Pretreatment with ibuprofen augments circulating tumor’ necrosis factor-alpha,- interleukin-6, and elastase during acute endotoxinemia

Plasma levelsof tumor necrosis factor-a (TNFa), interleukin-1 (IL-1),and interleukin-6 (IL-6) were monitored after intravenous administration of Escherichia coli endotoxin with or without ibuprofen pretreatment to healthy volunteers. Intravenous endotoxin (n = 7) resulted in elevated plasma TNFa concentrations with maximal levelsat 90 min (369 ± 44 pg/m1,P <.001vs, saline controls, n = 7). The rise in TNF-a was followed by a rise in plasma IL-6 (27 ± 12.8 ng/m1), peaking 30-90 min thereafter. Pretreatment with ibuprofen (n = 6) caused a significant augmen-tation and temporal shift in cytokine elaboration with maximal TNFa levels(627 ± 136 pg/m1) at 120 min and IL-6 peaks (113 ± 66 ng/m1) at 180 min. In ibuprofen-treated volunteers, the additional increase in TNFa was paralleled by increased levels of circulating elastase. In vitro experiments suggest a causal relationship between these events. Thus, the cyclooxygenaseinhibi-tor ibuprofen blunts the clinical response to endotoxin but augments circulating cytokine levels and leukocyte degranulation. Acute endotoxinemia is accompanied by a variety of meta-bolic changes such as fever, activation of hepatic protein syn-thesis, and increased numbers of circulating leukocytes. Thes