The pathophysiological origins of airway hyperresponsiveness (AHR) in asthma are unknown. The objectives of this thesis were to establish an association between AHR in an animal model of asthma and altered contractility of airway smooth muscle (ASM) and to elucidate changes in contractile signalling that could account for any observed differences in ASM contractility. The Fisher strain of rat is spontaneously hyperresponsive to methacholine inhalation challenge relative to Lewis rats. These inbred rat strains provide a model with which to study genetically-determined variations in airway smooth muscle that may underlie AHR. Fisher rats were found to be also hyperresponsive to serotonin (5-HT) in vivo compared to Lewis rats, indicating that their AHR is not agonist specific the narrowing capacity and velocity of contraction of Fisher intraparenchymal airways in cultured explants were also greater than explanted. Lewis intraparenchymal airways in response to 5-HT. In addition, 5-HT stimulated higher Ca2+ transients in Fisher than Lewis ASM, in parallel with their rank order of intraparenchymal airway responsiveness. These results suggest that ASM contractility may be determined by the extent of Ca2+ mobilization in airway myocytes. To examine the mechanism of enhanced intracellular Ca2+ mobilization in Fisher ASM, the role of the inositol (1,4,5)trisphospbate (Ins (1,4,5)P 3) pathway in determining interstrain differences in ASM Ca2+ was studied. 5-HT produced higher levels of Ins (1,4,5)P3 in Fisher than Lewis ASM. This appeared to be caused by a lower expression and activity in Fisher ASM of the type I and II 5-phosphatases which inactivate Ins (1,4,5)P3. Inhibition of 5-phosphatase activity increased Ins (1,4,5)P3-mediated Ca2+ release in ASM from both strains of rat, equalizing Ca2+ signals between Lewis and Fisher ASM. Since Ins (1,4,5)P3 receptor sensitivity to Ins (1,4,5)P 3 was found to be similar between the two rat strains, the differences in 5-phosphatas
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.35949 |
| Date | January 1998 |
| Creators | Tao, Florence C. Y., 1968- |
| Contributors | Martin, James (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Division of Experimental Medicine.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001650831, proquestno: NQ50267, Theses scanned by UMI/ProQuest. |
Page generated in 0.0058 seconds