Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Overwhelming sepsis continues to be a major source of morbidity and mortality in patients who have sustained severe traumatic injury. Recently, much interest has been focused on the role of the peripheral blood neutrophil (PMN) in infections in these patients. Two surface receptors, CD11b (CR3) and CD16 (Fc gamma RIII), are thought to participate in bacterial phagocytosis and are both present on greater than 85% of normal PMNs. We have previously shown that cells that lack both of these receptors have markedly reduced phagocytic function. The purpose of this study was to determine the effect of severe trauma on the expression of these PMN receptors. Twenty severe trauma patients, age 19-70 years, presenting with an initial APACHE II score of greater than or equal to 10 were arbitrarily divided into two groups to define severity of injury: Group A, initial APACHE II of 10-18 (n = 11) and Group B, initial APACHE II of 19-25 (n = 9). Blood was obtained on admission, on Day 3, and weekly thereafter. PMNs were stained with fluorochrome-labeled monoclonal antibodies directed against CD11b and CD16 and then analyzed by flow cytometry. Controls consisted of 14 normal adults, age 20-65 years. The percentage and absolute numbers of CD11b+/CD16+ PMNs were determined for each patient or control sample. ANOVA and multiple comparison of variables (P = 0.05) were performed for each week. Values for Group A were different from controls at Weeks 0, 1, and 3. Values for Group B were significantly lower than those of controls at all weeks.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Reduced expression of neutrophil CD11b and CD16 after severe traumatic injury. 153 18

We have investigated the effects of recombinant human tumor necrosis factor-alpha (rhTNF alpha) on polymorphonuclear leukocytes (PMNs), concentrating on the mechanisms involved in the alterations of PMN-directed migration and adherence by this cytokine. RhTNF alpha profoundly suppressed PMN chemotaxis toward FMLP by 80%. At similar concentrations, it enhanced adhesion to gelatin-coated plastic dishes by more than tenfold and increased the expression of the CD11b antigen to 182% of the control. The monoclonal antibody 60.1, which is directed against the alpha chain of the CD11b/CD18 complex, completely blocked rhTNF alpha, induced inhibition of the chemotactic response to FMLP, and rhTNF alpha induced hyperadherence, suggesting that these effects were related to rhTNF alpha's effects on CD11b antigen expression. The fluid state of the PMN membrane was also decreased by rhTNF alpha. N-butanol, a known membrane fluidizer, partially inhibited the effect of rhTNF alpha on membrane fluidity and chemotaxis and completely reversed its effects on adherence and the expression of the CD11b antigen. Pentoxifylline, an agent that has previously been studied for its ability to prevent some effects of rhTNF alpha on PMNs, completely prevented the effect of rhTNF alpha on chemotaxis, the expression of the CD11b antigen, and membrane fluidity. Pentoxifylline partially prevented changes in adherence caused by this cytokine. Increased CD11b antigen expression caused by rhTNF alpha may result in enhanced PMN adhesion and suppression of migration. These events may, in turn, lead to the accumulation of PMNs on the vascular endothelium, resulting in the extensive vascular and tissue damage that is seen in gram-negative sepsis.
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PMID:Mechanisms of tumor necrosis factor-alpha alteration of PMN adhesion and migration. 218 25

Neutrophil accumulation in tissue is a hallmark of inflammation and is associated with a variety of pathological conditions. In bacterial infection neutrophils are selectively attracted in large numbers to phagocytose and kill invading microorganisms. However, activated neutrophils can also cause injury to tissues. To investigate functional alterations in liver recruited neutrophils (PMNs), we studied the functional characteristics of circulating blood and liver sequestered PMNs in terms of host defense mechanisms, such as nitric oxide (NO) and superoxide (SO) generation, beta 2 integrin expression, phagocytosis, and eicosanoid profile. Cells were isolated from rats infused with a nonlethal dose (320 micrograms/kg) of E. coli endotoxin (ET) or pyrogen-free saline for 90 min. Liver PMNs produced significantly more NO both in the absence and in the presence of an in vitro endotoxin challenge than did blood PMNs. No significant difference was observed in phorbol myristate acetate-stimulated SO generation. Endotoxin infusion significantly up-regulated the expression of CD11b/c in circulating and even more so in liver PMNs. Phagocytosis was significantly enhanced by in vivo ET treatment in blood PMNs, and liver PMNs showed even greater phagocytic activity than blood PMNs or Kupffer cells. The percent distribution of prostaglandins D2 and E2 of total 14C-eicosanoids was significantly higher and that of thromboxane B2 and 5-, 12-, and 15-HETEs was significantly lower in liver than in blood PMNs. Our study demonstrates several functional differences between liver-recruited and circulating PMNs in an acute endotoxic model. The implications of altered neutrophil function may extend to mechanisms of host defense and hepatotoxicity associated with sepsis and endotoxemia.
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PMID:Functional characterization of peripheral circulating and liver recruited neutrophils in endotoxic rats. 752 Sep 27

