Hyperresponsiveness & airways inflammation in experimental models of asthma

• Main Author: Fernandez-Rodriguez, Sofia
• Published: Cardiff University 2005
• Subjects: 616.2
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.583630

The aim of this thesis was to obtain a mouse model of asthma to increase understanding of asthma pathogenesis and to investigate the mechanisms leading to gender differences. For this purpose, in vivo models of allergic asthma were developed and characterised in male and female mice to address both the acute and chronic conditions of the asthmatic airways. Male and female BALB/c mice were sensitised and challenged with the allergen, ovalbumin OVA, following acute and chronic protocols. The novel murine asthmatic models were characterised by the investigation of airway inflammation, airway hyperresponsiveness AHR, antibody production, eosinophil degranulation, plasma protein extravasation and production of nitric oxide and biogenic amines. OVA-treated mice were found to reproduce some of the important hallmarks of human asthma 24 and 72 hours after allergen challenge including infiltration of eosinophils and lymphocytes only in the chronic model , high serum levels of total IgE and OVA-specific IgG and evidence of plasma protein extravasation. Some other hallmarks, such as AHR, eosinophil degranulation and nitric oxide production could not be demonstrated, but their absence in the novel murine models cannot yet be confirmed for certain and alternative techniques were suggested for their determination. In addition, the novel chronic model exhibited gender differences which reflect the human situation where adult women are more susceptible to asthma than men, and could be used to investigate the role of sex hormones in asthma and their potential use as anti-asthma therapies. Mice have advantages over other species because their immune system is well characterized and knockout and transgenic mice are available. The acute murine model will be useful for investigation of the inflammatory and functional changes associated with the first few days of the asthma process. In contrast, the chronic model will be employed for investigation of airway wall remodelling and subsequent respiratory alterations.