UMLS:C0036690 - FACTA Search

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

Peritonitis induced by cecal ligation and puncture (CLP) produces a systemic inflammatory response that can be largely mitigated by pretreatment of the animals with lipopolysaccharide (LPS tolerance). Although cells of myeloid origin and endothelial cells have been shown to contribute to the development of LPS tolerance, little is known regarding the potential role of parenchymal cells in this phenomenon. The major aim of the present study was to assess whether cardiac parenchymal cells (myocytes) contribute to the development of LPS tolerance. Six hours after induction of CLP rats were neutropenic and acidotic, the myocardium contained a leukocyte infiltrate [myeloperoxidase (MPO) activity was increased], and myocardial contractile function was impaired (left ventricular developed pressure was decreased). In animals that were pretreated with LPS these manifestations of sepsis were largely reversed. Further studies focused on the responses of cardiac myocytes to CLP and whether myocytes contributed to the development of LPS tolerance. Myocytes were isolated from rat hearts 6 h after induction of CLP. These myocytes 1) exhibited an impaired ability to shorten in response to pacing, 2) contained the nuclear transcription factor NF-kappaB in their nuclei, 3) increased their surface levels of intercellular adhesion molecule-1 (ICAM-1), and 4) were hyperadhesive for neutrophils. All of these events did not occur in myocytes obtained from animals that were pretreated with LPS before induction of CLP. These findings indicate that LPS tolerance can be induced in myocytes with respect to polymorphonuclear leukocyte adhesion, presumably by an inability of CLP to mobilize NF-kappaB to the myocyte nuclei and, thereby, preventing an increase in surface levels of ICAM-1.
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PMID:LPS pretreatment ameliorates peritonitis-induced myocardial inflammation and dysfunction: role of myocytes. 1048 7

Interferon-gamma (IFN-gamma) has been implicated in the mortality of animal models of endotoxemia. On the other hand, the specific role of IFN-gamma in the development of organ inflammation in a model of polymicrobial sepsis has not been elucidated. In this study, we hypothesized that IFN-gamma plays an important role in lung inflammation after cecal ligation and puncture (CLP). To verify this hypothesis, lung tissue was removed 5 h after CLP or from sham controls. The mRNA expression (by RT-PCR) of IFN-gamma was increased in lung homogenates of CLP rats compared to sham controls. Using immunohistochemistry, we show for the first time the increased presence of IFN-gamma staining cells in the lung following CLP. Only very small amounts of positive staining for IFN-gamma was observed in lungs of sham controls. The presence of IFN-gamma in the lung 5 h after CLP correlated with a twofold increases in lung superoxide generation and MPO activity (index of neutrophil sequestration). Plasma and lung nitrite levels (breakdown product of nitric oxide) were also significantly increased in CLP rats. IFN-gamma antibody (1.2 mg/kg, i.v.) administered immediately after CLP significantly decreased lung superoxide levels to levels similar to the sham controls without affecting MPO activity, or lung or plasma nitrite levels. These results provide evidence that IFN-gamma may contribute to lung inflammation 5 h following CLP via increased production of superoxide.
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PMID:Role of interferon-gamma in lung inflammation following cecal ligation and puncture in rats. 1048

In our study the pathomechanism of sepsis-induced early myocardial depression was investigated. We determined the effects of the inducible nitric oxide synthase inhibitor and free radical scavenger mercaptoethylguanidine (MEG) on the myocardial contractility, the endothelial and inducible nitric oxide synthase (eNOS and iNOS) activities, and the activation and tissue accumulation of polymorphonuclear leukocytes in hyperdynamic endotoxemia in dogs. Group 1 served as endotoxemic control. Mean arterial pressure and cardiac output were measured, myocardial contractility was estimated from the end-systolic pressure-diameter relationship. The eNOS, iNOS and myeloperoxidase activities were determined on myocardial biopsy samples, and the free radical-producing capacity of granulocytes was measured from separated cells. The effect of MEG on the in vitro free radical production of isolated granulocytes was measured by chemiluminometry. Endotoxin induced a hyperdynamic circulatory reaction and significant myocardial depression. The myocardial eNOS activity was significantly increased 4 h after induction of endotoxemia and remained elevated, the iNOS activity was increased only 8 h after endotoxemia induction. The free radical-producing capacity and the myocardial accumulation of the granulocytes were significantly increased. In group 2, MEG treatment selectively inhibited the iNOS activity, prolonged the hyperdynamic circulatory reaction, prevented myocardial depression and decreased the activation and tissue accumulation of granulocytes. The compound dose-dependently decreased the in vitro activation of previously resting granulocytes. Our study demonstrates that iNOS do not contribute to the early cardiac failure in endotoxemia. MEG selectively inhibits iNOS in vivo, but its beneficial effects are rather related to the decreases in leukocyte and free radical-mediated myocardial dysfunction during early endotoxemia.
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PMID:Prevention of early myocardial depression in hyperdynamic endotoxemia in dogs. 1063 69

