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)

Major surgery as well as endotoxin-induced sepsis is accompanied by lymphocytopenia in peripheral blood. The purpose of this study was to investigate the redistribution of lymphocyte subpopulations and adhesion/activation molecules on lymphocytes. Twenty-four rats were included in the investigation. Eight rats received an intraperitoneal injection of E. coli endotoxin (2 mg kg-1), eight rats had a sham operation performed while eight rats received isotonic saline and served as a control group. Blood samples were obtained by making an incision in the tail before and 2 and 5 h after surgery or administration of endotoxin or saline. After isolation of lymphocytes by gradient centrifugation, flow-cytometric immunophenotyping was performed using CD2, CD3, CD4, CD8, CD11/CD18, CD20, CD44 and MHC II monoclonal antibodies. Endotoxemia and surgery were both accompanied by increased serum cortisol, lymphocytopenia, and a decrease in CD2, CD3 and CD4 lymphocytes. Only endotoxemia was followed by a decrease in CD8, CD11/CD18 and CD44 lymphocytes in peripheral blood. Our results show that several of the changes in lymphocyte subpopulations following surgery and sepsis are associated with increased serum cortisol. Sepsis is, in addition, accompanied by an upregulation of adhesion receptors.
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PMID:Changes in lymphocyte subpopulations and adhesion/activation molecules following endotoxemia and major surgery. 761 56

The aim of this study was to identify a novel immunological indicator useful for the early diagnosis (through a rapid and single determination) of neonatal sepsis (NS). Peripheral blood samples were taken from 63 neonates, who were classified into four groups: proven NS (n = 17); clinical NS (n = 14); disease without infection (n = 17); and healthy newborns (n = 15). Neutrophil expression of CD64, CD43, CD44, CD50, CD62L and Mac-1, and plasma levels of interleukin (IL)-1beta, IL-6, tumor necrosis factor-alpha (TNF-alpha) and soluble L-selectin (sCD62L), were determined. Expression of CD64 was significantly enhanced in the group with proven sepsis and clinical NS compared to newborns without infection (p < 0.05). Eight newborns with proven or clinical sepsis, but only one with disease without infection, showed an increased percentage of CD64+ cells (diagnostic specificity = 96.8%). No significant differences were found in the expression of the other leucocyte differentiation antigens studied. As previously described, TNF-alpha and IL-6 levels were significantly elevated in newborns with proven or clinical sepsis compared to neonates without infection (p < 0.05). Our results suggest that, through a single determination, the enhanced expression of CD64 is a highly specific indicator of NS, although its diagnostic sensitivity is low (25.8%). In contrast, we found that plasma levels of IL-1beta and sCD62L, as well as the expression of Mac-1, CD43, CD44, CD50, and CD62L, do not appear to be useful for the diagnosis of NS.
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PMID:Expression of CD64 as a potential marker of neonatal sepsis. 1243 Nov 90

Microvascular endothelial cells (mECs) circulate at higher numbers in patients with severe sepsis and hemophagocytic syndromes. Although these blood mECs might stem from damaged microvasculature, they are perfectly viable and lead to the establishment of cell lines. Such mECs were cultured in low-dose human serum pools (0.5%) and MEM-alpha medium. Antigenic profiling revealed the expression of CD36, factor VIIIa, CD95-ligand, and CD44, but also CD146. We studied the antioxidative effect of the hematopoietic growth factor G-CSF(1) after in vitro stimulation with LPS from E. coli 0111:B4; the growth factor appeared to exhibit a protective effect on organ function in patients with SIRS. mECs were stimulated with 1 micro g/mL of LPS for 24 h and 48 h with and without G-CSF (3x10(3) U/mL) preincubation. After 24 h, supernatants of the stimulated mEC were tested for IL-8 by ELISA, and cells were tested for hemoxygenase-1 (HO-1, Hsp32) by immunohistochemistry and flow cytometry using OSA110 (mAb, Stressgene). Stimulation with LPS upregulated IL-8 by a factor of 2 to 10 in mEC. Preincubation with G-CSF markedly downregulated the LPS-induced IL-8 secretion (20-50%), but IL-6 production was not affected. Upon 48 h of LPS stimulation, mECs developed massive signs of apoptosis and concomitant caspase 3 activation. Caspase 3 activity induced by LPS (24 h) or by staurosporin (6 h) was found to be dramatically downregulated by the G-CSF preincubation protocol.
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PMID:G-CSF modulates LPS-induced apoptosis and IL-8 in human microvascular endothelial cells: involvement of calcium signaling. 1503 98

