The central hypotheses of this protocol are : a) that surfactant is responsible for development and maintenance of the distinct phenotype of the alveolar macrophage and b) that SP-A and natural surfactants containing higher than normal amounts of SP-A relative to phospholipid can alter macrophage phenotype and promote the development of an inflammatory response.The proinflammatory phenotype includes the production and secretion of proinflammatory cytokines and the expression of cell surface molecules that prime the macrophage making it more response to activating stimuli and capable of stimulating other immune cells and initiating an inflammatory reaction. Using the human monocyte cell line, THP-1, human alveolarmacrophages and human peripheral blood monocytes, we will investigate these hypotheses with the following specific aims:
Specific aim 1 : To define the effects of surfactant components on the expression of THP-1 cell and monocyte surface markers related to macrophage differentiation and activation (CD14, ICAM-1, CD11b, et al).
Specific aim 2 : To study the effects of long term surfactant exposure and short term changes in surfactant composition on production of proinflammatory cytokines (TNF-(, IL-1(, IL-6 and IL-8) by monocytes and THP-1 cells both basally and in response to LPS treatment.
Specific aim 3 : To identify the molecules on the surface of THP-1 cells and macrophages that serve as ligands for SP-A, the conditions needed for SP-A binging to occur, the structural features of SP-A in the binding, and the impact of blocking binding to a specific surface molecule on other SP-A actions. The human studies component of this protocol will involve selected experiments with either peripheral blood cells or alveolar macrophages obtained by bronchial lavage. The object of these experiments is to confirm that the responses we are obtaining with the in vitro studies resemble the responses of actual immune cells. The volunteers are being used as a source of normal cells.
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