Shock : molecular, cellular, and systemic pathobiological aspects and therapeutic approaches : the official journal the Shock Society, the European Shock Society, the Brazilian Shock Society, the International Federation of Shock Societies
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Review
Sepsis research in the next millennium: concentrate on the software rather than the hardware.
Today the basic principles of septic conditions are understood. Nevertheless, sepsis research has reached a critical point. To integrate our knowledge towards a consistent theory of the disease process and to derive effective therapies, new perspectives for future research that fit the complexity of the problem have to be found. ⋯ We conclude that sepsis research needs new perspectives that allow us to handle the complex interactions occurring during the disease process. We propose to focus research on the interactions between the constituents of the system rather than only describing isolated aspects of the disease process. We also conclude that the ideas and techniques of non-linear systems theory are suitable tools for the analysis of complex and dynamic diseases like SIRS and sepsis.
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Host defense mechanisms preventing bacterial invasion are particularly important in the gastrointestinal tract, since most gram-negative infections originate from there. Intraepithelial lymphocytes (IEL) seem to play an important role in this immune surveillance of the intestine, although their function in sepsis is not fully understood. To evaluate the characteristics of IEL in sepsis, C57BL/6 mice received a non-lethal dose of LPS and IEL were harvested at various time points thereafter. ⋯ The production of IFN-gamma may have induced the increased intestinal NOS-2 mRNA expression which was observed after endotoxemia. In conclusion, endotoxemia leads to functional activation of IEL without phenotypic changes. The activation of IEL and the subsequently increased NOS-2 expression may be important mechanisms in maintaining the mucosal barrier after sublethal LPS challenge.
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Studies indicate that trauma-hemorrhage results in activation of Kupffer cells to release inflammatory mediators and it leads to immunosuppression and increased susceptibility to subsequent sepsis. The cyclooxygenase (COX) product prostaglandin (PG) E2 appears to be central to this process, however, non-selective inhibition of COX activity with non-steroidal anti-inflammatory agents that block both the constitutive (COX-1) and inducible (COX-2) isoforms of cyclooxygenase has not yielded promising results in trauma patients. Nonetheless, it remains unknown whether selective inhibition of COX-2 activity has any salutary effect following trauma-hemorrhage and subsequent induction of sepsis. ⋯ However, NS-398 had no effect on TNF-alpha levels, in vivo and in vitro. These findings indicate that activation of COX-2 following trauma-hemorrhage and subsequent sepsis up-regulates Kupffer cell IL-6 production. Thus, selective inhibition of COX-2 activity may reduce the deleterious consequences of sepsis under such conditions.
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During septic shock, circulating levels of anti-inflammatory mediators are increased relative to those of pro-inflammatory. The reduced capacity of septic shock blood leukocytes in expressing pro-inflammatory genes in response to bacterial lipopolysaccharide endotoxin (LPS) may contribute to reductions in these mediators, but the reasons for persistent increases in circulating anti-inflammatory mediators are unknown. We determined whether septic shock leukocytes that have adapted to LPS induction of the IL-1beta gene could continue to express sIL-1RA in response to LPS. ⋯ Repressed transcription of IL-1beta and rapid decay of IL-1beta mRNA in septic shock neutrophils correlated with reductions in levels of IL-1beta after stimulation with LPS. Transcription of sIL-1RA mRNA was also suppressed, but the ability of LPS to stimulate events that lead to efficient translation of a stable sIL-1RA mRNA appeared responsible for maintaining sIL-1RA production. We conclude that LPS adaptation of septic shock leukocytes selectively influences signaling pathways that regulate transcription, mRNA processing, and translation, leading to changes in the balance of production of pro- and anti-inflammatory mediators.