This research proposal is focused on determining the potential anti-inflammatory role of prostaglandins (PGs) (especially PGI2 and PGEs) in modulating neutrophil dependent inflammatory reactions in the lung. The effects of systemic treatment rats with PGs on immune complex (IC) induced lung injury using a Reverse Passive Arthus reaction model will be determined and correlated with changes in PGI2, PGE2, TxA2, and PGF2Alpha levels in bronchoalveolar lavage fluids and plasma. Lung injury will be assessed using morphologic and morphometric techniques and the extravasation of a radiolabeled protein marker from the intravascular compartment into the lung parenchyma. After determining the effects of PGs on immune complex induced lung injury in vivo, we will examine the ability of neutrophils isolated from IC lung lavage, rat peritoneal cavity, and peripheral circulation for their ability to produce superoxide anion (O-2) and secrete lysosomal enzymes in the presence and absence of PGs. In addition we will systematically determine the in vitro effects of PGEs and PGI2 on the different metabolic responses associated with stimulus response coupling in rat neutrophil. Similar studies will be performed on rat neutrophils isolated from IC lung lavage fluids from animals treated with PGEs and PGI2 in vivo and compared to cells from non-PG-treated control. Since the anti-inflammatory effects of PGEs and PGI2 have been associated with their ability to increase intracellular cyclic AMP levels we will also examine the effects of other pharmacologic agents that increase intracellular cyclic AMP levels and inhibitors of adenylate cyclase in the presence of PGEs, PGI2 and dibuturyl cAMP on the different metabolic responses involved in stimulus-response coupling in the neutrophil. The sequence of events that follow ligand receptor binding in the neutrophil membrane is complex, however, we feel the data derived from this proposed study will increase our understanding of the mechanisms by which prostaglandins modulate the inflammatory response associated with immune complex induced lung injury and neutrophil function, as well as provide insight into possible strategies for therapeutic modulation of neutrophil dependent inflammatory responses in the lung.
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