CYTOKINE ACTIVATION THROUGH SUBLETHAL HEMORRHAGE IS PROTECTIVE AGAINST EARLY LETHAL ENDOTOXIC CHALLENGE

Objectives: To determine the immunologic consequences of nonlethal hem orrhage on subsequent exposure to lipopolysaccharide (LPS) and to dete rmine the role of interleukin 1 beta (IL-1) specifically in mediating the response to LPS with and without prior hemorrhage. Design: Prospec tive, randomized, controlled experimental trial. Participants: Male BA LB/c mice and transgenic mice deficient in IL-1 converting enzyme. Int erventions: Animals were subjected to hemorrhage (by cardiac puncture) , LPS challenge by intraperitoneal injection, or hemorrhage followed 2 4 hours later by LPS challenge. Mortality was assessed every 4 hours F dr 96 hours following hemorrhage or LPS exposure. Serum IL-l levels we re determined 24 hours after exposure to hemorrhage and LPS. Setting: University of South Florida Core General Surgery Research Facility, Ta mpa. Main Outcome Measures: Mortality and serum IL-l levels. Results: Hemorrhage alone resulted in complete survival, whereas LPS alone resu lted in near-complete (95%) mortality. Hemorrhage, when given 24 hours before LPS challenge, afforded significant protection compared with L PS alone (67% survival vs 5%, survival; P<.001). Serum IL-1 levels 24 hours after exposure to LPS were significantly lower in prehemorrhaged mice than in those receiving LPS alone. Transgenic mice incapable of producing biologically active IL-1 were further protected, demonstrati ng near-complete (95%) survival following hemorrhage and LPS challenge . Conclusions: Cytokine activation through nonlethal hemorrhage attenu ates subsequent IL-l response to early immunologic challenge. Such imm une suppression appears to be protective early on and is supported by the near-complete immunity to LPS in animals incapable of producing bi ologically active IL-1.