The broad objective of these investigations is to establish the molecular, cellular and genetic basis of the acute and chronic granulomatous inflammation induced by the peptidoglycan-polysaccharide polymers isolated from group A streptococcal cell walls (PG-APS). These well-characterized PG-APS polymers are resistant to biodegradation, immunogenic and capable of modulating the immune response. Injection of a susceptible strain of rat with a PG-APS polymer of appropriate size and structure will induce a prolonged, remittent, chronic erosive arthritis which resembles many features of human inflammatory arthritis. This experimental model provides a defined structure upon which to focus study of the etiology of human rheumatoid and reactive arthritides, and an opportunity to examine in vivo the function of a variety of inflammatory mediator in evolving inflammation of joints. The first specific aim is designed to test the capacity of several highly purified cytokine or eicosanoid mediators to cause reactivation of erosive synovitis which has been initiated by PG-APS. Another experimental approach will involve testing the effect of specific inhibitors of cytokines or arachidonic acid metabolites on recurrence of arthritis induced by PG=APS or lipopolysaccharide. The effect of long term administration of nonsteroidal anti-inflammatory agents and steroids on progression of experimental chronic remittent erosive arthritis induced by PG-APS will also be examined. Another specific aim is to characterize an interleukin 1 inhibitor produced by rat macrophages stimulated by PG-APS and to determine its role in regulation of joint inflammation induced by PG-APS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR039480-05
Application #
2079539
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1989-04-30
Project End
1995-03-31
Budget Start
1993-04-01
Budget End
1995-03-31
Support Year
5
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Makarov, S S; Olsen, J C; Johnston, W N et al. (1996) Suppression of experimental arthritis by gene transfer of interleukin 1 receptor antagonist cDNA. Proc Natl Acad Sci U S A 93:402-6
Lichtman, S N; Wang, J; Sartor, R B et al. (1995) Reactivation of arthritis induced by small bowel bacterial overgrowth in rats: role of cytokines, bacteria, and bacterial polymers. Infect Immun 63:2295-301
Lichtman, S N; Wang, J; Schwab, J H et al. (1994) Comparison of peptidoglycan-polysaccharide and lipopolysaccharide stimulation of Kupffer cells to produce tumor necrosis factor and interleukin-1. Hepatology 19:1013-22
Schwab, J H; Brown, R R; Anderle, S K et al. (1993) Superantigen can reactivate bacterial cell wall-induced arthritis. J Immunol 150:4151-9
Schwab, J H (1993) Phlogistic properties of peptidoglycan-polysaccharide polymers from cell walls of pathogenic and normal-flora bacteria which colonize humans. Infect Immun 61:4535-9
Lichtman, S N; Bachmann, S; Munoz, S R et al. (1993) Bacterial cell wall polymers (peptidoglycan-polysaccharide) cause reactivation of arthritis. Infect Immun 61:4645-53
Dieter Geratz, J; Pryzwansky, K B; Schwab, J H et al. (1993) Suppression of local and systemic responses in streptococcal cell wall-induced acute inflammation of the air pouch by cyclosporine A. Comparison with the effects of two anti-inflammatory bis-benzimidazoles. Am J Pathol 142:1227-37
Bristol-Rothstein, L A; Schwab, J H (1992) Bone-resorbing activity is expressed by rat macrophages in response to arthropathic streptococcal cell wall polymers. Inflammation 16:485-96
Lichtman, S N; Okoruwa, E E; Keku, J et al. (1992) Degradation of endogenous bacterial cell wall polymers by the muralytic enzyme mutanolysin prevents hepatobiliary injury in genetically susceptible rats with experimental intestinal bacterial overgrowth. J Clin Invest 90:1313-22
Lichtman, S N; Keku, J; Clark, R L et al. (1991) Biliary tract disease in rats with experimental small bowel bacterial overgrowth. Hepatology 13:766-72

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