Mononuclear phagocytes play a central role in the orchestration of pulmonary inflammation. Mechanisms responsible for monocyte migration into the lung have been described, however little is known regarding the fate of these cells. The overall objectives of this project are to determine the fate of mononuclear phagocytes in the lung under normal conditions and during acute and chronic inflammatory states in the lung, and then to determine mechanisms which expedite or prolong the duration of residence of these cells in the lung. We hypothesize that a prolonged sojourn of macrophages in the lung under the proper set of conditions may promote fibrogenesis or granuloma formation. Delineation of mechanisms governing the fate of these cells will help us understand why certain inflammatory insults lead to an orderly progression of events which culminate in complete resolution and repair of lung tissue and why other insults lead to an endpoint of fibrosis or granuloma. In conjunction with project 5 we have also hypothesized that the differential expression of distinct macrophage phenotypes under certain conditions in the lung may regulate tissue debridement (""""""""degradative"""""""" phenotype) leading to the resolution of inflammation and normalization of tissue, or in other circumstances regulate tissue repair (""""""""reparative"""""""" phenotype) and fibrogenesis. We will determine whether these macrophage phenotypes are expressed in the lung under normal conditions or during acute self-limited and chronic inflammatory processes. We hypothesize that the """"""""reparative"""""""" phenotype will predominate during inflammatory conditions which lead to the development of fibrosis (bleomycin/oxygen-induced lung inflammation), and that the """"""""degradative"""""""" phenotype will predominate in acute self-limited inflammation (C5a-induced lung inflammation). We will examine the plasticity of these phenotypes in vivo and determine the pathways and mechanisms regulating their fate in the lung during inflammation. These studies, which utilize a combination of methods, will allow us to ask two important questions: What is the time course and plasticity of mononuclear phagocyte phenotypic differentiation in the lung during self-limited and chronic inflammatory states and how do these relate to the development of fibrosis. We feel that results from the studies proposed in this project in conjunction with information obtained from other projects of this SCOR will ultimately guide us in developing new strategies for the treatment of interstitial lung disease.
Showing the most recent 10 out of 220 publications
