Cystic Fibrosis and the Salt Controversy

Two critical questions are, how does the normal airway defend itself against bacterial colonization? and why are CF patients susceptible to chronic lung infections? Some defensin molecules in the airway are effective at killing bacteria only when the ASL salt concentration is low (Smith et al. 1996xSmith, J.J, Travis, S.M, Greenberg, E.P, and Welsh, M.J. Cell. 1996; 85: 229–236Abstract | Full Text | Full Text PDF | PubMed | Scopus (780)See all ReferencesSmith et al. 1996). However, other defensin molecules in the airway can kill bacteria at higher salt concentrations (9xKo, Y.H, Delannoy, M, and Pedersen, P.L. FEBS Lett. 1997; 405: 200–208Abstract | Full Text | Full Text PDF | PubMed | Scopus (17)See all References, 17xSingh, P.K, Jia, H.P, Wiles, K, Hesselberth, J, Liu, L, Conway, B.A.D, Greenberg, E.P, Valore, E.V, Welsh, M.J, Ganz, T, Tack, B.F, and McCray, P.B.J. Proc. Natl. Acad. Sci. USA. 1998; 95: 14961–14966Crossref | PubMed | Scopus (450)See all References). In normal airways, it is possible that during episodes of bacterial infection, enhanced fluid production by the submucosal glands reduces ASL ion concentration, allowing for additional bacterial killing by the more salt-sensitive defensins. In CF, reduced bacterial killing by salt-sensitive defensins may be only part of the problem. Other investigators have suggested that bacterial colonization in CF is a combination of increased binding of P. aeruginosa and a defect in bacterial internalization (6xImundo, L, Barasch, J, Prince, A, and Al-Awqati, Q. Proc. Natl. Acad. Sci. USA. 1995; 92: 3019–3023Crossref | PubMed | Scopus (197)See all References, 14xPier, G.B, Grout, M, Zaidi, T.S, Olsen, J.C, Johnson, L.G, Yankaskas, J.R, and Goldberg, J.B. Science. 1996; 271: 64–67Crossref | PubMedSee all References).One can look to other diseases for insights into the role of ASL composition and mucociliary clearance in lung infection. The salt hypothesis (Figure 2Figure 2, bottom) predicts that patients with loss-of-function mutations in ENaC, such as occurs in pseudohypoaldosteronism (PHA), should have a higher ASL salt concentration and bacterial infections. PHA patients have an increased ASL volume caused by reduced fluid absorption, and the ASL is isotonic to plasma (Kerem et al. 1997xKerem, E, Bistritzer, T, Hanukoglu, A, MacLaughlin, A, Boucher, R.C, and Knowles, M.R. Pediatr. Pulmonol. Suppl. 1997; 14: 78See all ReferencesKerem et al. 1997). However, PHA patients do not have infectious lung disease. One explanation might be that other Na+ channels could reduce ASL ion concentration somewhat in PHA. Alternatively, when ASL salt concentration is high, other mechanisms, such as enhanced mucociliary clearance, may come into play to clear away bacteria.What is the role of mucociliary clearance in recurring infections in CF? In primary ciliary dyskinesia (PCD), cilia cannot beat normally because of abnormalities in ciliary dyneins (Levison et al. 1983xLevison, H, Mindorff, C.M, Chao, J, Turner, J.A, Sturgess, J.M, and Stringer, D.A. Eur. J. Respir. Dis. Suppl. 1983; 127: 102–117PubMedSee all ReferencesLevison et al. 1983). The absence of mucociliary clearance in PCD results in recurrent lung infections, but the diagnosis is often delayed until adulthood. These patients would be expected to have normal ASL composition and hydration. The presence of bacterial infection in these patients is evidence of the importance of mucociliary clearance in preventing infection. The delayed onset of lung disease in PCD compared to the early onset of bacterial colonization in CF, and the lack of colonization by P. aeruginosa in PCD suggests that other factors are involved in CF.Mutations in a protein with multiple functions such as CFTR will disrupt both secretory and absorptive transport mechanisms (Figure 3Figure 3 bottom). This disruption will likely, as Boucher and collaborators speculate, “result in multiple hits” on mucociliary, cough, and airflow-dependent clearance mechanisms. This combination of effects may explain the more severe phenotype in CF lung disease as compared to other disorders of fluid transport and ciliary clearance.Many controversies in CF research stem from seemingly disparate results from high-quality laboratories (see Devidas and Guggino 1997xDevidas, S and Guggino, W.B. Curr. Opin. Cell Biol. 1997; 9: 547–552Crossref | PubMed | Scopus (45)See all ReferencesDevidas and Guggino 1997). Often, disparate results are obtained because biological processes are only partially reproduced in experimental systems. The two different models of salt and water transport lead to very different conclusions regarding therapies for CF. The hydration model suggests that to treat the respiratory problems of CF patients, more lung fluid is needed, whereas the salt model suggests that it is important to correct a salt imbalance in the airway. Thus, the resolution of this controversy will ultimately enhance our knowledge of the basic mechanisms of epithelial salt and fluid transport in the airway and add to a more complete understanding of why the CF airway is chronically infected. This will certainly be an important example of how basic research can help patients.