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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Studies of sepsis in humans are difficult because the seriousness of the disease mandates immediate intervention and because the heterogeneity of patient presentations imposes substantial limitations on clinical trials. Thus, animal models have been used extensively to explore the pathogenesis of sepsis and to generate preclinical data for therapeutic interventions. Translation of findings in these models into therapeutic strategies has been difficult, in part because of limitations in preclinical models and in part to imperfect understanding of the pathophysiology of sepsis. ⋯ Using continuous micromanometric pressure monitoring and assessment of hemodynamics by echocardiography, we have shown that this model reproduces the hyperdynamic state with hypotension seen in clinical sepsis. The use of transgenic technology in appropriate murine models is exciting because of its potential to permit significant strides in our understanding of the molecular mechanisms of sepsis, multiple organ system failure, and other diseases. The use of reproducible and clinically relevant mouse models of shock is essential for delineation of pathogenetic mechanisms and for initial testing of potential therapeutic strategies.
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Meningococcal septic shock is an important cause of morbidity and mortality in children and young adults worldwide and is the prototypical gram-negative septic shock. One of the key factors in the development of shock is increased microvascular permeability. Vascular endothelial growth factor (VEGF) is a central factor in angiogenesis and is an important mediator of vascular permeability. ⋯ In all patients, a decrease in VEGF was associated with a decrease in fluid intake during t=24 to 48 h. The results suggest that apart from correlation with IL-1 beta, -10, -12, and complement activation, microvascular permeability in sepsis is also closely linked to the plasma concentration of VEGF. The role of VEGF in sepsis-associated increased microvascular permeability needs further exploration and may represent a new therapeutic target.
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The release of the immunomodulator, interleukin 18 (IL-18) into sera early in acute pancreatitis (AP) corresponds to disease severity. IL-18 induces nitric oxide (NO), which is involved in the pathophysiology of pancreatitis. The objective of this study was to clarify the role of IL-18 in pathogenesis and NO production during early AP using recombinant mouse (rm) IL-18 protein and IL-18 gene knockout (KO) mice. ⋯ Administration of aminoguanidine, a selective iNOS inhibitor, before AP induction abolished the protective effect of pretreatment with rmIL-18 on pancreatic injury. IL-18 appears to protect the pancreas during early induced-induced AP in mice, probably through induction of NO release from an iNOS source. IL-18 may be a target for new AP therapeutics.
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Calcitonin gene-related peptide (CGRP), a potent vasodilatory peptide present in central and peripheral neurons, is released at inflammatory sites and inhibits several macrophage, dendritic cell, and lymphocyte functions. In the present study, we investigated the role of CGRP in models of local and systemic acute inflammation and on macrophage activation induced by lipopolysaccharide (LPS). Intraperitoneal pretreatment with synthetic CGRP reduces in approximately 50% the number of neutrophils in the blood and into the peritoneal cavity 4 h after LPS injection. ⋯ The protective effect of CGRP correlates with an inhibition of TNF-alpha and an induction of IL-6 and IL-10 in mice sera 90 min after LPS challenge. Finally, CGRP significantly inhibits LPS-induced TNF-alpha released from mouse peritoneal macrophages. These results suggest that activation of the CGRP receptor on macrophages during acute inflammation could be part of the negative feedback mechanism controlling the extension of acute inflammatory responses.
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Glutamine (GLN) has been shown to attenuate cytokine release from LPS-stimulated human peripheral blood mononuclear cells; however, the in vivo antiinflammatory effect of GLN in polymicrobial sepsis and ARDS is unknown. This study evaluates the effect of GLN on inflammatory cytokine release and the pathways that may mediate antiinflammatory effects of GLN in the lung. Either 0.75 g/kg of GLN or saline placebo (SP) was administered to male rats 1 h after cecal ligation and puncture (CLP). ⋯ These data reveal that GLN exerts an antiinflammatory effect in sepsis that may be mediated via attenuation of multiple pathways of inflammation such as NF-kappaB, p38 MAPK, ERK, and MKP-1. GLN also showed an inhibition of increases in iNOS expression. The antiinflammatory effect of GLN was associated with attenuation of ARDS and mortality.