| Chronic obstructive pulmonary disease (COPD) is a disease state characterized by airflow obstruction that is not fully reversible. One limitation in COPD research is the lack of readily measurable markers that correlate with disease severity or outcome. Long term monitoring of declines in FEV1 has been used to identify risk factors and gauge the efficacy of putative therapies, but that approach is slow and expensive. Validated surrogate markers of COPD are needed to serve as intermediate endpoints for evaluations of efficacy and appropriate dosage of potential therapeutic agents in relatively short-term studies. Also, identification of genes that predispose to the development of COPD could lead to discovery of novel therapeutic targets. The overall goal of this dissertation research is to contribute to the body of knowledge concerning the inflammatory and immune events associated with the pathogenesis of COPD and to identify the susceptibility and severity markers of COPD.; We used two parallel approaches in our study. In the first approach, we identified the molecular mediators of inflammation involved in the pathogenesis of COPD from two body fluid compartments, BAL and peripheral blood using microarray analysis. In the second approach, we investigated the polymorphisms in the candidate genes, which may have relevance for susceptibility to and pathogenesis of COPD. To identify new COPD susceptibility genes, we investigated the association of CXCR2 polymorphisms at positions 785, 1208 and 1440, and beta-2 adrenergic receptor (ADRB2) polymorphisms at amino acid positions 16 and 27, with the susceptibility and severity of airflow limitation.; Transcripts encoding for apoptosis, cell communication, adhesion and cytoskeleton, signal transcription, growth factor and oxidative stress were differentially expressed in BAL and blood of subjects with COPD compared to subjects with non-inflammatory disease.; We observed an excess heterozygosity of all three polymorphisms in cases, compared to controls. Also, a significant association between the CXCR2 polymorphisms and the severity of airflow limitation was observed.; We observed that the ADRB2 genotype polymorphism at amino acid position 27 was significantly associated with the susceptibility of developing airflow limitation. Also, a significant association between the Glu27 ADRB2 polymorphism and the severity of airflow limitation was observed. |
