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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Increased intestinal/epithelial permeability in sepsis and endotoxemia has been noted to be induced by proinflammatory cytokines such as interferon-gamma, TNF-alpha, and IL-1beta. The p38 mitogen-activated protein kinase (MAPK) signaling pathway plays an important role in regulating the inflammatory response induced by these cytokines. We tested the hypothesis that epithelial permeability changes are regulated through the p38 MAPK signaling pathway. ⋯ Treatment with SB203580 completely blocked p38 activity with transient inhibition of p38 phosphorylation. SB203580 also prevented the CytoMix-induced permeability increase and reduced NO, IL-6, and IL-8 levels. The results suggest that p38 MAPK plays an important role in regulating epithelial barrier function during inflammation.
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Sepsis, a lethal inflammatory syndrome, is characterized by organ system dysfunction. In the liver, we have observed decreased expression of genes encoding proteins modulating key processes. These include organic anion and bile acid transport. ⋯ Cecal ligation and puncture decreased HNF-1alpha expression and DNA binding activity in IL-6 +/+ but not IL-6 -/- mice. Recombinant human IL-6 restored the sepsis-induced decrease in Ntcp, MRP-2, OATP, and HNF-1alpha expression in IL-6 -/- mice. We conclude that sepsis decreases the expression of three key hepatic genes via a transcriptional mechanism that is IL-6, Stat-3, and HNF-1alpha dependent.
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Randomized Controlled Trial
Effects of the pan-selectin antagonist bimosiamose (TBC1269) in experimental human endotoxemia.
Selectins mediate the adhesion of leukocytes to activated endothelial cells and activated platelets. In addition to these cell-to-cell interactions, they influence the fibrin content and size of venous thrombi in different animal models. However, the exact role of selectins in human endotoxemia still remains unclear. ⋯ The pan-selectin antagonist bimosiamose does not attenuate TF-triggered coagulation or inflammation in human endotoxemia. This indicates a minor influence of this selectin antagonist in this model. In addition, infusion of bimosiamose was safe and well tolerated in human endotoxemia.