Reactive airways dysfunction syndrome (RADS), a form of irritant-induced asthma (IIA) has been observed in humans following acute chlorine (Cl 2) gas exposure in occupational and domestic settings. Following Cl 2 injury, subepithelial fibrosis, mucous hyperplasia, and non-specific airway hyperresponsiveness have been reported. Based on the disease profile, we hypothesized that pulmonary damage may be oxidative in nature. / The aim of this work was to develop a murine model of irritant-induced asthma in order to investigate the pathogenic processes and potential oxidative mechanisms involved in response to Cl2 exposure, with a secondary aim of examining the role of iNOS in response to Cl2 inhalation. / A/J, C57BI/6J (wild type) and iNOS-1- mice exposed to various concentrations of Cl2 were mechanically ventilated for measurement of lung mechanics and responses to i.v. methacholine (MCh). Bronchoalveolar lavage was performed to examine total protein, cell populations and nitrate/nitrates. Tissues were harvested for histology and immunocytochemistry for iNOS, 3NT and carbonyl residues. To examine the role of iNOS, a subset of animals were treated with a selective iNOS inhibitor (1400W) and non-selective NOS inhibitor LNAME. / Chlorine exposure caused airway hyperresponsiveness, which appeared to be mitigated by iNOS blockade with 1400W, however this was not the case in iNOS-1- mice. Cl2 exposure also caused increases in total BAL protein, total cells, NOx, neutrophils, iNOS, 3NT and carbonyl residues. / In conclusion, chlorine exposure causes lung injury, similar to reactive airways dysfunction syndrome, characterized by airway hyperresponsiveness, epithelial sloughing, inflammatory cell influx, oxidative injury and increases in both the activity and expression of iNOS. Chlorine-induced airway hyperresponsiveness is mitigated, in part, by selective blockade of iNOS with the use of pharmacological intervention.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.111574 |
| Date | January 2009 |
| Creators | Campbell, Holly R., 1976- |
| 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 | Master of Science (Department of Pathology.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 003163963, proquestno: AAIMR66876, Theses scanned by UMI/ProQuest. |
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