Chlorpromazine modulates cytokine expression in the liver and lung after burn injury and endotoxemia

Background: Previous data from our laboratory have demonstrated that altera tions in cytokine production occur in the lung and liver as the result of a two-hit model of injury, i.e., burn with subsequent endotoxin administrati on. The purpose of this study was to determine,whether the phenothiazine de rivative chlorpromazine would alter cytokine production in a sequential mod el of injury. Methods: By using a sublethal burn/endotoxemia model, B2D6F1 mice (n = 40) were assigned to two groups and subjected to a 15% full-thickness burn. Thr ee days after burn injury, one group (BURN/ETX) received 2.5 mg/kg Escheric hia coli endotoxin intraperitoneally, and the other group (CPZ) received 4 mg/kg chlorpromazine 1 hour before the administration of 2.5 mg/kg E. coli endotoxin intraperitoneally. At selected time points, the animals were kill ed and lung and liver were removed and processed for protein and total RNA. Northern blots and enzyme-linked immunosorbent assays were used to assess the production of tumor necrosis factor-alpha, macrophage inflammatory prot ein-1 alpha, and interleukin-10. Results: Chlorpromazine significantly reduced tumor necrosis factor-a mRNA and protein expression in the liver, Macrophage inflammatory protein-1 alph a mRNG was reduced by chlorpromazine in both liver and lung. Interleukin-10 production was not altered by chlorpromazine. Conclusion: The reduction of tumor necrosis factor-alpha and macrophage inf lammatory protein-1 alpha by chlorpromazine in the liver and lungs may have potential as a pharmaceutical agent that may dampen the inflammatory respo nse in a model of sequential injury.