salt and water that are essential for the proper consistency of the mucus in the lungs. In CF, losing serous cell function should severely compromise at least two components of the lung defense system: the mechanical clearance through mucus, and direct antibiotic defenses operating on the surface of the airway epithelium.

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