Macrophages play an important pathogenic role in immune- mediated glomerulonephritis. These cells are known to be capable of synthesizing a number of biologically active metabolites of arachidonic acid and to be able to influence the proliferation of resident glomerular mesangial cells. Essential fatty acid deficiency (which leads to a lack of arachidonate and an accumulation of the abnormal fatty acid 20:3(n-9)) has been shown to prevent the inflammatory cell infiltrate and glomerular damage in immune-mediated glomerulonephritis. Therefore, the central hypothesis of the proposed project is that arachidonate and its metabolites play a critical role in initiating and perpetuating the injury in glomerulonephritis. To test this hypothesis the changes in glomerular arachidonate metabolism that occur in nephritis will be determined. Immunologic agents (such as nitrogen mustard, radiation, glucan, and endotoxin) will be used to elucidate the relationship between the inflammatory cell infiltrate in nephritis and the observed changes in glomerular arachidonate metabolism. Essential fatty acid deficiency will be utilized to help determine the role of arachidonate and its metabolites in attracting leukocytes into the glomerulus and in the functional deficits of nephritis. The cellular and biochemical mechanisms underlying the changes in glomerular arachidonate metabolism in nephritis will be investigated by determining the effects of macrophages on mesangial cell arachidonate metabolism and proliferation in culture. Pharmacologic manipulations (inhibition of cyclooxygenase of lipoxygenase) will be utilized to establish the role of arachidonate metabolism in the functional deficits of glomerulonephritis. The goal of the proposed study is to develop pharmacologic and/or dietary strategies to prevent the tissue injury and renal dysfunction in glomerulonephritis which avoid the toxicity of present therapeutic modalities. Additionally, understanding the mechamisms by which inflammatory cells interact with resident tissue cells and produce changes in tissue metabolism and function may elucidate the pathogenesis of other inflammatory conditions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK037879-01
Application #
3236873
Study Section
Metabolic Pathology Study Section (MEP)
Project Start
1986-12-15
Project End
1989-11-30
Budget Start
1986-12-15
Budget End
1987-11-30
Support Year
1
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Washington University
Department
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Wu, X; Tiwari, A K; Issekutz, T B et al. (1996) Differing roles of CD18 and VLA-4 in leukocyte migration/activation during anti-GBM nephritis. Kidney Int 50:462-72
Wu, X; Dolecki, G J; Lefkowith, J B (1995) GRO chemokines: a transduction, integration, and amplification mechanism in acute renal inflammation. Am J Physiol 269:F248-56
Scandrett, A L; Kissane, J; Lefkowith, J B (1995) Acute inflammation is the harbinger of glomerulosclerosis in anti-glomerular basement membrane nephritis. Am J Physiol 268:F258-65
Wu, X; Helfrich, M H; Horton, M A et al. (1994) Fibrinogen mediates platelet-polymorphonuclear leukocyte cooperation during immune-complex glomerulonephritis in rats. J Clin Invest 94:928-36
Wu, X; Wittwer, A J; Carr, L S et al. (1994) Cytokine-induced neutrophil chemoattractant mediates neutrophil influx in immune complex glomerulonephritis in rat. J Clin Invest 94:337-44
Wu, X; Pippin, J; Lefkowith, J B (1993) Attenuation of immune-mediated glomerulonephritis with an anti-CD11b monoclonal antibody. Am J Physiol 264:F715-21
Wu, X; Pippin, J; Lefkowith, J B (1993) Platelets and neutrophils are critical to the enhanced glomerular arachidonate metabolism in acute nephrotoxic nephritis in rats. J Clin Invest 91:766-73
Lefkowith, J B; Pippin, J; Nagamatsu, T et al. (1992) Urinary eicosanoids and the assessment of glomerular inflammation. J Am Soc Nephrol 2:1560-7
Porras-Reyes, B H; Schreiner, G F; Lefkowith, J B et al. (1992) Essential fatty acids are not required for wound healing. Prostaglandins Leukot Essent Fatty Acids 45:293-8
Nagamatsu, T; Pippin, J; Schreiner, G F et al. (1992) Paradoxical exacerbation of leukocyte-mediated glomerulonephritis with cyclooxygenase inhibition. Am J Physiol 263:F228-36

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