The purpose of this study is to describe the role of the alveolar macrophage in the etiology of lung inflammation and fibrosis. Another goal of the study is to describe the molecular changes in the signal transduction pathways of the alveolar macrophage in response to environmental toxins. This study involves characterization of alveolar macrophages from subjects with lung disease and in vitro studies with macrophages from healthy volunteers. During the past year we have completed studies that have described the induction of apoptosis of human alveolar macrophages by a variety of inflammatory agents including asbestos, silica, respirable particulate matter, acrolein, ozone as well as bleomycin. In addition, the particulates caused a shift in alveolar macrophage phenotype to a higher immune active:immune suppressor ratio. Alveolar macrophages from patients with lung fibrosis demonstrate a similar immune active:immune suppressor ratio. These findings support our hypothesis that apoptosis of suppressor macrophages is an early step in the development of chronic lung inflammation and fibrosis that leads to activation of T helper cells and the immune system cascade in the lung. Future studies are planned to confirm that the immune suppressor population is most sensitive to apoptosis and determine the mechanism of apoptosis in this population and why it is more sensitive to apoptosis than the immune active population. In addition, we will confirm that apoptosis of the suppressor population leads to a more active immune system and determine whether activation of the Th1 or Th2 pathway is involved in chronic disease. The final goal of these studies is the development of new treatment strategies of lung inflammation based on a better knowledge of the important regulatory steps in the disease etiology.
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