Date of Award

2010

Document Type

Campus Access Thesis

Department

Environmental Health Sciences

First Advisor

Tara L. Sabo-Attwood

Abstract

Chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are chronic progressive lung diseases with rising mortality rates in the United States. Epidemiological studies have revealed gender specific trends in the prevalence and mortality of these diseases such that more males are afflicted with IPF whereas. the burden of COPD is higher in females. These observations suggest the cellular and molecular mechanisms driving the development and severity of COPD and IPF are not entirely conserved between sexes. Modulated expression of a number of genes related to immune regulation and extracellular matrix remodeling, important events involved in IPF and COPD, have been measured in lung cells and tissues however limited investigations have probed the expression of genes related to steroid hormone signaling between men and women. We hypothesize that the expression of steroid receptors and metabolizing enzymes will differ by gender and disease. To elucidate immune and extracellular matrix remodeling (ECM)- and hormonally-related genes that are differentially expressed by gender in human control and diseased lung tissues we employed custom designed gene arrays to measure the transcriptional expression of 48 genes (39 immune and ECM relevant genes and 9 sex-related genes) simultaneously by quantitative real-time PCR (qRT-PCR) methodology.

Gene profiles were generated for 36 lung tissue samples obtained from control individuals and males and females diagnosed with mild COPD and mild and medium severity IPF based on percent forced vital capacity (%FVC). Results reveal a number of genes that show trends of differential expression between gender and disease type and severity. Four immune-related genes, seven matrix-related genes, and six sex-related genes displayed interesting gender and disease specific trends. Interestingly estrogen receptors, including both nuclear forms (ESR1 and ESR2) and the membrane bound G protein-coupled estrogen receptor 1 (GPER), exhibited interesting expression patterns between disease and sex. ESR1 expression was stable across the control and mild COPD groups in both males and females, but expression increased with increased severity of IPF in females and decreased in medium IPF males. ESR2 expression decreased in female COPD relative to control expression and also decreased in male COPD and IPF relative to control expression. GPER expression was slightly augmented in female IPF patients. Male GPER expression was stable across control, mild COPD, and medium IPF, but was increased in mild IPF. These results expose, for the first time, the differential expression of hormone receptors and steroid metabolizing enzymes among human control and diseased lung tissue as well as altered expression between males and females. Furthermore, this study elucidates expression patterns of several immune/matrix-remodeling genes that are distinct to disease and sex that sex-related genes may regulate in order to affect disease development and progression.

Overall, this work increases our understanding of the mechanisms and role of gender in lung disease. Our findings may aid in the development of future therapeutics as well as enhance our understanding of potential risk factors and predispositions for obstructive and restrictive lung diseases.

Rights

© 2010, Sean Patrick McGee

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