Lipopolysaccharide-tumor necrosis factor-glucocorticoid interactions during cecal ligation and puncture-induced sepsis in mature versus senescent mice.

Abstract

Previous work in our laboratory demonstrated increased sensitivity of senescent (24-month-old) mice to cecal ligation and puncture (CLP) sepsis compared with that of mature (12-month-old) mice. In this study the median lethal dose of the strain of Escherichia coli most frequently isolated during CLP sepsis was determined. No significant age-associated difference in the mean lethal dose or the mean survival time was noted; however, sham surgery before injection of E. coli decreased the mean lethal dose by at least 100-fold. With surgical manipulation, the average time to death after bacterial injection simulated more closely that observed after CLP surgery. Host responses to CLP sepsis were investigated by measuring the levels of corticosterone, glucose, and tumor necrosis factor (TNF) in the sera of mature and senescent mice at 2-h intervals after surgery. Corticosterone levels increased gradually during the course of sepsis in mature mice; however, senescent mice demonstrated a pronounced elevation in hormone levels at 2 and 4 h after surgery. At subsequent sampling intervals the corticosterone levels remained elevated, although they were similar for both ages. At all sampling intervals, the glucose levels in serum were lower in senescent mice than in mature mice. Pronounced hypoglycemia (less than 80 mg/dl) was observed in senescent mice at 8 h postsurgery. TNF was detected in serum within a narrow time frame in both age groups at 6, 8, and 10 h postsurgery. Although elevated TNF levels in serum were not seen in every mouse in each group (approximately 50%), the data hinted that senescent animals produced larger quantities of TNF during CLP sepsis than did mature animals. E. coli lipopolysaccharide (1 mg/kg) was injected intraperitoneally, and the TNF levels in serum and peritoneal lavage fluid were measured at 30, 60, and 90 min. Senescent mice demonstrated a level of TNF in serum at 90 min after lipopolysaccharide treatment that was 20-fold higher than that of mature mice (299,877 pg/ml versus 15,594 pg/ml). The amount of TNF produced locally in the peritoneum was also substantially higher in senescent mice than in mature animals (1,716 pg/ml versus 776 pg/ml). The increased production of TNF in senescent animals, despite elevated circulating corticosterone levels, suggested an age-related defect in glucocorticoid-directed downregulation of TNF production. This was confirmed in lipopolysaccharide-treated animals given exogenous dexamethasone.(ABSTRACT TRUNCATED AT 400 WORDS)