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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Much effort has been made in recent years to clarify metabolic and renal function changes in sepsis. A number of studies performed in different models of sepsis have been described. One such model that is frequently used is cecal ligation and puncture (CLP) in rats. This model resembles human sepsis in several important aspects, such as an early phase of hyperdynamic, hypermetabolic sepsis followed by a late hypodynamic, hypometabolic phase. The present study evaluated the blood pressure (n = 5) and renal function changes during development of CLP renal failure and to determine the effects of NOS inhibition (L-NAME) and 0.15 M NaCl administration on tail blood pressure and renal function in randomly assigned five groups (n = 10 each): (1) Sham-operated, (2) Sham-operated L-NAME-treated, (3) CLP rats, (4) CLP L-NAME-treated, and (5) CLP 0.15 M NaCl-treated rats. The basal tail blood pressure was not significantly different among the four groups. One week later, arterial pressure was significantly increased in sham-operated L-NAME-treated rats (159 +/- 12 mmHg) compare with the other groups (118 +/- 9.0 mmHg in nontreated rats, p < 0.05). Blood pressure shows a slightly and not significant decrease up to 12h in L-NAME and 0.15 M NaCl treated rats, which in turn was followed by a significant reduced arterial pressure 18h after CLP in both groups (L-NAME: 96.0 +/- 3.6 mmHg, p < 0.05) and NaCl: 82.3 +/- 2.4 mmHg, p < 0.05) compared to sham-operated groups. The glomerular filtration rate estimated by CCr decreases significantly in the CLP untreated group (p < 0.001) and did not significantly differ from the sham-operated and L-NAME-treated groups (p = 0.4) during the studies of renal tubule sodium handling. On the other hand, subcutaneous 0.15 M NaCl administration prevented CCr decreases in CLP rats (p = 0.25). CLP increased the FENa in the sham-operated from: 857.2 +/- 85.1 delta%min(-1) to CLP: 1197.8 +/- 119.0 delta%min(-1). The high FENa to CLP was blunted and significantly reduced by previous systemic treatment of animals with L-NAME from sham-operated+L-NAME: 1368.0 +/- 72.0 delta%min(-1) to CLP+L-NAME: 1148.0 +/- 60.4 delta%min(-1) (p < 0.01). The enhanced FENa in the CLP group were accompanied by a significant increase in proximal sodium reabsorption rejection. The salient findings of the present study suggest that a decrease in the blood pressure and creatinine clearance caused by CLP may benefit from L-NAM and fluid resuscitation during initial bacteremia (first 12 h) by promoting an additional increase of tubule sodium reabsorption in the post-proximal segments of nephrons, but these therapies could not prevent acute renal failure after established endotoxemia.
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PMID:Effect of nitric oxide synthase inhibition and saline administration on blood pressure and renal sodium handling during experimental sepsis in rats. 1466 49

We investigated the effect of an i.v. infusion of highly purified vitamin B(2) (riboflavin 5'-sodium phosphate: purity >97%) on lipopolysaccharide-induced shock and bacterial infection in mice. Six hours after lipopolysaccharide injection or 1 h after bacterial infection, vitamin B(2) or human activated protein C (APC) was administered by 6-h i.v. infusion. Vitamin B(2) at 10 mg/kg/6 h and up to 80 mg/kg/6 h significantly improved lipopolysaccharide-induced endotoxin shock. APC was also effective at low doses, but was deleterious at higher doses. Moreover, vitamin B(2) at 80 mg/kg/6 h significantly reduced the lethality of Escherichia coli and Staphylococcus aureus infection, whereas APC at up to 600 units/kg/6 h was ineffective. The i.v. infusion of vitamin B(2) reduced the elevations of proinflammatory cytokines and nitric oxide induced by lipopolysaccharide. These results suggest that i.v. infusion of vitamin B(2) represents a promising strategy for the treatment of sepsis and septic shock.
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PMID:Effects of intravenous infusion of highly purified vitamin B2 on lipopolysaccharide-induced shock and bacterial infection in mice. 1517 75

