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Genetic determinants of neutrophil mediator mobilization and release and susceptibility to COPD

University of British Columbia

Polymorphonuclear leukocytes (PMNs) are believed to be one of the major effector cells in the chronic airway inflammation that is present in chronic obstructive pulmonary disease (COPD). Unrestrained serine protease activity in general and elastase specifically, are currently believed to play a crucial role in the pathogenesis of emphysema. CD63, Hck, and β-arrestins are important molecules in the process of azurophilic granule exocytosis. My thesis work mainly focused on defining the influence of genetic polymorphisms on gene expression and PMN function in healthy individuals and COPD patients. We hypothesized that functional polymorphisms of the CD63 gene, the Hck gene, and the β-arrestin 2 gene change the expression or function of these molecules, and as a consequence, they alter the release of azurophilic granule mediators, modulate the proteolytic activity and tissue injury and influence susceptibility to COPD or COPD related phenotypes. A number of putative genetic polymorphisms of the three genes have been validated, and their linkage disequilibrium maps have been estimated in Asians and Caucasians. Novel polymorphisms of the Hck gene (8,656L/S) and β-arrestin 2 gene (-159C/T) were discovered respectively. The 8,656L/S polymorphism was associated with the differential expression of the Hck protein and PMN MPO release upon IL-8 stimulation. It was also associated with different bronchodilator response in the COPD patients in the Lung Health Study cohort. The -159C/T polymorphism was associated with differential expression of β-arrestin 2 mRNA. A reporter gene assay demonstrated that the different alleles of the -159C/T polymorphism had different luciferase activity. The 3 detected polymorphisms in the CD63 gene were not associated with CD63 gene expression, whereas the polymorphism which was ~4kb downstream of the CD63 gene was associated with MPO release. In summary, this project offered key insight into the influence of genetic polymorphisms of the CD63 gene, the Hck gene, and the β-arrestin 2 gene on gene expression and azurophilic granule degranulation and this may improve our understanding of COPD pathogenesis and provide therapeutic guidance for COPD treatment.

Text

2010-01-16

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http://hdl.handle.net/2429/18228

Experimental Medicine

University of British Columbia

UBCV

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