Endothelial cells are highly sensitive to changes in the extracellular milieu. Sepsis results in activation of inflammatory and coagulation pathways. We hypothesized that sepsis-associated mediators may alter the response capacity (so-called "set point") of endothelial cells. Human umbilical vein endothelial cells (HUVEC) were preincubated in the presence or absence of tumor necrosis factor (TNF)-alpha, lipopolysaccharide (LPS), hypoxia, hyperthermia, and/or high glucose; treated with or without thrombin for 4 h; and then processed for RNase protection assays of selected activation markers. Priming with TNF-alpha and LPS significantly inhibited thrombin-mediated induction of vascular cell adhesion molecule-1, intercellular adhesion molecule-1, tissue factor, and E-selectin, but not platelet-derived growth factor-A or CD44. In electrophoretic mobility shift assays, thrombin-treated HUVEC demonstrated inducible binding of p65 NF-kappaB, an effect that was significantly blunted by pretreatment of cells with TNF-alpha and LPS. Consistent with these results, TNF-alpha and LPS attenuated the effect of thrombin on IkappaB phosphorylation, total cytoplasmic IkappaB, and nuclear translocation of p65 NF-kappaB. The inhibitory effect of TNF-alpha on thrombin signaling persisted for up to 24 h following removal of the cytokine. Taken together, these data suggest that inflammatory mediators prime endothelial cells to modulate subsequent thrombin response.
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PMID:Preconditioning of primary human endothelial cells with inflammatory mediators alters the "set point" of the cell. 1617 86

Immune function after hemorrhagic shock (shock) and subsequent sepsis is proofed to be sex- and age-related, showing an enhanced immune function and better survival of young females and a deteriorating immune response in advanced age. However, it remains unclear if the observed sex- and age-related effects observed on the immune function mirror the histomorphological changes of the affected organs. To scrutinize a possible association, male and female CBA/J mice (young, 2-3 months; aged 18-19 months) were subjected to shock (35 + 5 mmHg for 90 min and fluid resuscitation) or sham operation. At 48 h after shock, histological specimen at definite sites were harvested (lung, small bowel, liver, and kidney) and immediately stored in 10% formalin. After paraffin embedding, hematoxylin-eosin stain and immunohistochemical stains (vascular cell adhesion molecule 1 [VCAM-1], cluster of differentiation 44 [CD44], signal transducers and activators of transcription 3 [STAT-3]) were performed. In both sexes, aged animals developed significantly increased (P < 0.05) tissue damage in all analyzed organs compared with young mice. Sex differences were noticed in the lungs of young mice, showing a significantly (P < 0.05) lower organ damage score in female animals. Sex-related differences were found for VCAM-1 and cluster of differentiation 44 expression, whereas age-related changes were observed for STAT-3. These results demonstrate that the severity of tissue damage caused by hemorrhagic shock is influenced by sex- and age-related effects. Variances in the VCAM-1 and STAT-3 expression suggest that improved immune function in female and young subjects may be responsible for less shock-induced tissue damage.
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PMID:Influence of sex and age on morphological organ damage after hemorrhagic shock. 1799 89