Oxidative and nitrosative stressor agents can trigger DNA strand breakage, which then activates the nuclear enzyme poly(ADP-ribose) synthetase (PARS). Activation of the enzyme depletes the intracellular concentration of energetic substrates such as nicotinamide adenine dinucleotide (NAD). This process can result in cell dysfunction and cell death. PARS inhibitors have been successfully used in ischemia-reperfusion injury, inflammation and sepsis in several experimental models. In our experimental study, we investigated the role of 3-aminobeanzamide (3-AB), a non-specific PARS inhibitor, on the intestinal mucosal barrier after burn injury. Twenty-four Wistar rats were randomly divided into three groups. The sham group (n = 8) was exposed to 21 degrees C water while the burn group (n = 8) and the burn + 3-AB group (n = 9) were exposed to boiling water for 12s to produce a full thickness burn in 35-40% of total body surface area. In the burn + 3-AB group, 10mg/kg of 3-AB was given intraperitoneally 10min before thermal injury. Twenty-four hours later, tissue samples from mesenteric lymph nodes (MLN), spleen and liver were obtained under sterile conditions for microbiological analysis and ileum samples were obtained for biochemical and histopathological analysis. In burn group, the incidence of bacteria isolated from MLN and spleen was significantly higher than other groups (P < 0.05). 3-AB pre-treatment prevented burn induced bacterial translocation and it significantly reduced burn induced intestinal injury. Tissue malondialdehyde and 3-nitrotyrozine levels were found significantly lower than that of the burn group. These data suggest that the relationship between PARS pathway and lipid peroxidation in intestinal tissue and PARS has a role in intestinal injury caused by thermal injury.
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PMID:The role of poly(ADP-ribose) synthetase inhibition on the intestinal mucosal barrier after thermal injury. 1555 90

Poly (ADP-ribose) synthetase (PARS) is a nuclear enzyme activated by DNA single-strand breakage, which can be triggered by reactive oxygen and nitrogen species. Activation of this enzyme depletes the intracellular concentration of energetic substrates such as nicotinamide adenine dinucleotide (NAD). Eventually, this process results in cell dysfunction and cell death. PARS inhibitors have successfully shown benefits in several experimental models of ischemia-reperfusion injury, inflammation, and sepsis. In our experimental study, we investigated the role of 3-aminobenzamide (3-AB), a nonspecific PARS inhibitor, in systemic organ damage after burn. Twenty-four Wistar rats were randomly divided into three groups. The sham group (n=8) was exposed to 21 degrees C water, and the burn group (n=8) and the burn-plus-3-AB group (n=8) were exposed to boiling water for 12 s to produce a full-thickness burn of 35-40% of total body surface area. In the burn-plus-3-AB group, 3-AB 10 mg/kg was given intraperitoneally 10 min before thermal injury. Twenty-four hours later, tissue samples were obtained for biochemical analysis from lung, intestine, and kidney. In the burn group, tissue malondialdehyde, myeloperoxidase, and 3-nitrotyrosine levels in all organs were significantly increased compared with the sham group (p<0.05). Pretreatment with 3-AB significantly reduced burn-induced organ damage (p<0.05). These data provide evidence of the relationship between the PARS pathway and lipid peroxidation in systemic organ damage after thermal injury.
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PMID:Poly (adp-ribose) synthetase inhibition reduces oxidative and nitrosative organ damage after thermal injury. 1589 38

