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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We investigated the prognostic utility of changes in N-terminal pro-brain natriuretic peptide (NT-proBNP) in combination with Sequential Organ Failure Assessment (SOFA) score in patients with acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) concomitant with septic shock. Forty-nine mechanically ventilated patients with ALI/ARDS concomitant with septic shock were studied. N-terminal pro-brain natriuretic peptide levels were measured on the first 3 days (days 0, 1, and 2) in the intensive care unit. ⋯ On day 2, areas under the receiver operating characteristic curves for predicting 28-day mortality were 0.74 for SOFA alone and 0.85 (P = 0.028) for SOFA combined with percent change in NT-proBNP. In conclusion, in patients with ALI/ARDS concomitant with septic shock, a rising trend (high percent change) in NT-proBNP levels had better prognostic utility than absolute levels. The combination of percent change in NT-proBNP with SOFA may provide superior prognostic accuracy to SOFA alone.
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Evidence from animal models of trauma and hemorrhage has suggested that the gut plays an active role in the pathogenesis of systemic inflammatory responses and multiple organ dysfunction syndrome. The aim of the present study was to seek evidence for gut-derived signals in man in a group of eight patients undergoing elective abdominal aortic reconstruction, a procedure that is associated with sterile tissue injury, controlled colonic ischemia as a consequence of aortic cross-clamping, and a significant risk of developing systemic inflammation and multiple organ dysfunction syndrome. ⋯ There was, however, evidence of an increase in the expression of RAGE (receptor for advanced glycation end products) by endothelial cells following exposure to mesenteric venous, but not central, plasma sampled during maximum ischemia. In conclusion, during sterile tissue injury and controlled colonic ischemia-reperfusion in man, there is a marked systemic proinflammatory response, which is in part gut derived, in the absence of evidence for the presence of toxic endothelial factors or gut-derived microorganisms in the central or mesenteric circulations.
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Burn injury initiates an enhanced inflammatory condition referred to as the systemic inflammatory response syndrome or the two-hit response phenotype. Prior reports indicated that macrophages respond to injury and demonstrate a heightened reactivity to Toll-like receptor stimulation. Since we and others observed a significant increase in splenic GR-1 F4/80 CD11b macrophages in burn-injured mice, we wished to test if these macrophages might be the primary macrophage subset that shows heightened LPS reactivity. ⋯ However, further investigations showed that LPS-induced TNF-α production was significantly influenced by CD4 T cells. Taken together, these data indicate that GR-1 F4/80 CD11b macrophages represent the primary macrophage subset that expands in response to burn injury and that CD4 T cells do not influence the GR-1 macrophage expansion process, but do suppress LPS-induced TNF-α production. These data suggest that modulating GR-1 macrophage activation as well as CD4 T cell responses after severe injury may help control the development of systemic inflammatory response syndrome and the two-hit response phenotype.
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Indirect acute lung injury (ALI) is a common manifestation in critically ill patients. Using a model of indirect ALI in mice, our laboratory has shown that local/pulmonary inhibition of extrinsic death receptor protein (Fas) leads to a decrease in lung inflammation and improved survival. However, it is unknown if local, i.e., autocrine/paracrine, inhibition of Fas ligand (FasL) affects Fas-expressing target cells itself or blockade of the actions of a more distal/endocrine source of FasL that accounts for these findings. ⋯ After intratracheal delivery of FasL siRNA, there was a significant decrease in inflammatory cytokines, myeloperoxidase activity, and caspase 3 activity in lung tissue along with protein leak as compared with controls. There was no difference found in these various outcome markers between those treated with intravenously administered FasL siRNA versus controls. The observation that local silencing of FasL, as opposed to distal/systemic silencing, ameliorates the effects of indirect ALI suggests not only that FasL produced in an autocrine/paracrine fashion in local tissues has pathological consequences within the lungs, but also that FasL might be a valuable pulmonary therapeutic target.
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Burn induces myeloid-derived suppressor cells (MDSCs), a heterogeneous population of immature polymorphonuclear neutrophils (PMNs) and monocytes, which protect against infection. Previous work from our laboratory demonstrated that inflammatory monocytes (iMos) were the major MDSC source of TNF-α in the postburn spleen, and we hypothesized that they were also the major source of postburn IL-10. To test this hypothesis, we examined cytokine production by postburn CCR2 knockout (KO) mice, which have fewer iMos than burn wild-type (WT) splenocytes, but equal numbers of PMNs and F4/80 macrophages. ⋯ Polymorphonuclear neutrophil and iMos subpopulations from culture-derived MDSCs produced the same cytokine profiles in response to LPS and peptidoglycan as did the PMNs and iMos from postburn spleens: PMNs made IL-10, whereas iMos made IL-6. Finally, LPS-induced mortality of burn mice was made worse by anti-Gr-1 depletion of all PMNs and 66% of iMos from burn mice. This suggests that PMNs play a primarily anti-inflammatory role in vitro and in vivo.