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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acute lung injury is frequently associated with sepsis or blood loss and is characterized by a proinflammatory response and infiltration of activated neutrophils into the lungs. Hemorrhage or endotoxemia result in activation of cAMP response element-binding protein (CREB) and NF-kappa B in lung neutrophils as well as increased expression of proinflammatory cytokines, such as TNF-alpha and macrophage-inflammatory peptide-2, by these cells. Activation of the extracellular regulated kinase (ERK) pathway occurs in stress responses and is involved in CREB activation. In the present experiments, hemorrhage or endotoxemia produced increased activation of mitogen-activated protein kinase kinase (MEK)1/2 and ERK2 (p42), but not of ERK1 (p44), in lung neutrophils. ERK1, ERK2, and MEK1/2 were not activated in peripheral blood neutrophils after hemorrhage or endotoxemia. Inhibition of xanthine oxidase led to further increase in the activation of MEK1/2 and ERK2 in lung neutrophils after hemorrhage, but not after endotoxemia. Alpha-adrenergic blockade before hemorrhage resulted in increased activation in lung neutrophils of MEK1/2, ERK1, ERK2, and CREB, but decreased activation of NF-kappa B. In contrast, alpha-adrenergic blockade before endotoxemia was associated with decreased activation of MEK1/2, ERK2, and CREB, but increased activation of NF-kappa B. Beta-adrenergic blockade before hemorrhage did not alter MEK1/2 or ERK1 activation in lung neutrophils, but decreased activation of ERK2 and CREB, while increasing activation of NF-kappa B. Beta-adrenergic inhibition before endotoxemia did not affect activation of MEK1/2, ERK1, ERK2, CREB, or NF-kappa B. These data indicate that the pathways leading to lung neutrophil activation after hemorrhage are different from those induced by endotoxemia.
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PMID:Activation of extracellular signal-regulated kinases, NF-kappa B, and cyclic adenosine 5'-monophosphate response element-binding protein in lung neutrophils occurs by differing mechanisms after hemorrhage or endotoxemia. 1112 32

Reactive oxygen species contribute to diaphragm dysfunction in certain pathophysiological conditions (i.e., sepsis and fatigue). However, the precise alterations induced by reactive oxygen species or the specific species that are responsible for the derangements in skeletal muscle function are incompletely understood. In this study, we evaluated the effect of the superoxide anion radical (O(2)(-).), hydroxyl radical (.OH), and hydrogen peroxide (H(2)O(2)) on maximum calcium-activated force (F(max)) and calcium sensitivity of the contractile apparatus in chemically skinned (Triton X-100) single rat diaphragm fibers. O(2)(-). was generated using the xanthine/xanthine oxidase system;.OH was generated using 1 mM FeCl(2), 1 mM ascorbate, and 1 mM H(2)O(2); and H(2)O(2) was added directly to the bathing medium. Exposure to O(2)(-). or.OH significantly decreased F(max) by 14.5% (P < 0.05) and 43.9% (P < 0. 005), respectively.OH had no effect on Ca(2+) sensitivity. Neither 10 nor 1,000 microM H(2)O(2) significantly altered F(max) or Ca(2+) sensitivity. We conclude that the diaphragm is susceptible to alterations induced by a direct effect of.OH and O(2)(-)., but not H(2)O(2), on the contractile proteins, which could, in part, be responsible for prolonged depression in contractility associated with respiratory muscle dysfunction in certain pathophysiological conditions.
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PMID:Superoxide, hydroxyl radical, and hydrogen peroxide effects on single-diaphragm fiber contractile apparatus. 1113 92