Reactive oxygen and nitrogen species, particularly peroxynitrite, are potent inducers of tissue damage during systemic inflammatory response and circulatory shock. Recent evidence indicates that the toxicity of these species largely depends on their ability to trigger activation of the nuclear enzyme poly(adenosine 5'-diphosphate ribose) polymerase-1 (PARP-1). Following excessive activation, PARP-1 depletes the intracellular stores of its substrate, nicotinamide adenine dinucleotide, thus slowing glycolysis, generation of high energy phosphates, and mitochondrial electron transport. Consequently, the severe metabolic crisis induced by PARP-1 activation results in acute cell dysfunction and necrotic cell death. In addition, activation of PARP-1 plays an important role in the upregulation of inflammatory cascades via a functional association with mitogen-activated protein kinases and several transcription factors, such as nuclear factor kappa B, resulting in augmented expression of pro-inflammatory cytokines, chemokines, adhesion molecules, and enzymes. In severe sepsis and hemorrhage, PARP-1 activation has emerged as one of the central mechanisms of systemic inflammation, endothelial dysfunction, peripheral vascular failure, and reduction of cardiac contractility. Innovative therapeutic strategies based on the pharmacological inhibition of PARP-1 catalytic activity might provide benefits by preventing tissue injury, organ dysfunction, and lethality associated with these conditions.
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PMID:Role of nitrosative stress and activation of poly(ADP-ribose) polymerase-1 in cardiovascular failure associated with septic and hemorrhagic shock. 1602 25

Pre-B-cell colony-enhancing factor (PBEF) was recently found in high levels in visceral fat, and was therefore renamed visfatin. This new adipocytokine exerts insulin-mimetic effects in mice and in cultured cells by binding to and activating the insulin receptor. Despite some recent studies on this topic, the proposed role of visfatin in metabolism remains largely unknown. Initially, PBEF/visfatin was discovered as a cytokine for the differentiation of B-cells. Pre-B-cell colony-enhancing factor was also shown to inhibit apoptosis of neutrophils in sepsis and was discussed as a novel biomarker for acute lung injury (ALI). Although PBEF is missing a signal sequence, its secretion and function as a molecule involved in the regulation of inflammatory processes was reported in several studies. Investigations of PBEF/visfatin in gestational membranes suggest a function in the physiologic and pathologic pathways leading to labor. Furthermore, it was found upregulated in colorectal cancer and was brought into connection with the regulation of the cell cycle. Intra-cellular, PBEF/visfatin acts as a cytosolic enzyme involved in nicotinamide adenine dinucleotide (NAD) synthesis. This activity was shown to be important for vascular smooth muscle cell (SMC) maturation, indicating a possible involvement in vascular pathology. The important physiologic role of PBEF/visfatin is also underlined by its evolutionary highly conserved gene in different species. This review summarizes the current knowledge of the various functions of PBEF/visfatin towards involvements in pathophysiology of several diseases.
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PMID:Visfatin/pre-B-cell colony-enhancing factor: a protein with various suggested functions. 1739 4

Carbohydrates and lipid oxidations support energy metabolism by distinct pathways exhibiting similarities and differences. Alterations of energy metabolism during sepsis are well recognized; however, failure of oxygen or substrate supply is not a prominent cause. The occurrence of a "mitochondrial cytopathy" induced by sepsis explains some of these abnormalities, which may represent a "metabolic hibernation," a potential strategy of defense during the very acute phase of the illness. Our view of the involvement of mitochondrial metabolism in cell signaling has evolved considerably. Because of the structure of the respiratory chain, the way electrons are provided (upstream or downstream of complex 1 [i.e., nicotinamide adenine dinucleotide {reduced form} or flavin adenine dinucleotide {reduced form}]) plays an important role in the regulation of several functions, including the yield of adenosine triphosphate synthesis and the production of reactive oxygen species. Moreover, the modern view of energy channeling and compartmentation in the cell may open attractive hypotheses regarding the changes in cellular energy distribution in pathologic states, such as sepsis.
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PMID:Mitochondrial function and substrate availability. 1771 93