Oral administration of interleukin-6 (IL-6) has been shown to reduce hemorrhage-induced bacterial translocation from the gut in mice and rats. To examine the intestinal microvasculature, mice were given the electron-dense tracer horseradish peroxidase (HRP) after hemorrhage and IL-6 or vehicle administration. In normal mice and in those hemorrhaged and given IL-6, the electron-dense marker, administered intravenously, could be found in intestinal capillaries and between mucosal epithelial cells, suggesting that the microvasculature was patent. In mice given saline after shock, however, no marker was present in the gut, suggesting that the intestinal microvasculature was unable to deliver the marker to the epithelia. When mice were given HRP intralumenally (il) the tracer was able to penetrate between intestinal epithelial cells only in mice given vehicle after hemorrhage. This finding suggests that hemorrhaged mice were susceptible to sepsis and endotoxic shock from the leaky gut. In normal and IL-6-treated mice, the tracer was unable to pass from the lumen between mucosal epithelial cells, because the presence of an intact zonula occludens prevented passage. Functional studies supported the electron microscopy findings. Bacteria were cultured from the livers of mice fed vehicle after hemorrhage, but not from those fed IL-6. These data support the conclusions that parts of the intestinal microvasculature remain diminished after hemorrhage and resuscitation and that oral IL-6 restores this circulation.
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PMID:Microvascular effects of oral interleukin-6 on ischemia/reperfusion in the murine small intestine. 1075 42

Enteric gram-negative bacilli cause a severe, often life-threatening pneumonia. An improved understanding of the pathogenesis of this infection may lead to improved treatment. Nearly all of the responsible gram-negative bacilli possess capsular polysaccharides and/or an O-specific antigen as part of their lipopolysaccharide (LPS). We hypothesized that these surface polysaccharides may modulate the pulmonary host response. To investigate this, a rat pneumonitis model was used, and pulmonary neutrophil influx, a critical aspect of host defense, was measured. To assess for the effect of the capsule and O-specific antigen on this host response, three proven, isogenic derivatives that are deficient in capsular polysaccharide alone (CP9.137), the O-specific antigen moiety of the LPS alone (CP921), and both the capsular polysaccharide and O-specific antigen (CP923), as well as their wild-type parent (CP9), were used as challenge strains at various intratracheal challenge inocula (CI). Total lung myeloperoxidase (MPO), a surrogate marker for neutrophils, was measured for 15 h post-bacterial challenge. To determine the effect of capsule and the O-specific antigen on the measured MPO levels, a mathematical model was developed and used to describe the MPO levels as a function of time for each CI of each of the four strains. The results from this analysis demonstrated that in the absence of the K54 capsule, 80.7 times the CI is necessary to achieve the same maximum MPO level relative to K54 positive strains (P < 0.0001). In contrast, a diametric effect was observed in the absence of the O-specific antigen, where 0.13 times the CI was necessary to achieve the same maximum MPO level relative to O4-positive strains (P = 0.0032). No interactive effect was observed between the capsule and the O-specific antigen. These findings demonstrate that these surface polysaccharides modulate pulmonary neutrophil influx and suggest that the K54 capsular polysaccharide is a proinflammatory mediator and that the O4-specific antigen attenuates the proinflammatory response. If these speculations are substantiated, an understanding of how the capsule and the O-specific antigen modulate host response could have significant therapeutic implications. The potential use of biologic modulators directed against the host response, as well as approaches based on inactivating bacterial components (e.g., surface polysaccharides) in attempts to modify sepsis syndromes, could be developed.
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PMID:Capsular polysaccharide and O-specific antigen divergently modulate pulmonary neutrophil influx in an Escherichia coli model of gram-negative pneumonitis in rats. 1076 82

