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.
