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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Microvascular barrier damage, induced by thermal injury, imposes life-threatening problems owing to the pathophysiological consequences of plasma loss and impaired perfusion that finally may lead to multiple organ failure. The aim of the present study was to define the signaling role of selected mitogen-activated protein kinases (MAPKs) in general vessel hyperpermeability caused by burns and to look for a potential gene therapy. Rearrangement of cytoskeletons and cell tight junctions were evaluated by phalloidin labeling of actin and immunocytochemical demonstration of the ZO-1 protein, whereas blood vessel permeability was evaluated by a fluorescence ratio technique. ⋯ Using the adenoviral approach to transfect dominant negative forms of p38 MAPKs, we found that p38alpha and p38delta had similar effects. The in vivo part of the study showed that transfection of these two constructs significantly lowered general venular hyperpermeability and enhanced the survival of burned animals. Because the p38 MAPK pathway seems to play a crucial role in burn-induced vascular hyperpermeability, general transfection with p38 MAP dominant negative constructs might become a new therapeutic method to block burn-induced plasma leakage.
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Sepsis or endotoxemia produced by LPS followed by hypotension and multiorganic failure may lead to cardiac dysfunction contributing to mortality. Cardiac failure is usually associated to activation of nuclear factor kappaB (NF-kappaB) and mitogen-activated protein kinase (MAPK), which play an important role in proinflammatory enzymes expression. It has been shown that 15-deoxy-Delta12,14 prostaglandin J2 (15dPGJ2) can repress the inflammatory response by means of peroxisome proliferator-activated receptor gamma (PPARgamma)-dependent and -independent mechanisms. ⋯ To go inside the mechanisms by which 15dPGJ2 exerts inhibitory effects, cells were preincubated with specific chemical inhibitors of NF-kappaB and p38 MAPK, and we found that these signaling cascades are implicated in 15dPGJ2 action as well as PPARgamma. These results suggest that only the natural PPARgamma ligand, 15dPGJ2, but not the synthetic one, rosiglitazone, regulates the inflammatory response by inhibition of inducible NO synthase, cyclooxygenase 2, and metalloproteinase 9 expression. Moreover, our results offer an additional 15dPGJ2 mechanism of action, despite PPARgamma, showing NF-kappaB and p38 MAPK participation.
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To determine whether an epinephrine-induced early increase in arterial lactate concentration can prognosticate the outcome during shock state, we conducted a retrospective study in a 16-bed medical intensive care unit of a teaching hospital in France. One hundred consecutive patients admitted because of a shock state irrespective of etiology and treated with epinephrine were included. Patients were not enrolled if they received epinephrine administration before intensive care unit admission. ⋯ At a value of 100%, Deltalactate predicted death, with a 71% sensitivity (95% CI, 51%-87%) and a 67% specificity (95% CI, 43%-85%). Kaplan-Meier survival analysis confirmed this finding, with a 52.4% death rate among patients with Deltalactate greater than 100 comparatively to 84.7% when Deltalactate was less than 100 (log-rank test, P = 0.0002). An adapted response (lactate production) to a pharmacological trigger (epinephrine) is associated with better prognosis during shock of various etiologies.
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The rapid detection of pathogens in blood is critical for a favorable outcome of patients with suspected sepsis. Although blood culture (BC) is considered the criterion standard for diagnosis of bloodstream infection, it often takes several days to detect the causative organism. ⋯ In 30 among all positive cases (56.6%),both methods identified the same organisms, in 13 cases (24.5%), BC identified organisms not detected by real-time PCR,and in 10 cases (18.9%), SeptiFast PCR assay gave positive results, whereas the BC was negative. In this study, we wished to compare SeptiFast results obtained by standard procedures, but future clinical studies are necessary to define SeptiFast PCR as support for BC in the early diagnosis of severe bloodstream infections.
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Bacterial DNA (bDNA) can activate an innate-immune stimulatory "danger" response via toll-like receptor 9 (TLR9). Mitochondrial DNA (mtDNA) is unique among endogenous molecules in that mitochondria evolved from prokaryotic ancestors. Thus, mtDNA retains molecular motifs similar to bDNA. ⋯ In summary, mtDNA is released into the circulation by shock. Mitochondrial DNA activates PMN p38 MAPK, probably via TLR9, inducing an inflammatory phenotype. Mitochondrial DNA may act as a danger-associated molecular pattern or alarmin after shock, contributing to the initiation of systemic inflammatory response syndrome.