An antitumor activity associated with several bacterial pathogens, including Salmonella enterica serovar Typhimurium, has been reported; however, the underlying immunological mechanism(s) that lead to an antitumor effect are currently unclear. Furthermore, such pathogens cannot be used to suppress tumor growth because of their potential for causing sepsis. Recently, we reported the characterization of S. Typhimurium isogenic mutants from which Braun lipoprotein genes (lppA and B) and the multicopy repressor of high temperature requirement (msbB) gene were deleted. In a mouse infection model, two mutants, namely, lppB/msbB and lppAB/msbB, minimally induced proinflammatory cytokine production at high doses and were nonlethal to animals. We showed that immunization of mice with these mutants, followed by challenge with the wild-type S. Typhimurium, could significantly suppress tumor growth, as evidenced by an 88% regression in tumor size in lppB/msbB mutant-immunized animals over a 24-day period. However, the lppAB/msbB mutant alone was not effective in modulating tumor growth in mice, although the lppB/msbB mutant alone caused marginal regression in tumor size. Importantly, we showed that CD44(+) cells grew much faster than CD44(-) cells from human liver tumors in mice, leading us to examine the possibility that S. Typhimurium might downregulate CD44 in tumors and splenocytes of mice. Consequently, we found in S. Typhimurium-infected mice that tumor size regression could indeed be related to the downregulation of CD44(high) and CD4(+)CD25(+) T(reg) cells. Importantly, the role of lipopolysaccharide and Braun lipoprotein was critical in S. Typhimurium-induced antitumor immune responses. Taken together, we have defined new immune mechanisms leading to tumor suppression in mice by S. Typhimurium.
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PMID:An enteric pathogen Salmonella enterica serovar Typhimurium suppresses tumor growth by downregulating CD44high and CD4T regulatory (Treg) cell expression in mice: the critical role of lipopolysaccharide and Braun lipoprotein in modulating tumor growth. 1971 97

Fragments of hyaluronan released after injury bind and activate TLR4 in a complex with CD44. Here we investigated if the recognition of hyaluronan by CD44 and TLR4 alters lipopolysaccharide (LPS) responsiveness and thus could alter the septic response. In contrast to mice injected with LPS, mice exposed to hyaluronan prior to LPS had greatly decreased serum IL-6 and TNFalpha and were protected from symptoms of sepsis. The protective effect of HA was not seen in Cd44(-/-) mice. Consistent with our findings in vivo, addition of hyaluronan to macrophages before LPS exposure significantly decreased the release of IL-6 and TNFalpha and this effect was not seen in macrophages from Cd44(-/-) mice. Investigation of the mechanism responsible for inhibition of LPS activation showed hyaluronan treatment resulted in an increase in peritoneal macrophage A20 mRNA expression, and that this was significantly reduced in macrophages from Cd44(-/-) mice and Tlr4(-/-) mice. Suppression of the A20 response with siRNA inhibited the ability of hyaluronan to protect against the cytokine response to LPS. Therefore, our results show that hyaluronan acts through TLR4, CD44 and A20 to stimulate a unique cellular response that can protect against the septic response to LPS.
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PMID:Engagement of CD44 by hyaluronan suppresses TLR4 signaling and the septic response to LPS. 1978 86

CD44 is involved in several immune responses, such as cellular adhesion, migration, proliferation, and activation. Peritonitis is an important cause of sepsis, and Escherichia coli is one of the major pathogens involved therein. We sought to determine the role of CD44 in the host response to E. coli-induced abdominal sepsis and to assess the function of CD44 in the activation of primary peritoneal macrophages by E. coli or lipopolysaccharide (LPS) purified from this bacterium by using wild-type (WT) and CD44 knockout (KO) mice. CD44 KO mice already demonstrated enhanced CXC chemokine levels in peritoneal lavage fluid at 6 h after infection, whereas tumor necrosis factor alpha (TNF-alpha) and interleukin-6 levels were elevated at 20 h postinfection. In line with this, CD44 KO mouse peritoneal macrophages released more TNF-alpha and macrophage inflammatory protein 2 (MIP-2) than did WT cells upon stimulation with E. coli or LPS in the presence of autologous serum. In contrast, plasma TNF-alpha levels were lower in CD44 KO mice and CD44 KO blood leukocytes secreted similar amounts of TNF-alpha and MIP-2 upon ex vivo incubation with E. coli or LPS. The proinflammatory phenotype of CD44 KO macrophages was not associated with an altered expression of inhibitors of Toll-like receptor signaling, whereas it could be partially reversed by addition of WT serum. CD44 deficiency did not impact on leukocyte recruitment into the peritoneal cavity or organ failure. These data suggest that CD44 differentially influences cytokine and chemokine release by different leukocyte subsets.
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PMID:CD44 deficiency is associated with enhanced Escherichia coli-induced proinflammatory cytokine and chemokine release by peritoneal macrophages. 1990 Oct 64

