Down-regulation of tissue specific tumor necrosis factor-alpha in the liver and lung after burn injury and endotoxemia.

Burn injury and endotoxin lead to the development of a systemic inflammatory response. Because tumor necrosis factor-alpha (TNF-alpha) is a component of the proinflammatory response, we have determined the effect of burn injury and endotoxin in a murine model of thermal on tissue specific TNF-alpha levels in the liver and lung. Male mice were divided into four groups and injected with endotoxin (ETX) (2.5 mg/kg intraperitoneally) or saline (CNTL) or subjected to a 16% full-thickness scald burn (B), or ETX administration 72 hours after burn injury (B+ETX). Animals were killed at 0 to 24 hours after ETX or CNTL, 0 to 72 hours after B, and 72 to 96 hours after B+ETX (ETX administration 72 hours after B). TNF-alpha mRNA by Northern blot and protein analysis by enzyme-linked immunosorbent assay were determined and protein expressed as nanogram per gram of tissue. Statistical analysis was performed using analysis of variance with significance at p < 0.05. Burn injury did not result in detectable levels of liver or lung TNF protein or mRNA. Endotoxin administration resulted in a near six-fold rise in liver TNF protein compared with controls at 1, 2, and 6 hours after ETX (p < 0.05 to p < 0.001). Liver mRNA remained elevated from 20 minutes to 24 hours after ETX versus CNTL (p < 0.05). Endotoxin injection produced a persistent lung TNF protein elevation reaching significance at 1 and 2 hours (p < 0.001) and a rise in mRNA at 40 minutes to 6 hours (p < 0.05) versus CNTL. The liver showed a trend of reduced mRNA after B+ETX versus ETX (p = NS), whereas protein levels were reduced by 50 to 60% at 1 and 2 hours (p < 0.01). Lung mRNA values after B+ETX were only 40% compared with ETX at nearly all time points (p < 0.001) but were 15 times above CNTL values at 2 hours (p < 0.05). Based on these results, we conclude that burn injury did not cause an increase in liver or lung tissue specific TNF-alpha. However, the presence of a preexisting burn injury dramatically altered the response to endotoxin and the primary point of regulation appears to be at the posttranscriptional level.