T Cell Inflammation and Mucin Hypersecretion in COPD
Location(s): United States
The mechanisms of mucus hypersecretion in COPD are poorly understood, even though sputum production is associated with an accelerated rate of decline in FEV1 and with increased mortality from COPD. In addition, the reasons why only a minority of cigarette smokers develop COPD is unknown. To date, clinical research in COPD has been significantly hampered by problems in measuring outcome indicators related to mucus hypersecretion. We hypothesize that smokers with COPD have a T cell phenotype characterized by predominance of CD4+ T cells of the subtype which contributes to overexpression of mucin genes, increased numbers of goblet cells, and increased levels of both stored and secreted mucin. In addition, we hypothesize that the airway phenotype in smokers without COPD will not be normal but will be intermediate to that observed in healthy subjects and smokers with COPD. Finally, we hypothesize that treatment of smokers with COPD with inhaled corticosteroids will decrease lymphocytic inflammation, mucin gene expression, and the levels of stored and secreted mucin. We propose to test our hypotheses in three groups of human subjects smokers with COPD, smokers without COPD and healthy non smoking controls. We will apply methods recently developed in our laboratory for measuring mucin gene expression, goblet cell hyperplasia and secreted mucin levels as well as methods we have adopted from others for purifying and phenotyping airway T cells. Aim 1 will determine the phenotype of the airway mucosa in smokers with COPD compared to smokers without COPD and non smoking controls with emphasis on the numbers and subtypes of T lymphocytes, the numbers of goblet cells, and the relationship between stored and secreted mucin glycoproteins. Aim 2 will determine which of the nine currently identified mucin genes are overexpressed in smokers with and without COPD. Aim 3 will determine in inhaled corticosteroid treatment in smokers with COPD is associated with a reduction in lymphocyte number, mucin gene expression, goblet cell number, or in the levels of stored and secreted mucin. The proposed studies address an unmet need, because no clinical studies have been published focusing on T cell subtypes, mucin genes, and goblet cells in human COPD. The application of the methods described here provide the opportunity to begin to understand the relationship between lymphocytic inflammation and mucin gene expression in COPD, and may suggest strategies for improving treatment.