Endothelial cell (EC) barrier dysfunction results in increased vascular permeability, a perturbation observed in inflammatory states, tumor angiogenesis, atherosclerosis, and both sepsis and acute lung injury. Therefore, agents that enhance EC barrier integrity have important therapeutic implications. We observed that binding of high-molecular-weight hyaluronan (HMW-HA) to its cognate receptor CD44 within caveolin-enriched microdomains (CEM) enhances human pulmonary EC barrier function. Immunocytochemical analysis indicated that HMW-HA promotes redistribution of a significant population of CEM to areas of cell-cell contact. Quantitative proteomic analysis of CEM isolated from human EC demonstrated HMW-HA-mediated recruitment of cytoskeletal regulatory proteins (annexin A2, protein S100-A10, and filamin A/B). Inhibition of CEM formation [caveolin-1 small interfering RNA (siRNA) and cholesterol depletion] or silencing (siRNA) of CD44, annexin A2, protein S100-A10, or filamin A/B expression abolished HMW-HA-induced actin cytoskeletal reorganization and EC barrier enhancement. To confirm our in vitro results in an in vivo model of inflammatory lung injury with vascular hyperpermeability, we observed that the protective effects of HMW-HA on LPS-induced pulmonary vascular leakiness were blocked in caveolin-1 knockout mice. Furthermore, targeted inhibition of CD44 expression in the mouse pulmonary vasculature significantly reduced HMW-HA-mediated protection from LPS-induced hyperpermeability. These data suggest that HMW-HA, via CD44-mediated CEM signaling events, represents a potentially useful therapeutic agent for syndromes of increased vascular permeability.
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PMID:High-molecular-weight hyaluronan is a novel inhibitor of pulmonary vascular leakiness. 2070 28

During Gram-negative sepsis and endotoxemia, CD14 is essential for the recognition of LPS by the TLR4 complex and subsequent generation of systemic inflammation. However, CD14-independent responses to LPS have been reported in vitro and in vivo in selected tissues including the skin. As the liver is a key target organ for neutrophil sequestration and inflammatory pathology during sepsis and endotoxemia, we investigated the role of CD14 in the recruitment of neutrophils into the liver in a mouse model of endotoxemia. Using dynamic in vivo imaging of the liver, we observed that neutrophil recruitment within the sinusoids and post-sinusoidal venules occurred equivalently between LPS-treated wild-type and CD14-knockout mice. Neutrophil recruitment within the liver was completely independent of CD14 regardless of whether it was expressed on cells of hematopoietic or nonhematopoietic origin or in serum as soluble CD14. Whereas CD14 expression was essential for activation of circulating neutrophils and for the development of LPS-induced systemic inflammation (pulmonary neutrophil sequestration, leukopenia, and increased serum proinflammatory cytokine levels), deficiency of CD14 did not limit the adhesion strength of neutrophils in vitro. Furthermore, wild-type and CD14-knockout mice displayed identical deposition of serum-derived hyaluronan-associated protein within liver sinusoids in response to LPS, indicating that the sinusoid-specific CD44/hyaluronan/serum-derived hyaluronan-associated protein-dependent pathway of neutrophil adhesion is activated independently of CD14. Therefore, the liver microcirculation possesses a unique CD14-independent mechanism of LPS detection and activation of neutrophil recruitment.
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PMID:The role of CD14 in neutrophil recruitment within the liver microcirculation during endotoxemia. 2121 12


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