Lung effects during a generalized Shwartzman reaction and therapeutic intervention with dexamethasone or vitamin E
Department of Medical Countermeasures, Divison of NBC Defence, Swedish Defence Research Agency, Umeå, Sweden. Shock
(Impact Factor: 3.05).
12/2004; 22(5):482-90. DOI: 10.1097/01.shk.0000142254.38630.36
We investigated if a two-hit shock model, commonly referred to as generalized Shwartzman reaction (GSR), can prime for indirect acute respiratory distress syndrome (ARDS) in mice. The GSR was provoked in C57BL/6 mice by two consecutive i.p. injections of 100 microg lipopolysaccharide (LPS) at t = 0 and t = 20 h. These mice demonstrated a dramatic decrease in respiratory capacity and 80% mortality after the second injection. No such effect was observed when LPS was given as a single 200 microg dose at t = 0. Increased expression of proinflammatory cytokines in serum (interleukin-1beta, interleukin-6 and interferon-gamma), lung neutrophilia, and edema formation were observed in mice injected with one dose of LPS, but notably, mice exposed twice did not further increase their inflammatory response. Early treatment 1 h after the first LPS injection (t = 1 h) with either dexamethasone (10 mg/kg) or vitamin E (50 mg/kg) improved respiratory function and down-modulated the induction of proinflammatory cytokines in serum. In conclusion, mice with a generalized Shwartzman reaction exhibited features resembling some aspects of the pathophysiology in septic ARDS, i.e., neutrophilic inflammation, edema formation, impaired respiratory capacity, and mortality. Our data indicate that a systemic cytokine response and lung neutrophilia may prime for the GSR but that other mechanisms account for the rapid decline in lung function after the second challenge. We suggest that this model can be used for studies of pathogenesis and therapeutic prevention of acute respiratory failure.
Available from: Hitoshi Iwahashi
- "Notably, the role of vitamin E against deleterious effects of LPS has been the subject of many in vitro and in vivo studies. In general, it has been observed that vitamin E suppresses inflammatory responses and oxidative damage induced by LPS in both cell culture systems and animal experiments     . Vitamin E is composed of eight isoforms: a, b, g, and d-tocopherols and a, b, g, and d-tocotrienols. "
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ABSTRACT: Lipopolysaccharide (LPS) induces host inflammatory responses and tissue injury and has been implicated in the pathogenesis of various age-related diseases such as acute respiratory distress syndrome, vascular diseases, and periodontal disease. Antioxidants, particularly vitamin E, have been shown to suppress oxidative stress induced by LPS, but the previous studies with different vitamin E isoforms gave inconsistent results. In the present study, the protective effects of α- and γ-tocopherols and α- and γ-tocotrienols on the oxidative stress induced by LPS against human lung carcinoma A549 cells were studied. They suppressed intracellular reactive oxygen formation, lipid peroxidation, induction of inflammatory mediator cytokines, and cell death. Tocopherols were incorporated into cultured cells much slower than tocotrienols but could suppress LPS-induced oxidative stress at much lower intracellular concentration than tocotrienols. Considering the bioavailability, it was concluded that α-tocopherol may exhibit the highest protective capacity among the vitamin E isoforms against LPS-induced oxidative stress.
- "This is unlike the situation in pneumonia where bacteria grow and hence the body is confronted with a continuous rise in endotoxins. This notion appears relevant, because LPS is well known to shape the host's response to further endotoxin, a behavior which has been denoted as endotoxin tolerance if responses are mitigated (Buttenschoen et al., 2008; Mokart et al., 2008) and priming (Welty-Wolf et al., 2006) or the Shwartzman reaction (Rocksen et al., 2004) if responses are exacerbated. "
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ABSTRACT: Acute lung injury (ALI) and its more severe form acute respiratory distress syndrome (ARDS) are life-threatening diseases that are characterized by acute onset, pulmonary inflammation, oedema due to increased vascular permeability and severe hypoxemia. Clinically, ARDS can be divided into ARDS due to direct causes such as pneumonia, aspiration or injurious ventilation, and due to extrapulmonary indirect causes such as sepsis, severe burns or pancreatitis. In order to identify potential therapeutic targets, we asked here whether common molecular mechanisms can be identified that are relevant in different models of the direct form of ALI/ARDS. To this end, we reviewed three widely used models: (a) one based on a biological insult, i.e. instillation of bacterial endotoxins; (b) one based on a chemical insult, i.e. instillation of acid; and (c) one based on a mechanical insult, i.e. injurious ventilation. Studies were included only if the mediator or mechanism of interest was studied in at least two of the three animal models listed above. As endpoints, we selected neutrophil sequestration, permeability, hypoxemia (physiological dysfunction) and survival. Our analysis showed that most studies have focused on mechanisms of pulmonary neutrophil sequestration and models with moderate forms of oedema. The underlying mechanisms that involve canonical inflammatory pathways such as MAP kinases, CXCR2 chemokines, PAF, leukotrienes, adhesions molecules (CD18, ICAM-1) and elastase have been defined relatively well. Further mechanisms including TNF, DARC, HMGB1, PARP, GADD45 and collagenase are under investigation. Such mechanisms that are shared between the three ALI models may represent viable therapeutic targets. However, only few studies have linked these pathways to hypoxemia, the most important clinical aspect of ALI/ARDS. Since moderate oedema does not necessarily lead to hypoxemia, we suggest that the clinical relevance of experimental studies can be further improved by putting greater emphasis on gas exchange.
Available from: Liwu Li
- "The Shwartzman-like reaction has been well documented, but generally in vivo, with little molecular-level work having been done since the 1990s. Indeed, the phenomenon appears to have been largely overlooked, relegated to the status of a clinical curiosity useful only as a disease model for other conditions (Berg et al. 1995; Heremans et al. 1990; Motegi et al. 2006; Rocksén et al. 2004; Slofstra et al. 2006). The mechanisms governing the decision between a Shwartzman-like or tolerogenic response have been largely unexplored, with existing research on the subject having turned up a labyrinthine tangle of signaling cascades. "
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ABSTRACT: Lipopolysaccharide (LPS), a component of Gram-negative bacteria, is a potent inflammatory stimulant, with high doses due to disseminated bacterial infection resulting in systemic inflammatory response syndrome and death. Lower doses can induce a state of tolerance to subsequent toxic doses of LPS, but extremely low doses have an opposite effect, priming the immune system for an even more violent response to subsequent challenge. A substantial body of research exists on the phenomenon of endotoxin tolerance, which appears to be a state of generalized dampening of inflammatory pathways. Comparatively little is known about the mechanisms or indeed the phenomenon of priming, particularly regarding the shift from a priming to a tolerizing response. Our aim is to review recent findings in the field of the inflammatory response to endotoxin, with a focus on highlighting the gaps in current understanding and attempting to reconcile the competing tolerance and priming phenomena.
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