[Truncated abstract] Asthma affects millions of people worldwide and places a substantial burden on the healthcare system. Despite advances in our understanding of disease mechanisms and the role of respiratory viruses in asthma exacerbations, there is little known regarding the role of the epithelium in commonly observed structural changes in the airway wall. The epithelium of the airways provides an essential protective barrier between the environment and underlying structures and is responsible for the secretion of diverse compounds. Since it is likely that dysregulated epithelial characteristics and function in childhood asthma are critical determinants of disease progression in adults, it is pertinent to investigate the cellular mechanisms involved in paediatric asthma. However, full comprehension of paediatric respiratory diseases and the childhood antecedents of adult respiratory disease are currently hampered by the difficulty in obtaining relevant target organ tissue and most of the data to date have been generated from studies involving adults or commercially derived cell lines. This laboratory has successfully developed methodologies of obtaining and studying samples of paediatric primary airway epithelial cells (pAECs) and has identified significant biochemical and functional differences between healthy non-atopic (pAECHNA) and atopic asthmatic (pAECAA) airway cells, which have assisted in the identification of potential mechanisms responsible for abnormal epithelial function. Stevens 2009 ... Exposure of pAECs with RV resulted in elevated PAI-1 mRNA expression and reduced MMP-9 release in both pAECAA and pAECHNA samples. Collectively, the data presented indicate that RV exposure induces a pronounced antiproliferative and retardative repair effect in pAECAA and that the presence of virus may have a role in the PAI-1 and MMP expression witnessed in these cells. In conclusion, this investigation has further characterised the essential role the airway epithelium plays in childhood asthma by demonstrating for the first time that pAECs from asthmatic children lack the ability to successfully repair mechanically induced wounds. This investigation also showed that PAI-1 is elevated in pAECAA and has a functional role in the pAEC proliferative and regenerative processes. It was demonstrated that MMP-2 and MMP-9 activities and the MMP-9/TIMP-1 as well as MMP2/TIMP2 ratios were significantly reduced in pAECAA thereby providing additional evidence that there is a dysregulation in the mechanisms that monitor the turnover of the ECM in childhood asthma. Furthermore, this study has shown for the first time that pAECs from untreated mild atopic-asthmatic children are more sensitive to the pathogenic effects of RV than healthy control cells and that RV exposure delays cellular proliferation and repair. Ultimately, these findings support the hypothesis postulated and provide evidence that indeed the dysregulated epithelial functional characteristics seen in childhood mild asthma may be a critical determinant of disease progression in adults.
| Identifer | oai:union.ndltd.org:ADTP/279684 |
| Date | January 2009 |
| Creators | Stevens, Paul |
| Publisher | University of Western Australia. School of Paediatrics and Child Health |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | Copyright Paul Stevens, http://www.itpo.uwa.edu.au/UWA-Computer-And-Software-Use-Regulations.html |
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