Journal of endotoxin research最新文献

Type I interferons (IFNs) were first described several decades ago as soluble factors that were capable of 'interfering' with viral replication when added to infected cells. Type I IFNs have been shown to be induced by recognition of viral DNA and RNA via three distinct pathways: (i) a TRIF-dependent pathway in macrophages via TLRs 3 and 4; (ii) a MyD88-dependent pathway in plasmacytoid dendritic cells (pDCs) via TLRs 7/8 and 9; and (iii) an intracellular recognition pathway utilizing the cytoplasmic receptors RIG-I/MDA5. Interestingly, these viral recognition pathways converge on TRAF3, which induces interferon through the activation of IRF3 or IRF7 by the TBK-1 and IKKi complexes. While type I IFN has been traditionally associated with antiviral responses, recent studies have demonstrated that many bacteria also induce type I interferon responses. The mechanisms of type I IFN induction and its role in host defense, however, are largely unclear. Studies with the Gram-positive intracellular bacterium Listeria monocytogenes indicated that it may trigger type I IFN induction through novel TLR-independent intracellular receptors and type I IFN may play a detrimental role to host response against listerial infection. In this article, we summarize some of these findings and discuss the functional differences of type I IFNs in bacterial and viral infections.

Although porcine intravenous endotoxin shock models are widely employed in experimental sepsis, endotoxin dose-effect studies are scarce. Our primary aim was to establish the dose response to increasing endotoxin doses in inflammatory, coagulatory and haemodynamic effect variables, as well as to determine the optimal time point for assessment in a pig model. A secondary aim was to study pathophysiological covariations between the different responses. Twenty anaesthetised piglets received endotoxin intravenously in doses of 0.063 (n = 3), 0.25 (n = 3), 1.0 (n = 3), 4.0 (n = 3), 8 (n = 3) and 16 microg/kg/h (n = 2). In addition, non-endotoxin piglets constituted a control group (n = 3). Physiological variables were registered and blood samples analysed for TNF-alpha, IL-6, leukocyte, platelet and haemoglobin concentrations hourly for 6 h. Increases in the endotoxin dose induced significant log-log cytokine responses as well as log-linear leukocyte and platelet responses. Significant log-linear responses were observed for circulatory parameters, plasma leakage, hypoperfusion and pulmonary compliance. Significant covariations in the responses were noted. In conclusion, there were log-log or log-linear responses to endotoxin suggesting a greater effect of a given dose at lower pre-existing endotoxin concentrations and lower doses of < or = 1 microg/kg/h may be of advantage in experiments designed to study potential anti-endotoxin effects of experimental drugs or measures.

Many host cell types, including endothelial and epithelial cells, neutrophils, monocytes, natural killer cells, dendritic cells and macrophages, initiate the first line of defense against infection by sensing conserved microbial structures through Toll-like receptors (TLRs). Recognition of microbial ligands by TLRs induces their oligomerization and triggers intracellular signaling pathways, leading to production of pro- and anti-inflammatory cytokines. Dysregulation of the fine molecular mechanisms that tightly control TLR signaling may lead to hyperactivation of host cells by microbial products and septic shock. A prior exposure to bacterial products such as lipopolysaccharide (LPS) may result in a transient state of refractoriness to subsequent challenge that has been referred to as 'tolerance'. Tolerance has been postulated as a protective mechanism limiting excessive inflammation and preventing septic shock. However, tolerance may compromise the host's ability to counteract subsequent bacterial challenge since many septic patients exhibit an increased incidence of recurrent bacterial infection and suppressed monocyte responsiveness to LPS, closely resembling the tolerant phenotype. Thus, by studying mechanisms of microbial tolerance, we may gain insights into how normal regulatory mechanisms are dysregulated, leading ultimately to microbial hypo-responsiveness and life-threatening disease. In this review, we present current theories of the molecular mechanisms that underlie induction and maintenance of 'microbial tolerance', and discuss the possible relevance of tolerance to several infectious and non-infectious diseases.