Cystic fibrosis is an inherited disorder, whose principal pathologic characteristic is the elaboration of viscous mucous secretions from many of the exocrine cells of the body. Studies of the composition of mucous glycoproteins and proteoglycans from tracheobronchial secretions of cystic fibrosis patients have shown these to exhibit increased sulfation of the carbohydrate chains, but the metabolic basis for this production of altered mucous components is unknown. Since cystic fibrosis appears to be a primary disorder of membrane ion transport characterized by increased sodium and chloride concentrations in sweat, altered S042- levels in tissue may be a primary or secondary consequence of the electrolyte abnormalities of this disease. Little attention has been paid to the possible role of S042- levels in this disease which may be a critical controlling factor in the production of abnormal sulfated glycoproteins. We have recently established that human lung and skin fibroblasts have carrier-mediated, SITS and DIDS-sensitive anion exchange transport systems for sulfate which are stimulated by protons and mediate H+SO4= cotransport. In these respects sulfate transport in these cells is strikingly similar to that mediated by the band 3 anion exchanger in erythrocytes. The sulfate uptake system in CF fibroblasts has an increased capacity compared to that of normals at both pH 7.5 and pH 5.5 and this alteration in transport function may lead to increased levels of intracellular sulfate and the production of oversulfated macromolecules. Moreover, if the CF fibroblast anion exchanger is a better sulfate and poorer chloride transporter than that of normals, it may reflect the generalized impermeability of membranes to chloride ion in this disease and suggest that there may be some structural and/or regulatory components which are common to the electroneutral anion exchanger and the conductive chloride channel, which appears to be the primary site of the defect in CF. Therefore, it is proposed to study the properties of the transport system of S042- , the activation of S042- to the sulfate donor PAPS and the effects of varying S042- levels, and agents which affect sulfate transport and sulfation, on the production of sulfated macromolecules in cultured IMR-90 human lung fibroblasts and in skin fibroblasts cultured from cystic fibrosis patients and age/sex-matched controls with no family history of the disease. The long term goal of this project is to better understand the ionic environment which leads to a change in the sulfation pattern of macromolecules in CF.
| Elgavish, A; Meezan, E (1992) Altered sulfate transport via anion exchange in CFPAC is corrected by retrovirus-mediated CFTR gene transfer. Am J Physiol 263:C176-86 |
| Elgavish, A; Meezan, E (1989) Sulfate transport in human lung fibroblasts (IMR-90): effect of pH and anions. Am J Physiol 256:C486-94 |