During sepsis the host's system-wide response to microbial invasion seems dysregulated. Here we explore the diverse multiorgan transcriptional programs activated during systemic inflammation in a cecal ligation/puncture model of sepsis in rats. Using DNA microarrays representing 7398 genes, we examined the temporal sequence of sepsis-induced gene expression patterns in major organ systems including lung, liver, kidney, thymus, spleen, and brain. Although genes known to be associated with systemic inflammation were identified by our global transcript analysis, many genes and expressed sequence tags not previously linked to the septic response were also elucidated. Taken together, our results suggest activation of a highly complex transcriptional response in individual organs of the septic animal. Several overlying themes emerged from our genome-scale analysis that includes 1) the sepsis response elicited gene expression profiles that were either organ-specific, common to more than one organ, or distinctly opposite in some organs; 2) the brain is protected from sepsis-induced gene activation relative to other organs; 3) the thymus and spleen have an interesting cohort of genes with opposing gene expression patterns; 4) genes with proinflammatory effects were often balanced by genes with anti-inflammatory effects (eg, interleukin-1beta/decoy receptor, xanthine oxidase/superoxide dismutase, Ca2+-dependent PLA2/Ca2+-independent PLA2); and 5) differential gene expression was observed in proteins responsible for preventing tissue injury and promoting homeostasis including anti-proteases (TIMP-1, Cpi-26), oxidant neutralizing enzymes (metallothionein), cytokine decoy receptors (interleukin-1RII), and tissue/vascular permeability factors (aquaporin 5, vascular endothelial growth factor). This global perspective of the sepsis response should provide a molecular framework for future research into the pathophysiology of systemic inflammation. Understanding, on a genome scale, how an organism responds to infection, may facilitate the development of enhanced detection and treatment modalities for sepsis.
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PMID:Molecular signatures of sepsis: multiorgan gene expression profiles of systemic inflammation. 1158 46

The molecular sources of reactive oxygen species (ROS) in skeletal muscles are not well understood. We hypothesized that nonphagocyte NAD(P)H oxidase could be a source of ROS in muscle fibers. We thus investigated the existence, structure, and contribution of nonphagocyte NAD(P)H oxidase to ROS production in rat skeletal muscles. ROS production and NAD(P)H oxidase activity were evaluated by lucigenin-enhanced chemiluminescence and NADH consumption rate, whereas enzyme composition was monitored by reverse transcription-polymerase chain reaction and immunoblotting. Basal O(-)(2) production in muscle strips from normal rats averaged 1.4 nmol/mg per 10 min and increased to approximately 18 nmol/mg per 10 min in the presence of NADH. Muscle O(-)(2) production and NADH consumption were inhibited by Tiron, superoxide dismutase, apocynin, and diphenyleneiodonium but not by inhibitors of cyclo-oxygenases, xanthine oxidase, nitric oxide synthases (NOS), and mitochondrial enzymes. We detected mRNA and proteins of p22(phox), gp91(phox), p47(phox), and p67(phox) subunits in normal rat muscles. These subunits were localized in close proximity to the sarcolemma. Induction of sepsis in rats doubled muscle O(-)(2) production with no major changes in muscle NADPH oxide subunit expression. In lipopolysaccharide-treated but not in control muscles, O(-)(2) production was increased significantly by NOS inhibition. We conclude that a constitutively active NAD(P)H oxidase enzyme complex exists in normal skeletal muscle fibers and contributes to ROS production. In septic rats, this production is increased but measurable O(-)(2) is reduced by enhanced NO production.
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PMID:Molecular characterization of a superoxide-generating NAD(P)H oxidase in the ventilatory muscles. 1255 34

Free radicals have been implicated in the etiology of cardiac dysfunction during sepsis, but the actual species responsible remains unclear. We studied the alterations in myocardial nitric oxide (NO), superoxide, and peroxynitrite generation along with cardiac mechanical function and efficiency in hearts from lipopolysaccharide (LPS)-treated rats. Six hours after LPS (4 mg/kg ip) or saline (control) treatment, hearts were isolated and perfused for 1 h with recirculating Krebs-Henseleit buffer and paced at 300 beats/min. Cardiac work, O(2) consumption, and cardiac efficiency were markedly depressed in LPS hearts compared with controls. Plasma nitrate/nitrite level was elevated in LPS rats, and ventricular NO production was enhanced as measured by electron spin resonance spectroscopy, Ca(2+)-independent NO synthase (NOS) activity, and inducible NOS immunohistochemistry. Ventricular superoxide production was also enhanced in LPS-treated hearts as seen by lucigenin chemiluminescence and xanthine oxidase activity. Increased nitrotyrosine staining (immunohistochemistry) and higher lipid hydroperoxides levels were also detected in LPS-treated hearts, indicating oxygen radical-induced stress. Enhanced generation of both NO and superoxide, and thus peroxynitrite, occur in dysfunctional hearts from endotoxemic rats.
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PMID:Enhanced NO and superoxide generation in dysfunctional hearts from endotoxemic rats. 1218 Nov 41

