Effect of simvastatin on airway inflammation, remodelling and hyperreactivity in a house dust mite challenged murine model of allergic asthma
| dc.contributor.author | Jha, Aruni | |
| dc.contributor.examiningcommittee | Singal, Pawan (Physiology and Pathophysiology) Kroeger, Ed (Physiology and Pathophysiology) Marshall, Aaron (Immunology) Keijzer, Richard (Surgery) Newton, Robert (University of Calgary) | en_US |
| dc.contributor.supervisor | Halayko, Andrew (Physiology and Pathophysiology) | en_US |
| dc.date.accessioned | 2018-02-22T20:53:50Z | |
| dc.date.available | 2018-02-22T20:53:50Z | |
| dc.date.issued | 2018-01 | en_US |
| dc.degree.discipline | Physiology and Pathophysiology | en_US |
| dc.degree.level | Doctor of Philosophy (Ph.D.) | en_US |
| dc.description.abstract | Asthma is a chronic lung disease characterized by airway inflammation, remodelling and hyperresponsiveness. Many patients remain symptomatic despite use of current therapies. Awareness of pleiotropic benefits of statins positions them as a candidate for alternate asthma therapy. Though high dose simvastatin treatment is effective in disease models, this has not been replicated in clinical trials. My project tested the hypothesis that lung-targeted delivery of simvastatin alleviates pathophysiologic hallmarks of allergen-induced ‘asthma’ in mice. Using a clinically relevant murine model of allergic asthma, in Chapter Four, we show that though high-dose systemically delivered simvastatin does not prevent house dust mite (HDM) challenge-induced airway hyperreactivity; it does blunt airway inflammation (immune cell infiltration and cytokine release), and even more so using a prophylactic treatment regime. Notably, Ultra High Performance Liquid Chromatography-tandem Mass Spectrometry (UHPLC-MS/MS) showed that pharmacologically active simvastatin does not accumulate in the lungs. In Chapter Five, we delivered low dose simvastatin by intranasal instillation, and in addition to ablating lung inflammation; it also prevented HDM challenge-induced airway hyperreactivity. This effect was at least equivalent to that for standard fluticasone therapy. To understand the mechanism of action of intranasally instilled simvastatin, in Chapter Six, using HPLC-MS/MS lipidomics we revealed that allergen challenge induces lung accumulation of pro-inflammatory oxidised phosphatidylcholine (OxPCs) in mice as well as in humans. Moreover, intranasally delivered simvastatin concomitantly prevented OxPC accumulation, and allergen challenge-induced lung inflammation and dysfunction. In Chapter Seven, we reveal that intranasally instilled simvastatin can reverse established airway inflammation, goblet cell hyperplasia and hyperreactivity. Our results reveal potential therapeutic benefits of simvastatin to treat human asthma and need for clinical trials to test the effects of inhaled simvastatin delivery. We show that intranasally instilled simvastatin therapy uniquely mitigates the accumulation of lung OxPCs. Oxidative stress is primarily responsible for the generation these bioactive compounds; however, they are controlled by several mechanisms, and our data suggest new asthma therapies that target such pathways may be clinically effective. Our findings also suggest that OxPCs may play a heretofore-unappreciated role in asthma pathogenesis, and they also have a potential for use as biomarkers for asthma sub-phenotypes and disease control. | en_US |
| dc.description.note | May 2018 | en_US |
| dc.identifier.citation | Brit J Pharmacology | en_US |
| dc.identifier.uri | http://hdl.handle.net/1993/32888 | |
| dc.language.iso | eng | en_US |
| dc.publisher | Wiley | en_US |
| dc.rights | open access | en_US |
| dc.subject | Asthma | en_US |
| dc.subject | Inflammation | en_US |
| dc.subject | Lung-function | en_US |
| dc.subject | OxPC | en_US |
| dc.subject | Phospatidylcholine | en_US |
| dc.title | Effect of simvastatin on airway inflammation, remodelling and hyperreactivity in a house dust mite challenged murine model of allergic asthma | en_US |
| dc.type | doctoral thesis | en_US |