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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL032024-04
Application #
3343221
Study Section
Pathology A Study Section (PTHA)
Project Start
1985-07-01
Project End
1990-06-30
Budget Start
1988-07-01
Budget End
1989-06-30
Support Year
4
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Peters-Golden, M; McNish, R W; Brieland, J K et al. (1990) Diminished protein kinase C-activated arachidonate metabolism accompanies rat macrophage differentiation in the lung. J Immunol 144:4320-6
Crockett-Torabi, E; Fantone, J C (1990) Soluble and insoluble immune complexes activate human neutrophil NADPH oxidase by distinct Fc gamma receptor-specific mechanisms. J Immunol 145:3026-32
Simpson, P J; Todd 3rd, R F; Mickelson, J K et al. (1990) Sustained limitation of myocardial reperfusion injury by a monoclonal antibody that alters leukocyte function. Circulation 81:226-37
Vissers, M C; Fantone, J C; Wiggins, R et al. (1989) Glomerular basement membrane-containing immune complexes stimulate tumor necrosis factor and interleukin-1 production by human monocytes. Am J Pathol 134:1-6
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Brieland, J K; Vissers, M C; Phan, S H et al. (1989) Human platelets mediate iron release from transferrin by adenine nucleotide-dependent and -independent mechanisms. Biochim Biophys Acta 978:191-6
Vissers, M C; Wiggins, R; Fantone, J C (1989) Comparative ability of human monocytes and neutrophils to degrade glomerular basement membrane in vitro. Lab Invest 60:831-8
Lucchesi, B R; Werns, S W; Fantone, J C (1989) The role of the neutrophil and free radicals in ischemic myocardial injury. J Mol Cell Cardiol 21:1241-51
Fantone, J; Jester, S; Loomis, T (1989) Metmyoglobin promotes arachidonic acid peroxidation at acid pH. J Biol Chem 264:9408-11

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