[71] Oxy radicals in endotoxin shock
Publisher Summary
There is considerable indirect evidence supporting the role of oxygen radicals in circulatory shock. Endotoxin is a toxin released from dead gram-negative bacteria, and this toxin produces circulatory depression in septicemic patients concomitantly with a variety of other cellular dysfunctions. This chapter discusses the role of oxy radicals in endotoxin shock. Polymorphonuclear leukocytes (PMN)-depleted rats are used to examine the effect of PMNs on experimental shock. Anti-rat PMN antibody is obtained by immunizing rabbits with rat PMNs in Freund's complete adjuvant, using the methods of Ward and Cochrane. The PMN preparation is obtained by instilling 0.12% oyster glycogen type II intraperitoneally into rats, followed by peritoneal lavage with sterile saline 6 hours later. Antirat PMN antibody is injected intraperitoneally into the rats to produce PMN-depleted rats. The number of PMNs is significantly reduced at 18 hours after injection of antibody. The reduction of systolic blood pressure and the increase in serum lysosomal enzymes induced by the injection with endotoxin are significantly inhibited by the pretreatment with anti-rat PMN antibody. The chapter also demonstrates that superoxide radicals and catalase effectively protects the aggravation of shock induced by endotoxin. This is a very important observation that suggests that superoxide and hydrogen peroxide exert certain effects on the experimental shock state.
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Cited by (12)
Aminophylline therapy during endotoxemia in anesthetized spontaneously breathing rats
2004, Pharmacological ResearchPhosphodiesterase inhibitors, such as pentoxifylline and aminophylline, may reduce inflammatory cytokine-induced endothelial permeability. We tested the hypothesis that aminophylline treatment may ameliorate the pulmonary and extrapulmonary effects of endotoxemia in a rat model. In anesthetized rats, a tracheotomy was performed along with catheterization of a femoral vein and artery. Anesthesia, fluid balance, and normothermia were maintained throughout the 6-h experiment. A stable hemodynamic and gas-exchange baseline was established at which time the rats were randomly divided into three groups. Group I received aminophylline (1 mg/kg) over 30 min followed by 0.5 mg/kg/h. Group II received a single dose of endotoxin (4 mg/kg) while Group III received both aminophylline and endotoxin as described for Groups I and II, respectively. Gas-exchange profiles, mean arterial blood pressure, and heart rate were determined every 2 h. At hour 6, the rats were euthanized and lung, kidney, and heart tissue were removed for determination of water content. As our control group, we utilized data from our previously published study involving an identical surgical procedure with normal saline. Endotoxemia produced characteristic respiratory and hemodynamic signs of sepsis including hypotension, hyperventilation, tachycardia, and renal and pulmonary edema. Aminophylline treatment failed to prevent these endotoxemia-induced respiratory and hemodynamic manifestations of sepsis, but significantly improved the acid–base imbalance that developed during surgical procedures in saline-treated control rats. Further studies are warranted to determine potentially beneficial doses of aminophylline and resulting theophylline serum concentrations under such septic conditions.
Regulation of macrophage inflammatory protein-1α mRNA by oxidative stress
1996, Journal of Biological ChemistryAccumulation of inflammatory cells within the lung has been implicated in oxidative injury. Recruitment of these cells to a tissue site is a complex process that depends in part upon the local expression of appropriate proinflammatory chemokines. Macrophage inflammatory protein-1α (MIP-1α), a member of the CC subfamily of chemokines, has been shown to contribute to monocyte/macrophage and neutrophil chemotaxis and activation. Our previous work demonstrated that MIP-1α mRNA expression in macrophages is induced by bacterial endotoxin. The objective of this study was to test the hypothesis that an oxidative stress alone may trigger expression of MIP-1α mRNA in macrophages and to determine the mechanism leading to increased expression. A rat alveolar macrophage cell line (NR8383) was exposed to H2O2 or menadione (2-methyl-1,4-naphthoquinone (MQ)), a quinone compound that undergoes redox cycling and generates reactive oxygen species continuously. Steady-state mRNA levels encoding MIP-1α were markedly increased (3-fold) in these cells after 1 h of exposure to 0.5 mM H2O2, remained higher than control levels after 4 h, and decreased after 6 h. Similarly, MQ (25 or 50 μM) caused a significant increase of MIP-1α mRNA with a maximal induction after 4 h of exposure (5-fold). Both H2O2 and MQ-induced up-regulation of MIP-1α mRNA was suppressed by co-treatment with N-acetylcysteine, a synthetic antioxidant. Co-treatment with actinomycin D reduced the MQ induction of MIP-1α mRNA to a greater extent than the H2O2-induced increase. Transcription of the MIP-1α gene was increased by exposure to both H2O2 and MQ. H2O2 treatment also induced a marked increase of the MIP-1α mRNA half-life, indicating post-transcriptional stabilization. These observations indicate that an oxidative stress can regulate MIP-1α mRNA expression by two distinct mechanisms: transcriptional activation of the MIP-1α gene and post-transcriptional stabilization of MIP-1α mRNA.
Oxidative metabolism in sepsis and sepsis syndrome
1995, Journal of Critical CareThe high mortality associated with sepsis syndrome and multiple organ dysfunction syndrome has persisted despite extraordinary research efforts in the laboratory and the intensive care unit. These syndromes produce systemic tissue damage that is likely to result from widespread inflammation and subsequent endothelial injury. This article reviews the oxidative metabolic effects and responses to sepsis syndrome at several levels: the oxygen transport system, the cell, and the mitochondrion. Specifically, aerobic metabolism of carbon substrates and oxygen is altered in sepsis. As a result of systemic inflammation and nonmetabolic oxygen use, oxidative stress may occur both outside and inside the cell. The consequences of these oxidative processes during sepsis may be ongoing cell damage mediated by reactive oxygen and nitrogen oxide species that culminates in multisystem organ failure.
Reactive oxygen species produced by liver mitochondria of rats in sepsis
1995, Archives of Biochemistry and BiophysicsReactive oxygen species (ROS) can be generated in experimental shock states through several different mechanisms. We measured ROS production in metabolically active liver mitochondria from rats rendered septic by cecal ligation and puncture. By polarography, the State 4 and State 3 respiration rates of liver mitochondria isolated from septic animals were no different from control organelles. During oxidation of succinate, however, nonenzymatic hydroxylation of salicylic acid to 2,3-dihydroxybenzoic acid by mitochondria from septic rats was increased, indicating generation of hydroxyl radical (OH.). Inhibition of electron transport at Complex I with rotenone had no effect on this pattern of OH. production, but rotenone and cyanide abolished the differences in OH. formation between control and septic liver mitochondria. Measurements of H2O2 release suggested that septic mitochondria will increase rates of H2O2 production in the presence of succinate. Additional investigations revealed no difference in the release of iron between septic and control mitochondria. When referenced to respiration rate, both OH. and H2O2 production were greater in septic liver mitochondria. The reproducible effect of sepsis on generation of reactive oxygen species by liver mitochondria utilizing FAD-linked but not NAD-linked substrates suggests that enhanced mitochondrial oxidative stress in sepsis is related to alterations in the activity of Complex II of the electron transport chain.
Flaxseed and endotoxic shock
2014, Current Pharmaceutical DesignSuperoxide, NO, peroxynitrite and PARP in circulatory shock and inflammation
2009, Frontiers in Bioscience