The primary function of airway smooth muscle is to contract, regulating the airway tone and bronchial narrowing. Research extending over a number of decades has identified many of the major factors contributing to the degree of bronchial contraction at a cellular level including receptor mediated activation of airway smooth muscle by agonists, electrical and other membrane events, intracellular cascades and assembly of contractile and cytoskeletal proteins. Furthermore, airways function is also regulated by a number of key airway, lung and teleological events that collectively determine the bronchial tone. Therefore, the aim of this thesis was to investigate a number of factors influencing directly and indirectly the responsiveness of human bronchi. The tone of human bronchi was studied in isolated organ bath systems in both normal tissues and passively sensitized bronchi, a model that mimics some aspects of the airway wall of patients with allergic airways disease, since it is very difficult to obtain bronchi from such people. Furthermore, immunohistochemistry and PCR were carried out in bronchial tissues whilst immunoenzymatic assays were performed in cultured bronchial smooth muscle cells. A range of studies were carried out in order to investigate factors influencing bronchial responsiveness, including the pharmacological characterization of adenosine receptors, the effects of brain natriuretic peptide, the influence of lipopolysaccharide, the role of hyperglycemia, the activity of vasoactive intestinal peptide receptors and the influence of phosphodiesterase 3/4 enzymes and their interaction with both sympathetic (β2 mediated) and parasympathetic pathways. This study provides evidence for the role of adenosine AI receptor in causing human airway smooth muscle contraction, both directly, and indirectly following the activation of capsaicin sensitive sensory nerves, and the release of leukotrienes. Evidence is also provided for the relaxant effect of brain natriuretic peptide mainly regulated by the autocrine activity of epithelial cells. Furthermore, the contribution of neutral endopeptidases, capsaicin-sensitive sensory nerves, the mevalonate pathway and the protective influence of statins against lipopolysaccharide induced airway hyperresponsiveness has been demonstrated. Other results have shown that high glucose concentrations leads to an enhanced responsiveness of human airway smooth muscle, and that the Rho/ROCK pathway may play a crucial role for reducing lung function in hyperglycemic conditions. Finally, findings concerning the bronchial relaxation mediated by the selective activation of vasoactive intestinal peptide receptor 2 and the synergism of phosphodiesterase 3/4 inhibitors in association with antimuscarinics and β2-agonist drugs suggest new paradigms for treating obstructive lung diseases. Results presented in this thesis provide strong evidence of several novel pharmacological approaches to influence human airway smooth muscle tone.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:628176 |
| Date | January 2012 |
| Creators | Calzetta, Luigino |
| Publisher | King's College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://kclpure.kcl.ac.uk/portal/en/theses/factors-influencing-the-responsiveness-of-human-bronchi(d5f898eb-1800-478a-8588-561acbabb102).html |
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