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, leading to the term mucoviscidosis which has been given to this disease. 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. Recently evidence has been presented that the sulfation of cartilage glycosaminoglycans and tracheal mucous glycoproteins is controlled at the level of the sulfate donor 3' -phosphoadenylyl sulfate (PAPS) and that the intracellular level of this universal sulfate donor may be determined by the endogenous concentration of S042-. 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. Such highly sulfated polymers are known to have altered rheologic properties and to be more resistant to proteolytic degradation. These properties would exacerbate the pathologic effects of the altered mucous secretions. Recent evidence has implicated the Cl-/X- anion exchange system of cystic fibrosis sweat ducts as being defective, leading to the characteristic elevation of Na+ and Cl- levels in the sweat of affected individuals. This defect of Cl- reabsorption in CF sweat ducts would be expected to lead to elevated intracellular levels of S04= if this anion exchange system has similar characteristics to those described in other cells such as erythrocytes and fibroblasts. Therefore, it is proposed to study the properties of the transport system for S042-, the activation of S042- to the sulfate donor PAPS, and the effects of varying S042- levels, and drugs and hormones which may affect 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.
| 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 |
