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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Although aberrant fibrinolysis and plasminogen activator inhibitor 1 (PAI-1) are implicated in acute lung injury, the role of this serpin in the pathogenesis of wood bark smoke (WBS)-induced acute lung injury (SIALI) and its regulation in resident lung cells after exposure to smoke are unclear. A total of 22 mechanically ventilated pigs were included in this study. Immunohistochemical analyses were used to assess fibrin and PAI-1 in the lungs of pigs with SIALI in situ. ⋯ In pleural mesothelial cells, lung fibroblasts, and alveolar type II cells, PAI-1 mRNA was stabilized by WBS extract and contributed to induction of PAI-1. The mechanism involves dissociation of a novel 6-phospho-d-gluconate-NADP oxidoreductase-like PAI-1 mRNA binding protein from PAI-1 mRNA. Exposure to WBS induces prominent airway and mesothelial expression of PAI-1, associated with florid distribution of fibrin in SIALI in vivo Wood bark smoke components induce PAI-1 in vitro in part by stabilization of PAI-1 mRNA, a newly recognized pathway that may promote extravascular fibrin deposition and lung dysfunction in SIALI.
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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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Clinical Trial
Interplay between the acute inflammatory response and heart rate variability in healthy human volunteers.
The autonomic nervous system and the inflammatory response are intimately linked. Heart rate variability (HRV) analysis is a widely used method to assess cardiac autonomic nervous system activity, and changes in HRV indices may correlate with inflammatory markers. Here, we investigated whether baseline HRV predicts the acute inflammatory response to endotoxin. ⋯ Heart rate variability indices do not predict the acute inflammatory response in a standardized model of systemic inflammation. Although the acute inflammatory response results in HRV changes, no correlations with inflammatory cytokines were observed. Therefore, the magnitude of endotoxemia-related HRV changes does not reflect the extent of the inflammatory response.
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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.
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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.