Acta Paediatr Scand Suppl 363: 25-30, 1989 Epithelial Cell Dysfunction in Cystic Fibrosis: Implications for Airways Disease THOMAS F. BOAT and PI WAN CHENG From the Department of Pediatrics, University of North Carolina School of Medicine. Chapel Hill, N.C. 27514, USA ABSTRACT. Boat, T. F. and Cheng, P. W. (Department of Pediatrics, University of North Carolina School of Medicine, Chapel Hill, N.C., USA). Epithelial cell dysfunction in cystic ftbrosls: lmpllcadons for airways disease. Acta Paedlatr Scand Suppl 363: 25, 1989. An Important pathophysiologic factor In CF airways Is the failure to clear poorly hydrated secretions. The water deficit In CF mucous secretions can now be ascribed to a fundamental defect or epithelial cell regulatory processes which promotes sodium reabsorption from surface liquids and interferes with chloride secretion onto the luminal surface. In addldon, It Is now known that CF airway epithelial cells cwersuifate high molecular weight glycocoi\Ju· gates, both secreted and cell surface-associated. Oversulfatlon of glycocoi\Jugates may con· tribute to the altered clearance properties of CF airways mucus and In addldon could favor colonization of airways by organisms such as P. urugittosa. Recent studies have confirmed that the CF gene is expressed most consistently in epithelial cells, including those lining the airways. Epithelial dysfunction in CF is nowhere more critical than in the conducting airways. Failure to clear secretions, initially from the small airways, and eventually from larger airways, is directly responsible for much of the air flow obstruction which characterizes lung disease in CF. Mucus stasis and perhaps other factors also contribute to chronic endobronchial infection, which disrupts the structural integrity of airways and results ultimately in ventilatory failure. Understanding the pathophysiologic basis for airway dysfunction is of paramount importance if new and more successful approaches to the therapy of CF lung disease are to be forthcoming. A number of hypotheses have been advanced to explain the failure to clear secretions from CF airways: I) Hypersecretion of mucus is a constant feature of CF lung disease, but most evidence suggests that this process is probably secondary to chronic infection and inflammation (l). 2) Abnormal electrolyte content of secretions and high levels of calcium in particular have been implicated. However, there is little evidence that calcium levels are universally altered in CF secretions or that they play a major pathophysiologic role (2). 3) A paucity of water has been noted in airway secretions, meconium, and cervical mucus of individuals with CF (Table I). Insufficient water may alter the viscoelastic properties of secretions and result in failure of clearance (3). This possibility and the potential mechan- isms involved will be addressed. 4) Increased sulfation of secreted glycoconjugates has been reported to be a fundamental property of CF airways epithelial cells (4). and implications of this biochemical abnormality for mucus clearance and airways dysfunction in CF also will be discussed. Finally. we will examine potential relationships between insufficient hydration of airways secretions and oversulfation of secretory components. ALTERED ELECTROLYTE TRANSPORT A key observation in the early 1980s by Knowles and colleagues (5) triggered a series of productive studies of CF airways epithelial cells. These investigators found that the potential difference across the nasal epithelium of CF subjects was uniformly more