After severe burns, a wound revision is often done to remove devitalized tissue and minimize bacterial growth. After such revision, the patient may show signs of sepsis. In a group of burned patients we found a transient endotoxemia, and a subsequent leukocyte activation, monitored as increased expression of the beta 2-integrin CD11b, after such wound revision. In most patients we could detect elevated levels of plasma TNF-alpha before the operation, with no increases in these levels after the operation. Plasma levels of IL-6 were elevated in all patients and increased after the wound revision in all patients. They also had elevated plasma levels of soluble E-selectin, indicating systemic inflammation. The close relation between endotoxin levels and CD11b expression, and lack of evidence for additional production of TNF-alpha, suggests that up-regulation of the beta 2 adhesion protein during wound revision is mainly caused by endotoxin interaction with the leukocyte.
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PMID:Transient endotoxemia during burn wound revision causes leukocyte beta 2 integrin up-regulation and cytokine release. 755 50

Reduced concentrations of glutamine (GLN) in plasma and skeletal muscle, defective host defense systems, and a diminished expression of the HLA-DR antigen on monocytes are important diagnostic parameters for late post-injury sepsis. In this in vitro study, we investigated whether blood monocyte-derived macrophage antigen expression and function from healthy donors is influenced by GLN. Lowering the GLN concentration in culture medium from 2 mmol/L to 200 mumol/L reduced the expression of HLA-DR by 40% (P < .001) on monocyte-derived macrophages, and decreased tetanus toxoid-induced antigen presentation. In addition, low GLN levels downregulated the expression of intercellular adhesion molecule-1 (ICAM-1/CD54), Fc receptor for IgG (Fc gamma RI/CD64), and complement receptors type 3 (CR3; CD11b/CD18) and type 4 (CR4; CD11c/CD18). A correlation was found between the phagocytosis of IgG-sensitized ox erythrocytes or opsonized Escherichia coli and the decreased expression of Fc gamma RI and CR3. Monocyte expression of CD14, CD71, and Fc gamma RIII/CD16 and capacity to phagocytose latex beads were not affected by altering the level of GLN. Depletion of GLN was associated with a significant reduction in cellular adenosine triphosphate (ATP), which may have influenced cell surface marker expression and phagocytosis. It remains to be seen whether these in vitro findings are of clinical significance in the treatment of sepsis.
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PMID:Influence of glutamine on the phenotype and function of human monocytes. 763 65

Vascular endothelial injury observed in overwhelming sepsis may be caused by neutrophil-derived enzymes. Adherence to the endothelium, a prerequisite for this process, is mediated sequentially by the neutrophil adhesion molecules L-selectin and the beta 2 integrins including CD11b/CD18. The relationship between expression of these molecules, neutrophil adherence, endothelial activation, and consequent endothelial injury was assessed by changes in heparan sulfate and fibronectin matrices. Endothelial prestimulation with lipopolysaccharide caused both an increase in adherence and a generalized reduction in heparan sulfate; disruption of the fibronectin matrix occurred only on the further addition of FMLP. Although maximal disruption of these matrices was associated with elevation of neutrophil CD11b/CD18 and reduction in L-selectin expression, these changes did not determine either the nature or extent of endothelial damage. This model may provide further insights into the interrelationship between neutrophil activation and endothelial damage in gram-negative sepsis.
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PMID:Degradation of glycosaminoglycans and fibronectin on endotoxin-stimulated endothelium by adherent neutrophils: relationship to CD11b/CD18 and L-selectin expression. 768 Jul

