Cockroach allergen induced asthma: Pulmonary mechanics, inflammation and tolerance

Asthma is one of the most common chronic health conditions in the developed world. However, the mechanisms of this insidious disease remain poorly characterized. Animal models of allergic pulmonary inflammation can offer valuable insights into the management of human disease. Urban environments contain potent respiratory allergens and a greater incidence of new asthma diagnosis, especially in children. One particularly common urban antigen is the German cockroach allergen (CRA). The lab of Daniel G. Remick developed a model of CRA induced pulmonary inflammation in inbred BALB/c mice which closely resembles the human disease. In the current research the model was established and validated in outbred HSD-ICR mice. Outbred animals were chosen because of their genetically heterogeneous background which more closely mimics the human population. Outbred ICR mice were found to display roughly equivalent overall variability to BALB/c mice in a model of CRA induced asthma. Using equivalent overall variability to BALB/c mice in a model of CRA induced asthma. Using this model treatment with dexamethasone ameliorated respiratory distress and improved pulmonary function. The lung inflammatory response of the outbred mice was characterized at a series of early (1.5, 4, 12 hours) and late timepoints (24, 48 hours) following final allergen challenge. It was found that the airways hyperreactivity (AHR) of the experimental mice displayed a biphasic pattern. The early peak in AHR was determined to be potentiated partially by immune cell action and partially by the action of leukotrienes. The late peak of the AHR response, in contrast, was mainly dependent on cellular components of the allergic response. Finally, the establishment of oral tolerance to CRA as a method for improving lung inflammation and AHR was investigated. It was found that gastric exposure to CRA prior to CRA immunization and challenge led to significant decreases in AHR, bronchoalveolar lavage eosinophil levels and lung homogenate eosinophil specific peroxidase activity. In conclusion these studies greatly extended, characterized and induced tolerance in a highly reproducible model of CRA induced asthma in outbred mice.