Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

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

We investigated whether perfusion with control blood improves pulmonary functions compromised by lipopolysaccharide (LPS) infusion. This was an animal study in a research laboratory at a university hospital by using Sprague-Dawley rats (n = 19), each weighing 325 to 350 g. All animals were pretreated with a 24 hour infusion of either LPS (5 mg/kg) or vehicle, after which, excised lungs were reperfused for 2 hours with either LPS+ or control blood. Three groups were studied: (1) group S (n = 6); LPS pretreated lungs reperfused with LPS containing blood to mimic persistent sepsis, (2) group N (n = 6); LPS pretreated lungs reperfused with control blood to mimic the removal of the septic blood components, and (3) group C (n = 7); vehicle pretreated lungs reperfused with normal blood as a control. Blood gas exchange, shunt fraction (Qs/Qt), alveolar-arterial oxygen gradient (A-aDO2), and variables for lung mechanics were measured. Leukosequestration was quantified with a myeloperoxidase (MPO) assay. The PO2 (mm Hg) values at 90 min after reperfusion in groups S, N, and C were 67.8 +/- 7.0*, 85.2 +/- 9.2, and 90.1 +/- 7.5, respectively (*p < 0.05; vs. group N and C). In addition to PO2, A-aDO2 and Qs/Qt significantly deteriorated in group S. MPO activity in the lungs after LPS infusion was significantly higher than that after vehicle infusion (1.7 +/- 0.3 vs. 0.12 +/- 0.04 units/g tissue; p < 0.001). Subsequent reperfusion with LPS+ blood (group S) increased MPO activity to 3.1 +/- 0.6 (p < 0.05), but reperfusion with normal blood (group N) caused a significant decrease to 1.1 +/- 0.2 (p < 0.05). MPO activity in group C did not significantly change compared with those after vehicle infusion. Reperfusion with control blood normalized lung function compromised by pretreatment with LPS and significantly reduced leukosequestration. These results favor the possibility that the removal of LPS+ blood components may eliminate septic lung injury.
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PMID:Perfusion with lipopolysaccharide negative blood eliminates lipopolysaccharide induced lung injury. 1119 14

In vitro, nitric oxide (NO) decreases leukocyte adhesion to endothelium by attenuating endothelial adhesion molecule expression. In vivo, lipopolysaccharide-induced leukocyte rolling and adhesion was greater in inducible NO synthase (iNOS)-/- mice than in wild-type mice. The objective of this study was to assess E- and P-selectin expression in the microvasculature of iNOS-/- and wild-type mice subjected to acute peritonitis by cecal ligation and perforation (CLP). E- and P-selectin expression were increased in various organs within the peritoneum of wild-type animals after CLP. This CLP-induced upregulation of E- and P-selectin was substantially reduced in iNOS-/- mice. Tissue myeloperoxidase (MPO) activity was increased to a greater extent in the gut of wild-type than in iNOS-/- mice subjected to CLP. In the lung, the reduced expression of E-selectin in iNOS-/- mice was not associated with a decrease in MPO. Our findings indicate that NO derived from iNOS plays an important role in sepsis-induced increase in selectin expression in the systemic and pulmonary circulation. However, in iNOS-/- mice, sepsis-induced leukocyte accumulation is affected in the gut but not in the lungs.
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PMID:Endothelial E- and P-selectin expression in iNOS- deficient mice exposed to polymicrobial sepsis. 1120 53