To evaluate the role of cellular activation markers and functional surface molecules in sepsis, specific immunophenotypes on peripheral blood leukocytes were studied in 40 subjects consisting of the following: (1) patients with septic shock; (2) patients with sepsis; (3) critically ill nonseptic patients; and (4) normal control subjects. These assays included phagocyte adhesion molecule CD11b expression, monocyte receptors HLA-DR and CD14, and lymphocyte activation markers IL-2R and HLA-DR. Patients with septic shock and sepsis had significantly increased neutrophil CD11b expression compared with normal subjects. Neutrophil HLA-DR expression did not significantly differ between groups. Monocytes from septic shock patients had significantly less HLA-DR expression than normal subjects and there was a trend toward a lower proportion of gated monocytes that expressed CD14 in septic shock patients. Septic shock patients had no significant increases in IL-2R or HLA-DR expression on CD3 lymphocytes compared with control subjects, but they had significantly lower numbers of total, CD3, CD4, and CD8 lymphocytes and a higher prevalence of anergy. Septic shock patients manifested an increase in neutrophil CD11b expression that may play a role in organ injury. In contrast, a more specific decrease in monocyte expression of functional antigens is also observed in patients with septic shock that may have implications for immunologic defense mechanisms.
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PMID:Altered leukocyte immunophenotypes in septic shock. Studies of HLA-DR, CD11b, CD14, and IL-2R expression. 768 46

We report that, in rats, the lethal consequences of high-dose endotoxin challenge are exacerbated by the intravascular administration of prostaglandin E1 but attenuated by the intravascular administration of endocytosable particles. This protection is mediated by opsonins. Nonopsonizable particles were unable to provide protection unless first pseudoopsonized with antibody directed against the CR3 (CD11b/CD18) phagocyte receptor. We show that endogenously opsonized particles can act in concert with prostaglandin E1 (putatively by elevation of neutrophil intracellular cAMP and the resultant downregulation of CR3) to completely rescue animals from the lethal late-stage sequelae of experimental endotoxemia. These data illustrate that the interaction of particles with cellular receptors can transform the overall systemic response to prostaglandin E1 from pro- to antiinflammatory. This suggests a role for multiple receptor engagement events in defining the systemic prostaglandin response and offers a rationale for developing new therapeutic modalities in the treatment of sepsis and other inflammatory diseases.
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PMID:Endogenously opsonized particles divert prostanoid action from lethal to protective in models of experimental endotoxemia. 770 30

It has been suggested that major surgery induces polymorphonuclear leukocyte (PMNL) dysfunction, which exposes patients to the development of sepsis. Conversely, the sepsis response and multisystem organ failure in patients after surgery is thought to be mediated by activated PMNLs. In a preliminary attempt to investigate this paradox, we studied functional (hydrogen peroxide production) and phenotypic (the adhesion/complement receptor CD11b) markers of PMNL activation in 28 patients undergoing elective major resectional surgery; 11 (39%) of these patients developed postoperative sepsis (the septic group). The mean (SEM) preoperative level of neutrophil CD11b expression (97.8 [6.2] mean channel fluorescence [MCF] and 101.42 [7.9] MCF; P = .74) and hydrogen peroxide production (109.51 [4.91] MCF and 104.53 [6.3] MCF; P = .5) were similar for the uncomplicated and septic groups, respectively. However, on the first postoperative day, both mean CD11b expression and hydrogen peroxide production were greater in those patients who subsequently developed postoperative sepsis (192.5 [38] MCF vs 128.6 [8.1] MCF for the septic group vs the uncomplicated group, respectively [P < .05], and 120.43 [2.56] MCF vs 109.61 [3.05] MCF for the septic group vs the uncomplicated group, respectively [P < .0001]). We suggest that an exaggerated PMNL activation response to surgery is an early event in those patients destined to develop postsurgical sepsis.
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PMID:Polymorphonuclear leukocyte activation. An early marker of the postsurgical sepsis response. 809 29

We investigated the pathogenesis of septic liver injury in rats caused by cecal ligation and puncture. In this model, numerous neutrophils accumulated in the liver in parallel with the development of liver dysfunction. The supernatants of hepatic macrophages isolated from these septic rats 24 hr after cecal ligation and puncture had enhanced chemotactic activities for human neutrophils. These results suggest that in sepsis, hepatic macrophages attract neutrophils to the liver. Human neutrophils preincubated in this macrophage supernatant had the following biological activities not seen in the sham-operated controls. (a) They became more adherent to cultured endothelial cells through up-regulation of adhesion molecules such as CD11b/CD18, (b) their chemiluminescence was markedly elevated. These functional changes of cecal ligation and puncture hepatic macrophages were the same as those in endotoxin-pretreated hepatic macrophages after isolation from normal rats. Therefore we suspect that hepatic macrophages are activated by portal vein endotoxin in sepsis. These activated hepatic macrophages secreted chemical mediators of inflammation, including leukotriene B4 and tumor necrosis factor. In conclusion, hepatic macrophages seem to interact closely with neutrophils and play an important role in the pathogenesis of septic liver injury.
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PMID:Potential role of hepatic macrophages in neutrophil-mediated liver injury in rats with sepsis. 809 95


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