Abnormal Na+ transport by distal airway surface epithelia in cystic fibrosis swine
| dc.contributor.advisor | Ianowski, Juan Dr. | |
| dc.contributor.committeeMember | Campanucci, Veronica Dr. | |
| dc.contributor.committeeMember | Lee, Paul Dr. | |
| dc.contributor.committeeMember | Cayabyab, Francisco Dr. | |
| dc.creator | Grishchenko, Nikolay | |
| dc.creator.orcid | 0000-0002-8643-3733 | |
| dc.date.accessioned | 2018-10-04T22:07:22Z | |
| dc.date.available | 2018-10-04T22:07:22Z | |
| dc.date.created | 2018-07 | |
| dc.date.issued | 2018-10-04 | |
| dc.date.submitted | July 2018 | |
| dc.date.updated | 2018-10-04T22:07:22Z | |
| dc.description.abstract | Abstract One of the most prevalent hypotheses pertaining to the sequence of events that lead to cystic fibrosis (CF) airway disease is that in normal airway epithelia the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) anion channel inhibits the activity of the Epithelial Na+ Channel (ENaC). In CF patients, where CFTR is mutated, the inhibition of ENaC is lost. Consequently, ENaC becomes hyperactive, resulting in fluid depletion from the airway, collapse of the mucociliary apparatus, and impaired clearance of microbes, which initiates a cycle of infection and inflammation that may eventually result in respiratory failure. This hypothesis has recently been challenged by reports suggesting that animal models of CF do not exhibit hyperactive ENaC, and that the cilia in their airway appear normally functioning. This constitutes a paradigm shift in CF with serious consequences for current and future CF treatments. However, there is evidence that ENaC hyperactivity in CF may depend on the stimulation of airway epithelia by secretagogues. Thus, using a self-referencing ion selective microelectrode technique with unparalleled spatial resolution, we tested the Na+ transport properties of the surface epithelia in the distal airway (~2mm) of CFTR- \- swine after stimulation of intracellular cAMP or Ca2+ signaling pathways. We show that the epithelial cells located at the folds of the distal airway are capable of both secreting and reabsorbing Na+, and are sensitive to CFTR and ENaC inhibition with CFTRinh172 and amiloride, suggesting that both ENaC and CFTR are expressed at the folds. Most importantly, using the response to amiloride as an assay for ENaC activity, we detected hyperactive ENaC in forskolin-stimulated CFTR-/- airways. This indicates that CFTR-/- swine airways do indeed suffer from hyperactive ENaC after increased intracellular cAMP, thus potentially collapsing the PCL at those sites. | |
| dc.format.mimetype | application/pdf | |
| dc.identifier.uri | http://hdl.handle.net/10388/11300 | |
| dc.subject | CF, ion transport | |
| dc.title | Abnormal Na+ transport by distal airway surface epithelia in cystic fibrosis swine | |
| dc.type | Thesis | |
| dc.type.material | text | |
| thesis.degree.department | Physiology | |
| thesis.degree.discipline | Physiology | |
| thesis.degree.grantor | University of Saskatchewan | |
| thesis.degree.level | Masters | |
| thesis.degree.name | Master of Arts (M.A.) |