The objectives of this study were to determine 1) the changes in endothelial cell adhesion molecule expression that occur in a clinically relevant model of sepsis and 2) the dependence of these changes on endotoxin [lipopolysaccharide (LPS)]. The dual radiolabeled monoclonal antibody technique was used to quantify the expression of E- and P-selectin in LPS-sensitive (C3HeB/FeJ) and LPS-insensitive (C3H/HeJ) mice that were subjected to acute peritonitis by cecal ligation and perforation (CLP). At 6 h after CLP, the expression of both E- and P-selectin was increased in the gut (mesentery, pancreas, and small and large bowel) compared with the sham-operated and/or control animals, with a more marked response noted in LPS-insensitive mice. The lung also exhibited an increased P-selectin expression in both mouse strains. An accumulation of granulocytes, assessed using tissue myeloperoxidase activity, was noted in the lung and intestine of LPS-sensitive but not LPS-insensitive mice exposed to CLP. These results indicate that the CLP model of sepsis is associated with an upregulation of endothelial selectins in the gut vasculature and that enteric LPS does not contribute to this endothelial cell activation response.
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PMID:Role of endotoxin in the expression of endothelial selectins after cecal ligation and perforation. 1080 Dec 80

Until recently, inflammation was believed to arise from events taking place exclusively in the periphery. However, it is now clear that central neurogenic influences can either enhance or modulate peripheral inflammation. Therefore, it should be possible to improve treatment of inflammation by use of antiinflammatory agents that reduce peripheral host responses and inhibit proinflammatory signals in the central nervous system (CNS). One such strategy could be based on alpha-melanocyte stimulating hormone (alpha-MSH). Increases in circulating TNF-alpha and nitric oxide (NO), induced by intraperitoneal administration of endotoxin in mice, were modulated by central injection of a small concentration of alpha-MSH. Inducible nitric oxide synthase (iNOS) activity and iNOS mRNA in lungs and liver were likewise modulated by central alpha-MSH. Increase in lung myeloperoxidase (MPO) activity was significantly less in lungs of mice treated with central alpha-MSH. Proinflammatory agents induced by endotoxin were significantly greater after blockade of central alpha-MSH. The results suggest that antiinflammatory influences of neural origin that are triggered by alpha-MSH could be used to treat systemic inflammation. In addition to its central influences, alpha-MSH has inhibitory effects on peripheral host cells, in which it reduces release of proinflammatory mediators. alpha-MSH reduces chemotaxis of human neutrophils and production of TNF-alpha, neopterin, and NO by monocytes. In research on septic patients, alpha-MSH inhibited release of TNF-alpha, interleukin-1 beta (IL-1 beta), and interleukin-8 (IL-8) in whole blood samples in vitro. Combined central and peripheral influences can be beneficial in treatment of sepsis.
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PMID:alpha-MSH in systemic inflammation. Central and peripheral actions. 1081 51