Burn trauma produces significant fluid shifts that, in turn, reduce cardiac output and tissue perfusion. Treatment approaches to major burn injury include administration of crystalloid solutions to correct hypovolemia and to restore peripheral perfusion. While this aggressive postburn volume replacement increases oxygen delivery to previously ischemic tissue, this restoration of oxygen delivery is thought to initiate a series of deleterious events that exacerbate ischemia-related tissue injury. While persistent hypoperfusion after burn trauma would produce cell death, volume resuscitation may exacerbate the tissue injury that occurred during low flow state. It is clear that after burn trauma, tissue adenosine triphosphate (ATP) levels gradually fall, and increased adenosine monophosphate (AMP) is converted to hypoxanthine, providing substrate for xanthine oxidase. These complicated reactions produce hydrogen peroxide and superoxide, clearly recognized deleterious free radicals. In addition to xanthine oxidase related free radical generation in burn trauma, adherent-activated neutrophils produce additional free radicals. Enhanced free radical production is paralleled by impaired antioxidant mechanisms; as indicated by burn-related decreases in superoxide dismutase, catalase, glutathione, alpha tocopherol, and ascorbic acid levels. Burn related upregulation of inducible nitric oxide synthase (iNOS) may produce peripheral vasodilatation, upregulate the transcription factor nuclear factor kappa B (NF-kappaB), and promote transcription and translation of numerous inflammatory cytokines. NO may also interact with the superoxide radical to yield peroxynitrite, a highly reactive mediator of tissue injury. Free radical mediated cell injury has been supported by postburn increases in systemic and tissue levels of lipid peroxidation products such as conjugated dienes, thiobarbituric acid reaction products, or malondialdehyde (MDA) levels. Antioxidant therapy in burn therapy (ascorbic acid, glutathione, N-acetyl-L-cysteine, or vitamins A, E, and C alone or in combination) have been shown to reduce burn and burn/sepsis mediated mortality, to attenuate changes in cellular energetics, to protect microvascular circulation, reduce tissue lipid peroxidation, improve cardiac output, and to reduce the volume of required fluid resuscitation. Antioxidant vitamin therapy with fluid resuscitation has also been shown to prevent burn related cardiac NF-kappaB nuclear migration, to inhibit cardiomyocyte secretion of TNF-alpha, IL-1beta, and IL-6, and to improve cardiac contractile function. These data collectively support the hypothesis that cellular oxidative stress is a critical step in burn-mediated injury, and suggest that antioxidant strategies designed to either inhibit free radical formation or to scavage free radicals may provide organ protection in patients with burn injury.
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PMID:Free radicals and lipid peroxidation mediated injury in burn trauma: the role of antioxidant therapy. 1282 Dec 84

Transactivation of the DNA-binding proteins nuclear factor-kappa B (NF-kappa B) and activator protein (AP)-1 by de novo oxyradical generation is a stereotypic redox-sensitive process during hypoxic stress of the liver. Systemic trauma is associated with splanchnic hypoxia-reoxygenation (H/R) followed by intraportal gram-negative bacteremia, which collectively have been implicated in posttraumatic liver dysfunction and multiple organ damage. We hypothesized that hypoxic stress of the liver before stimulation by Escherichia coli serotype O55:B5 (EC) amplifies oxyradical-mediated transactivation of NF-kappa B and AP-1 as well as cytokine production compared with noninfectious H/R or gram-negative sepsis without prior hypoxia. Livers from Sprague-Dawley rats underwent perfusion for 180 min with or without 0.5 h of hypoxia (perfusate PO(2), 40 +/- 5 mmHg) followed by reoxygenation and infection with 10(9) EC or 0.9% NaCl infusion. In H/R + EC livers, nuclear translocation of NF-kappa B and AP-1 was unexpectedly reduced in gel shift assays vs. normoxic EC controls, as were perfusate TNF-alpha and IL-1 beta levels. Preceding hypoxic stress paradoxically increased postbacteremic reduced-to-oxidized glutathione ratios plus nuclear localization of I kappa B alpha and phospho-I kappa B alpha, but not JunB/FosB profiles. Notably, xanthine oxidase inhibition increased transactivation as well as cytokine production in H/R + EC livers. Thus brief hypoxic stress of the liver before intraportal gram-negative bacteremia potently suppresses activation of canonical redox-sensitive transcription factors and production of inflammatory cytokines by mechanisms including xanthine oxidase-induced oxyradicals functioning in an anti-inflammatory signaling role. These results suggest a novel multifunctionality of oxyradicals in decoupling hepatic transcriptional activity and cytokine biosynthesis early in the posttraumatic milieu.
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PMID:Hypoxic suppression of E. coli-induced NF-kappa B and AP-1 transactivation by oxyradical signaling. 1505 91

