Old age is accompanied by changes in the capacity and propensity to mount an inflammatory response. People are less likely to become febrile while aged mice are more susceptible to pyrogenicity. On the other hand, certain inflammatory diseases such as arthritis occur more frequently in the aged. The mechanisms of altered inflammatory responses in aging are poorly understood. Thus, the specific aims of the present proposal are fourfold. First, the effects of aging on inflammatory response.-, in mice will be investigated. Acute inflammation will be induced in the skin and in the hind paws by injection of various doses of phlogistic materials and putative endogenous mediators of inflammation. Changes in the distribution of neutrophils serum proteins and erythrocytes will be followed by the use of radioactively labeled tracers. Gram negative bacterial endotoxin (lipopolysaccharide; LPS) will be used as an extrinsic phlogiston. Interleukins 1, 2 and 6, as well as tumor necrosis factor, histamine, prostaglandins and leukotrienes will be investigated for their ability to induce an inflammatory response in mice of different ages. Histological studies of representative lesions will be undertaken. Conversely, the ability of LPS or a bacterial challenge (Bacillus subtilis) to induce inflammatory mediators in skin will be investigated in mice of different ages. Secondly, synergistic interactions between inflammatory mediators will be sought using suboptimal doses of two or more endogenous mediators injected into rabbit skin. once active combinations have been determined, they will be investigated in the mouse models using mice of different age,--,. Thirdly, the roles of histamine, neutrophils and arachidonic acid derivatives in the development of inflammatory responses will be sought by pretreating animals with inhibitors of these mediators. Analysis of the data may reveal an order by which endogenous mediators act in vivo. Fourth, the regulation of the inflammatory response by naturally occurring interleukin 1 inhibitors will be investigated. One such inhibitor is derived from tumor cells of the B cell lineage. This inhibitor will be purified, characterized in vitro and assessed for its ability to inhibit inflammatory changes in vivo in mica-of different ages.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
2R01AR036028-04A1
Application #
3157448
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1985-09-23
Project End
1994-02-28
Budget Start
1989-04-01
Budget End
1990-03-31
Support Year
4
Fiscal Year
1989
Total Cost
Indirect Cost
Name
State University New York Stony Brook
Department
Type
Schools of Medicine
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
Lahdenne, P; Porcella, S F; Hagman, K E et al. (1997) Molecular characterization of a 6.6-kilodalton Borrelia burgdorferi outer membrane-associated lipoprotein (lp6.6) which appears to be downregulated during mammalian infection. Infect Immun 65:412-21
Wheeler, C M; Garcia Monco, J C; Benach, J L et al. (1993) Nonprotein antigens of Borrelia burgdorferi. J Infect Dis 167:665-74
Katona, L I; Beck, G; Habicht, G S (1992) Purification and immunological characterization of a major low-molecular-weight lipoprotein from Borrelia burgdorferi. Infect Immun 60:4995-5003
Beck, G; Habicht, G S (1991) Purification and biochemical characterization of an invertebrate interleukin 1. Mol Immunol 28:577-84
Habicht, G S; Katona, L I; Benach, J L (1991) Cytokines and the pathogenesis of neuroborreliosis: Borrelia burgdorferi induces glioma cells to secrete interleukin-6. J Infect Dis 164:568-74
Beck, G; Benach, J L; Habicht, G S (1990) Isolation, preliminary chemical characterization, and biological activity of Borrelia burgdorferi peptidoglycan. Biochem Biophys Res Commun 167:89-95
Beck, G; Benach, J L; Habicht, G S (1989) Isolation of interleukin 1 from joint fluids of patients with Lyme disease. J Rheumatol 16:800-6
Beck, G; Vasta, G R; Marchalonis, J J et al. (1989) Characterization of interleukin-1 activity in tunicates. Comp Biochem Physiol B 92:93-8
Habicht, G S; Beck, G; Benach, J L (1988) The role of interleukin-1 in the pathogenesis of Lyme disease. Ann N Y Acad Sci 539:80-6