Septicaemia is a major threat to survival during the early stages of life. There are several reports that suggest that reactive oxygen species (ROs) play a role in a wide variety of diseases. We estimated the activity of xanthine oxidase (XO), malondialdehyde (MDA) content, creatine phosphokinase (CPK) activity, activities of key enzymatic antioxidants, such as superoxide dismutase (SOD), glutathione peroxidase (GPx) and peroxidase (PO), and non-enzymatic antioxidants, viz. uric acid (UA) and albumin (ALB), in 30 neonates with sepsis and 20 age-matched controls. The babies were categorized as preterm/term, early onset/late onset, and shock/without shock, as per clinical and laboratory investigations. The study was carried out to evaluate the status of antioxidant enzymes and non-enzymatic antioxidants with a view to suggesting the introduction of antioxidant therapy in neonatal sepsis. The activities of serum XO, CPK, SOD and GPx, and the content of MDA were found to be significantly elevated in the neonates with sepsis when compared with controls. Conversely, the activity of PO and the levels of UA and ALB were decreased. The septic, full-term neonates registered significantly higher CPK activity (70%) than the preterm septic neonates. However, infants with late-onset and shock sepsis had a significant decrease in CPK activity (p < 0.05) compared with their corresponding sub-groups. Likewise, UA levels were found to be 28% depressed (p < 0.05) in the babies with late-onset sepsis and 51% increased (p < 0.001) in babies with shock compared with their respective sub-groups. Neonates with septic shock also registered a significant elevation in GPx activity (28%) compared with those without shock. This study suggests increased production of ROs in neonates with sepsis, as evidenced by the positive regulation of XO, SOD and GPx activity. The elevation of antioxidant enzymes, however, was not so effective as to protect from cellular damage and thereby result in higher MDA production. It is evident that antioxidant therapy might be useful in the management of neonates with sepsis but further detailed clinico-biochemical investigations are required to define effective antioxidant therapy.
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PMID:Alterations in antioxidant status during neonatal sepsis. 1082 10

Interleukin (IL)-10 is a biologically active anti-inflammatory and immunomodulatory cytokine. The respective effects or combined effect of ceftriaxone (Ctri) and IL-10 on host response was studied in a mouse model of lethal pneumococcal pneumonia. A once daily intraperitoneal (ip) injection of IL-10 (1 microg/mouse) for 2 days did not affect inflammation but accelerated bacterial dissemination to the bloodstream. Of mice treated with 1 ip 20 mg/kg Ctri injection, 40% developed septicemia, and only 52% survived. However, the addition of IL-10 to Ctri enhanced bacterial clearance, prevented septicemia, and yielded a 95% survival rate (P<.001). This approach also significantly (P<.05) decreased IL-1beta, IL-6, macrophage inflammatory protein-2, and myeloperoxidase levels in lungs and the production of nitric oxide in bronchoalveolar lavage fluid. Furthermore, Ctri plus IL-10 significantly (P<.05) reduced pulmonary vascular leakage and the appearance of red blood cells in alveoli. These data indicate a beneficial role for IL-10 as an adjunctive therapy to antibiotics against pneumococcal pneumonia.
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PMID:Modulation of cytokines and chemokines, limited pulmonary vascular bed permeability, and prevention of septicemia and death with ceftriaxone and interleukin-10 in pneumococcal pneumonia. 1097 29

Gram-negative sepsis and septic shock remain major causes of morbidity and mortality in the newborn. Respiratory failure is a common feature in neonatal sepsis regardless of the presence or absence of associated pneumonia. In adult animal models, cytokine-induced neutrophil chemoattractant (CINC) is a potent chemoattractant for neutrophils and believed to play a role in endotoxin-induced lung injury. We examined this in a neonatal model. Ten-day-old Sprague-Dawley rats were injected with Salmonella enteritidis endotoxin (ETX) 0.03 mg/kg i.p. and sacrificed at baseline, 30 min, 1, 2, 4, 8 and 16 h post-ETX. Blood was collected by cardiac puncture. After bronchoalveolar lavage, lung tissue was collected and evaluated for neutrophil (polymorphonuclear leukocyte) recruitment by myeloperoxidase assay (MPO). Lung CINC expression was measured by Northern blot and ELISA. Peripheral blood leukocytosis was noted at 1 h (p < 0.001) with counts below baseline at 2 and 4 h. Differential counts revealed neutrophilia at 8 h (p < 0.001). MPO revealed pulmonary PMN recruitment peaking at 1 h (p < 0.05) and CINC RNA and protein expression peaked slightly later at 2 h (p < 0. 001). No overt lung injury was noted by bronchoalveolar lavage cell counts or by histology. Therefore, pulmonary CINC expression and neutrophil recruitment follows LPS exposure in neonatal rats. This may represent priming of the lung tissue and a secondary event may be necessary for injury to occur.
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PMID:Sublethal endotoxemia promotes pulmonary cytokine-induced neutrophil chemoattractant expression and neutrophil recruitment but not overt lung injury in neonatal rats. 1109 12

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