Airway hyperresponsiveness (AHR) is a cardinal feature of asthma that is aggravated by environmental air pollution (EAP). Splenocyte tyrosine kinase Syk has been associated with asthma pathogenesis. Therefore, we sought to investigate the effect of Syk inhibition on AHR and its exacerbation by EAP. For this purpose, we examined Syk protein expression in lung homogenates from three murine models of ovalbumin (OVA)-induced asthma expressing different pathophysiological features of the disease: airway inflammation, AHR and remodeling. Increased Syk expression was observed only in the chronic model of airway inflammation and remodeling. In vivo Syk inhibition attenuates AHR in this model, and further augmentation induced by EAP without affecting the underlying airway inflammation. We demonstrated, for the first time, that Syk inhibition effectively reverted AHR in an already established chronic model of asthma. These findings highlight the therapeutic potential of targeting Syk for the treatment of asthma and its exacerbations by EAP.

Airway hyperresponsiveness (AHR) is a cardinal feature of asthma that is aggravated by environmental air pollution (EAP). Splenocyte tyrosine kinase Syk has been associated with asthma pathogenesis. Therefore, we sought to investigate the effect of Syk inhibition on AHR and its exacerbation by EAP. For this purpose, we examined Syk protein expression in lung homogenates from three murine models of ovalbumin (OVA)-induced asthma expressing different pathophysiological features of the disease: airway inflammation, AHR and remodeling. Increased Syk expression was observed only in the chronic model of airway inflammation and remodeling. In vivo Syk inhibition attenuates AHR in this model, and further augmentation induced by EAP without affecting the underlying airway inflammation. We demonstrated, for the first time, that Syk inhibition effectively reverted AHR in an already established chronic model of asthma. These findings highlight the therapeutic potential of targeting Syk for the treatment of asthma and its exacerbations by EAP.

Asthma is a chronic respiratory disease with a high prevalence in Western countries, including Canada, and increased exacerbations have been associated with ambient air pollution. The maintenance of airways tone is critically dependent on the endogenous bronchodilator, nitric oxide (NO). The nitric oxide synthase (NOS) isoenzymes produce NO from the amino acid, L-arginine, and competition for substrate with the arginase isoenzymes can limit NO production. Imbalances between these pathways have been implicated in the airways hyperresponsiveness (AHR) of asthma. The overall objective of this work was to determine whether arginase and downstream polyamine metabolites are functionally involved in airways responsiveness in animal models of asthma and the adverse responses of allergic animals to air pollution. To this purpose, the expression profiles of proteins involved in L-arginine metabolism were determined in lung tissues from human asthmatics and murine models of ovalbumin (OVA)-induced airways inflammation. Expression of arginase 1 was increased in human asthma and animal models. Competitive inhibition of arginase attenuated AHR in vivo. The roles of the downstream metabolites of arginase, the polyamines (putrescine, spermidine and spermine) were examined by administering them via inhalation to anaesthetized mice. It was demonstrated that spermine increases methacholine responsiveness in normal and allergic mice. Additionally, inhibition of polyamine synthesis improved AHR in a murine model. Thus, arginase and downstream polyamine metabolites contribute to AHR in asthma. Finally, the potential role of arginase in the exacerbation of asthma by air pollution was investigated. For this purpose, murine sub-acute and chronic murine models of allergic airways inflammation were employed, which exhibit inflammatory cell influx and remodeling/AHR, respectively, to determine the role of arginase in the response to concentrated ambient fine particles plus ozone. Allergic mice that were exposed to air pollution exhibited increased arginase activity and expression, compared to filtered air-exposed controls. Furthermore, inhibition of arginase attenuated the air pollution-induced AHR. Thus, the studies of the arginase pathway and downstream metabolites described in this thesis indicate that arginase inhibition may be a therapeutic target in asthma and may also protect susceptible populations against the adverse health effects of air pollution.

Asthma is a chronic respiratory disease with a high prevalence in Western countries, including Canada, and increased exacerbations have been associated with ambient air pollution. The maintenance of airways tone is critically dependent on the endogenous bronchodilator, nitric oxide (NO). The nitric oxide synthase (NOS) isoenzymes produce NO from the amino acid, L-arginine, and competition for substrate with the arginase isoenzymes can limit NO production. Imbalances between these pathways have been implicated in the airways hyperresponsiveness (AHR) of asthma. The overall objective of this work was to determine whether arginase and downstream polyamine metabolites are functionally involved in airways responsiveness in animal models of asthma and the adverse responses of allergic animals to air pollution. To this purpose, the expression profiles of proteins involved in L-arginine metabolism were determined in lung tissues from human asthmatics and murine models of ovalbumin (OVA)-induced airways inflammation. Expression of arginase 1 was increased in human asthma and animal models. Competitive inhibition of arginase attenuated AHR in vivo. The roles of the downstream metabolites of arginase, the polyamines (putrescine, spermidine and spermine) were examined by administering them via inhalation to anaesthetized mice. It was demonstrated that spermine increases methacholine responsiveness in normal and allergic mice. Additionally, inhibition of polyamine synthesis improved AHR in a murine model. Thus, arginase and downstream polyamine metabolites contribute to AHR in asthma. Finally, the potential role of arginase in the exacerbation of asthma by air pollution was investigated. For this purpose, murine sub-acute and chronic murine models of allergic airways inflammation were employed, which exhibit inflammatory cell influx and remodeling/AHR, respectively, to determine the role of arginase in the response to concentrated ambient fine particles plus ozone. Allergic mice that were exposed to air pollution exhibited increased arginase activity and expression, compared to filtered air-exposed controls. Furthermore, inhibition of arginase attenuated the air pollution-induced AHR. Thus, the studies of the arginase pathway and downstream metabolites described in this thesis indicate that arginase inhibition may be a therapeutic target in asthma and may also protect susceptible populations against the adverse health effects of air pollution.