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|Factors associated with mouse strain-dependent susceptibility to pathology in models of allergic asthma.
|Tumes, Damon John
|School of Molecular and Biomedical Science : Microbiology and Immunology
|Although exposed to similar environmental stimuli, not all humans develop asthma. Similarly, mouse strains vary in the degree of pathophysiology seen following induction of experimental asthma. A model involving immunization and aerosol challenge with ovalbumin (OVA) was used to investigate factors that may confer strain-dependent resistance or susceptibility to pathology. BALB/c and C57BL/6 mice developed many features of human asthma including inflammation, mucus production and airway obstruction. In contrast, CBA/Ca mice were relatively resistant to development of disease. This was despite the presence of a robust systemic allergic response, as indicated by high levels of OVA-specific and total immunoglobulin and increases in circulating eosinophils comparable to those in BALB/c and C57BL/6 mice. In interleukin (IL)-5 transgenic (Tg) mice the strain specific susceptibility to lung mucus production and airway obstruction was maintained and pathology was greatly accentuated in C57BL/6 and BALB/c but not in CBA/Ca mice. Eosinophils recovered by bronchoalveolar lavage (BAL) from wt and IL-5 Tg CBA/Ca mice lost viability faster than BAL eosinophils from the other two strains and this phenomenon was lung-specific. This may result in less eosinophil accumulation in the lungs of CBA/Ca mice and resistance to asthma-like pathology. Fl hybrids of CBA/Ca mice crossed with either BALB/c or C57BL/6 mice had BAL leukocyte, eosinophil lifespan and cell-free protein profiles similar to those of the respective disease-susceptible parental strains. It is likely that eosinophil apoptosis was not mediated through the extrinsic or receptor mediated pathway. Bcl-2 and Bcl-xL, which both inhibit the intrinsic pathway of apoptosis were highest in BAL eosinophils from the BALB/c strain and this correlated with relatively high IL-5 levels in the lungs. Survivin inhibits apoptosis and expression was significantly higher in BALB/c and C57BL/6 BAL eosinophils than in cells from CBA/Ca mice. This suggests a possible mechanism whereby eosinophils from the asthma-susceptible C57BL/6 and BALB/c mice are more resistant to apoptosis and may account, in part, for the more extensive pathology in these strains. Using global gene expression analysis we identified groups of genes that were differentially regulated in the lungs of mice that are susceptible or resistant to development of asthma-like pathology. 242, 145 and 42 genes were differentially regulated in the lungs of the C57BL/6, BALB/C and CBA/Ca strains respectively. In C57BL/6 mice, transcripts were significantly enriched for adhesion molecules and we postulate that heightened expression of L-selectin, CD 18, PGSL-1 and LPAM-l on lung eosinophils is responsible for robust recruitment and therefore accumulation of these cells in C57BL/6 mice. 64 genes were differentially regulated only in the asthma-susceptible strains, several of which have not previously been associated witb asthma. The late expression of Chi313, Retnla and Mmp12 correlated with increased expression of IL-10 in the lungs and we hypothesise that this cytokine may be produced by alternatively activated macrophages as part of the resolution of disease. This study identifies several novel genes and mechanisms associated with the modulation of airway inflammation and pathology. The identification of factors that control allergic inflammation may provide novel therapeutic targets for disease intervention.
|Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2009
|asthma; eosinophil; apoptosis; microarray
|Copyright material removed from digital thesis. See print copy in University of Adelaide Library for full text.
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