UBC Theses and Dissertations
Impact of IL-4 receptor inhibition on morbidity related to H1N1 infection in a murine model of allergic asthma Shahangian, Kimeya
The 2009 H1N1 pandemic observed a large percentage of morbidity and mortality attributed to individuals with asthma. However, a consistent lack of preventative and therapeutic interventions failed to protect this vulnerable population. Vaccines are the most effective method of prevention, yet they take at least 6 months to be developed following outbreak of a pandemic strain. Meanwhile, antiviral drugs are the sole method of treatment, yet their clinical use can be restricted due to drug resistance. Hence, pre-planning is required to develop interventions that could protect the vulnerable asthmatic population prior to the occurrence of the next influenza pandemic. A Th2-skewed inflammatory response has been implicated in the development of some of the characteristics of asthma, whereby IL-4, IL-5, and IL-13 signaling promotes airway eosinophilia and lung remodeling. IL-4 and IL-13 signal through the common alpha subunit of the IL-4 receptor (IL-4Rα) to induce their effector function. Clinical trials have found the blockade of IL-4Rα to be highly effective at reducing the rate of asthmatic exacerbations. However, it has yet to be determined whether IL-4Rα blockade could protect against pandemic H1N1 (pH1N1)-mediated morbidity. We hypothesized that IL-4Rα blockade could be used as a treatment method in an established pH1N1 infection, and as a prevention method prior to and after pH1N1 infection, in a murine model of allergic asthma. Our findings indicate that both the treatment and prevention strategies of IL-4Rα blockade induce a significant reduction in pH1N1-mediated weight-loss in house dust-mite (HDM) sensitized mice. Furthermore, reduced weight-loss was associated with a significant reduction in the number of viral copies, indicating improved viral control. Lastly, IL-4Rα preventative intervention induced a significant reduction in the level of airway goblet cell metaplasia and the percentage of eosinophils in Bronchoalveolar Lavage (BAL), pointing to lessened allergic manifestations. While influenza pandemics are rare, they have a devastating effect on the most vulnerable individuals suffering from asthma. Hence, developing pharmaceutical interventions that could benefit this population are of outmost value. Findings from our study could be considered as a strategy to reduce the risk of complications in asthmatic individuals during an H1N1 influenza pandemic.
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