The major goal of this study was to investigate the mechanisms that link the host response to a local infection in the peritoneal cavity with the development of sepsis and lung injury. Rabbits were infected by intraperitoneal inoculation of fibrin clots containing Escherichia coli at 10(8), 10(9), or 10(10) cfu/clot. Physiologic, bacteriologic, and inflammatory responses were monitored, and the lungs were examined postmortem. At a dose of 10(8) cfu/clot the animals had resolving infection, and a dose of 10(9) cfu/clot resulted in persistent infection at 24 h, with minimal systemic manifestations. In contrast, inoculation of 10(10) cfu/clot resulted in rapidly lethal local infection, with septic shock and lung injury. The onset of septic shock was associated with a paradoxical lack of identifiable polymorphonuclear leukocytes (PMN; neutrophils) in the peritoneal cavity. The absence of PMN in the peritoneum was due in part to lysis of intraperitoneal PMN, because the peritoneal fluids contained free myeloperoxidase and induced rapid death of normal rabbit PMN in vitro. Although most animals became bacteremic, only those with a severe systemic inflammation response developed lung injury. These data show that control of an infection in the first compartment in which bacteria enter the host is a critical determinant of the systemic response. Above a threshold dose of bacteria, failure of the local neutrophil response is a key mechanism associated with deleterious systemic responses. Bacteremia alone is not sufficient to cause lung injury. Lung injury occurs only in the setting of a severe systemic inflammatory response and an inadequate leukocyte response at the primary site of infection.
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PMID:Septic shock and acute lung injury in rabbits with peritonitis: failure of the neutrophil response to localized infection. 1120 51

Neutrophil influx into the lung is an important event in the pathogenesis of acute lung injury in gram-negative sepsis. We hypothesized that administration of a monoclonal antibody to intercellular adhesion molecule 1 (ICAM-1, CD54), a molecule mediating neutrophil adhesion to endothelial cells, would decrease neutrophil sequestration and transmigration in the lung and attenuate lung injury in Escherichia coli sepsis. Sepsis was induced in 12 baboons primed with heat-killed E. coli (1 x 10(9) CFU/kg) 12 h before infusion of live bacteria (1 x 10(10) CFU/kg). Six animals received monoclonal antibody to CD54 (1 mg/kg) intravenously at the time of live E. coli infusion. After 48 h or when blood pressure could not be maintained, tissues were harvested and bronchoalveolar lavage (BAL) samples were obtained. Median survival time was decreased in anti-CD54-treated animals. This group also had decreased mean arterial pressure, increased metabolic acidosis, and decreased urine output. Measures of lung injury including gas exchange, lung lavage protein and lactate dehydrogenase (LDH), lung thiobarbituric acid-reactive species, and lung histology, including alveolar neutrophil volumes, were unaffected by treatment. The effect of anti-CD54 on neutrophil influx into tissues as measured by myeloperoxidase was organ specific. These data show that monoclonal antibody to CD54 does not ameliorate acute lung injury in E. coli sepsis, and septic primates given anti-CD54 have worsened metabolic parameters and decreased survival.
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PMID:Antibody to intercellular adhesion molecule 1 (CD54) decreases survival and not lung injury in baboons with sepsis. 1125 21

Sepsis and endotoxemia impair hypoxic pulmonary vasoconstriction (HPV), thereby reducing systemic oxygenation. To assess the role of leukotrienes (LTs) in the attenuation of HPV during endotoxemia, the increase in left lung pulmonary vascular resistance (LPVR) before and during left mainstem bronchus occlusion (LMBO) was measured in mice with and without a deletion of the gene encoding 5-lipoxygenase (5-LO). LMBO increased the LPVR equally in saline-challenged wild-type and 5-LO-deficient mice (96+/-20% and 94+/-19%, respectively). Twenty-two hours after challenge with Escherichia coli endotoxin, the ability of LMBO to increase LPVR was markedly impaired in wild-type mice (27+/-7%; P<0.05) but not in 5-LO-deficient mice (72+/-9%) or in wild-type mice pretreated with MK886, an inhibitor of 5-LO activity (76+/-10%). Compared with wild-type mice, endotoxin-induced disruption of lung structures and inflammatory cell influx in the lung were markedly attenuated in 5-LO-deficient mice. Administration of MK571, a selective cysteinyl LT(1) receptor antagonist, 1 hour before endotoxin challenge preserved HPV and attenuated pulmonary injury in wild-type mice but did not prevent the endotoxin-induced increase in pulmonary myeloperoxidase activity. Taken together, these findings demonstrate that a 5-LO product, most likely a cysteinyl LT, contributes to the attenuation of HPV and to pulmonary injury after challenge with endotoxin.
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PMID:Attenuation of hypoxic pulmonary vasoconstriction by endotoxemia requires 5-lipoxygenase in mice. 1132 76


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