The most common lethal genetic disease in the Caucasian population is cystic fibrosis (CF). In 1970, the median life expectancy was 8 yr; today, with the concerted effort of scientists and clinicians, the median survival age has risen to 30 yr. About 1 in 23 people carry a single defective copy of the CF gene in the United States population and 40,000 people in the US have cystic fibrosis. The disease is characterized by a generalized exocrine dysfunction, and lung disease is the leading cause of death in CF patients (
To understand the basis for each of the two theories, we first must understand the function of the CF gene product. The CF gene was first discovered by Riordan and colleagues (
The high salt hypothesis was first proposed by
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The authors hypothesized that the salt concentration was higher in the CF cultures than in normal cultures. This was borne out in direct measurements of the NaCl concentrations, with the concentrations from CF cells being significantly higher, approximately equal to plasma. The paper by 150 mM NaCl) in the surface fluid. The discovery of such a compound playing a role in CF lung disease has rejuvenated the field of innate host defenses in CF.
In contrast, the low volume hypothesis contends that the salt concentration in both normal and CF are identical and high, approximately equal to plasma. In this theory, the lack of CFTR enhances the sodium absorption from the airway surface liquid. Because the airway surface cells form a monolayer that is leaky to water (
Just about all aspects of these two theories are in contention. However, three main points separate the two theories. First, is the salt concentration in the ASL from CF subjects higher than in normals (
This paper uses well differentiated human primary airway cultures to look at each of the possible mechanisms whereby the NaCl concentration may be reduced in the apical ASL. The results are consistent with previous work (7 µm) on the apical surface and if those cilia fall over as the solution level is decreased then the surface tension will not hold the water level to 7 µm, but rather to the height of the fallen cilia (3 µm). Can the surface tension of the fallen cilia lead to a lowered NaCl concentration?
120 mM). Why do the cilia not fall over in normal cultures?
However, some questions seemed to have been resolved. This paper, along with two previous papers, (
Why has this controversy lasted for 5 yr? Both theories have support from many laboratories measuring the NaCl content in the ASL from cultured cells and in vivo. Is there some basic truth that we are missing? If there is, I don't know what it is. Could the explanation be simply that there is some difference between the cultures? Both cultures grown in Chapel Hill and Iowa City have cilia and mucus, so this is unlikely to be the source of the difference. But maybe the cells from Iowa City secrete an uncharged osmolyte and those from Chapel Hill do not. This would be a simple, but elegant, method for modifying the salinity of the surface fluid while maintaining isotonicity. Is this hypothetical osmolyte also present in the ASL of normal lungs and absent in CF lungs? Alternatively, could there be some artifact that can explain all the results on one side of the controversy? Measurements of ASL in vivo have well-known possible artifacts. Filter paper and capillaries can pull fluid not only from the ASL, but possibly also from inside cells and from the basolateral side of the epithelial monolayer. Ion-sensitive microelectrodes may accidentally touch the surface of the epithelium and cause secretion, which is thought to be isotonic. So most laboratories have resorted to primary cultures. But primary cultures may not express the same features of cells in vivo. Experiments by
The resolution of this controversy is key to understanding the lung pathophysiology of cystic fibrosis and to the lives of individuals with cystic fibrosis. The two competing theories offer different routes to treat the lung disease. If the problem is that the surface liquid has too much salt so that antimicrobial activity is absent, then hypotonic solution to dilute the ASL will improve lung function. If the volume of the ASL is too small then hypertonic (
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