Adenosine is a ubiquitous molecule that influences every physiological system studied thus far. In this review, we consider the influence of this purine nucleoside on some of the physiological systems affected during sepsis and SIRS. In the control of perfusion and cardiac output distribution, endogenous adenosine appears to play an important role in regulating perfusion in various vascular beds. Some of this control is mediated by stimulation of adenylyl cyclase, while part occurs by stimulating the production of nitric oxide. In the heart, adenosine may act as an inhibitory modulator of TNF-alpha expression. With regard to innate immune responses the effects of adenosine vary considerably, and are complex. However, the dominant responses relevant to SIRS indicate attenuation of inflammatory responses. Many of the effects of adenosine may also involve modulating oxyradical-mediated response. This occurs via increased oxyradical production via adenosine degradation (xanthine oxidase pathway), or limiting inflammatory oxyradical generation. Attempts to exploit the beneficial responses to adenosine have met with some success, and are considered here.
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PMID:Advances in understanding adenosine as a plurisystem modulator in sepsis and the systemic inflammatory response syndrome (SIRS). 1597 May 17

Five horses were evaluated because of severe cutaneous burn injuries following a barn fire. Gross hemolysis and morphologic changes in RBCs consistent with oxidative damage were detected in all of the horses. Of these horses, 4 became azotemic. The overall goals of treatment included wound care, correction of dehydration and provision of diuresis, control of inflammation, pain management, and prophylaxis against sepsis. After treatment, 2 horses survived and were discharged from the hospital. Red blood cell damage and hemolysis following cutaneous burn injury have been investigated in other species and appear to be a result of the release of oxygen radicals from complement-activated neutrophils. Early intervention with aggressive fluid therapy is recommended in the treatment of human burn patients and is likely to be of benefit in horses with burn injuries; a beneficial role of free radical scavengers and xanthine oxidase inhibitors has also been suggested.
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PMID:Intravascular hemolysis associated with severe cutaneous burn injuries in five horses. 1598 88

Myocardial dysfunction contributes to the high mortality of patients with endotoxemia. Although nitric oxide (NO) has been implicated in the pathogenesis of septic cardiovascular dysfunction, the role of myocardial NO synthase 3 (NOS3) remains incompletely defined. Here we show that mice with cardiomyocyte-specific NOS3 overexpression (NOS3TG) are protected from myocardial dysfunction and death associated with endotoxemia. Endotoxin induced more marked impairment of Ca(2+) transients and cellular contraction in wild-type than in NOS3TG cardiomyocytes, in part, because of greater total sarcoplasmic reticulum Ca(2+) load and myofilament sensitivity to Ca(2+) in the latter during endotoxemia. Endotoxin increased reactive oxygen species production in wild-type but not NOS3TG hearts, in part, because of increased xanthine oxidase activity. Inhibition of NOS by N(G)-nitro-l-arginine-methyl ester restored the ability of endotoxin to increase reactive oxygen species production and xanthine oxidase activity in NOS3TG hearts to the levels measured in endotoxin-challenged wild-type hearts. Allopurinol, a xanthine oxidase inhibitor, attenuated endotoxin-induced reactive oxygen species accumulation and myocardial dysfunction in wild-type mice. The protective effects of cardiomyocyte NOS3 on myocardial function and survival were further confirmed in a murine model of polymicrobial sepsis. These results suggest that increased myocardial NO levels attenuate endotoxin-induced reactive oxygen species production and increase total sarcoplasmic reticulum Ca(2+) load and myofilament sensitivity to Ca(2+), thereby reducing myocardial dysfunction and mortality in murine models of septic shock.
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PMID:Cardiomyocyte-specific overexpression of nitric oxide synthase 3 prevents myocardial dysfunction in murine models of septic shock. 1720 56


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