Pre-B cell colony-enhancing factor (PBEF), also known as visfatin, is a highly conserved, 52-kDa protein found in living species from bacteria to humans. Originally a curiosity identified serendipitously in microarray studies but having no obvious functional importance, PBEF has now been shown to exert three distinct activities of central importance to cellular energetics and innate immunity. Within the cell, PBEF functions as a nicotinamide phosphoribosyl transferase, the rate-limiting step in a salvage pathway of nicotinamide adenine dinucleotide (NAD) biosynthesis. By virtue of this role, it can regulate cellular levels of NAD and so impact not only cellular energetics but also NAD-dependent enzymes such as sirtuins. Although it lacks a signal peptide, PBEF is released by a variety of cells, and elevated levels can be found in the systemic circulation of patients with a variety of inflammatory diseases. As an extracellular cytokine, PBEF can induce the cellular expression of inflammatory cytokines such as TNF-alpha, IL-1beta, and IL-6. Finally, PBEF has been shown to be an adipokine expressed by fat cells that exerts a number of insulin mimetic and antagonistic effects. PBEF expression is up-regulated in a variety of acute and chronic inflammatory diseases including sepsis, acute lung injury, rheumatoid arthritis, inflammatory bowel disease, and myocardial infarction and plays a key role in the persistence of inflammation through its capacity to inhibit neutrophil apoptosis. This review summarizes the admittedly incomplete body of emerging knowledge about a remarkable new mediator of innate immunity.
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PMID:Pre-B cell colony-enhancing factor (PBEF)/visfatin: a novel mediator of innate immunity. 1825 66

A significant role for alveolar macrophages (AM) in the pathophysiology of sepsis-induced acute lung injury (ALI) has been shown; however, the mechanisms behind AM-related lung injury remain relatively uncertain. We examined the role of AM nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in pulmonary endothelial cell septic injury. NADPH oxidase is one of the major sources of cellular reactive oxygen species and has been implicated in endothelial injury in ALI. Pulmonary microvascular endothelial cells (PMVEC) monolayers were grown on Transwell inserts and incubated with wild-type and NADPH oxidase-deficient AM in the presence or absence of cytomix (equimolar TNF-alpha, IL-1beta, and IFN-gamma). Injury to the monolayers was assessed by trans-PMVEC Evans blue (EB)-labeled albumin flux. We found AM under cytomix stimulation caused significant EB-albumin flux across the PMVEC monolayers, and this effect was attenuated by the genetic deletion of AM NADPH oxidase. The pharmacological inhibition of AM NADPH oxidase with apocynin and PR-39 also significantly reduced AM-dependent PMVEC injury. In the AM-PMVEC cocultures, we also assessed PMVEC injury through measurement of protein oxidation and lipid peroxidation. AM were shown to cause a significant increase in these markers of PMVEC injury, which was also attenuated by the inhibition of NADPH oxidase or through the use of NADPH oxidase-deficient AM. PMVEC NADPH oxidase was shown not to significantly contribute to PMVEC injury in our studies. From our findings we have concluded that AM NADPH oxidase is crucial for the septic increase in pulmonary vascular permeability.
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PMID:Septic pulmonary microvascular endothelial cell injury: role of alveolar macrophage NADPH oxidase. 1907 58

Neutrophils are highly specialized innate effector cells that have evolved for killing of pathogens. Human neonates have a common multifactorial syndrome of neutrophil dysfunction that is incompletely characterized and contributes to sepsis and other severe infectious complications. We identified a novel defect in the antibacterial defenses of neonates: inability to form neutrophil extracellular traps (NETs). NETs are lattices of extracellular DNA, chromatin, and antibacterial proteins that mediate extracellular killing of microorganisms and are thought to form via a unique death pathway signaled by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-generated reactive oxygen species (ROS). We found that neutrophils from term and preterm infants fail to form NETs when activated by inflammatory agonists-in contrast to leukocytes from healthy adults. The deficiency in NET formation is paralleled by a previously unrecognized deficit in extracellular bacterial killing. Generation of ROSs did not complement the defect in NET formation by neonatal neutrophils, as it did in adult cells with inactivated NADPH oxidase, demonstrating that ROSs are necessary but not sufficient signaling intermediaries and identifying a deficiency in linked or downstream pathways in neonatal leukocytes. Impaired NET formation may be a critical facet of a common developmental immunodeficiency that predisposes newborn infants to infection.
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PMID:Impaired neutrophil extracellular trap (NET) formation: a novel innate immune deficiency of human neonates. 1996 99


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