Cystic Fibrosis (CF) is an autosomal recessive disorder in which the genetic defect is the ΔF 508 deletion in 70% of patients (Tsui and Collins et al, 1989). The ΔF 508 deletion gene predicts encodement of the cystic fibrosis transmembrane conductance regulator (CFTR), (Riordan, 1989). The mechanisms by which this abnormal regulatory protein leads to chronic airway infection, respiratory failure and death in CF are not clear. This thesis examines one basic problem seen in patients with F, namely the incrased viscosity of their sputum. The increased viscosity leads to decreased mucociliary clearance and may be one of the factors leading to delayed bacterial clearance, chronic respiratory infection and respiratory failure. The problem of increased mucus viscosity is examined by looking at two molecules which contribute to the increased viscosity of sputum: mucins and DNA. The fundamental physicochemistry of mucin rheology is explored, and the theoretical model of mucin expansion is developed further in an experimental intervention in patients with CF using an experimetal new drug, aerosolized recombinant human DNase which fragments DNA and decreases sputum viscosity. The models used to examine the questions of mucus rheology were the giant secretory granule of the slug, <i>Ariolimax columbianus</i>, and the goblet cell of the trachea of the New Zealand white rabbit. Normal subjects and patients with CF were used for the human studies. Mucus is a polymer hydrogel that functions as a protective coat on the skin and mucosa of many species ranging from simple animals such as <i>coelenterates</i> to mammals. The polymer matrix of mucus is made out of long-chain glycoproteins called mucins that are tangled together to form a randomly woven, polyionic network. The swelling kinetics of both slug granules and the mucin granules of the goblet cell of the rabbit are similar to those of artificial polyacrylamide gels. Mucins are condensed within granules and expand by hydration during or after exocytosis. The polyionic charges of mucins would prevent condensation unless they were shielded by a balancing cation. The experiments using the slug granule demonstrate the presence of shielding cations in the granule and the role of these cations at the time of secretion.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:640260 |
| Date | January 1992 |
| Creators | Aitken, Moira Lesley |
| Publisher | University of Edinburgh |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/1842/20048 |
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