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

Alveolar macrophages, which play a central role in lung defense, produce cytokines that help orchestrate local inflammatory responses. In sepsis and other pathological conditions, bacterial lipopolysaccharide endotoxin can induce alveolar macrophages (AM) to release proinflammatory cytokines, including tumor necrosis factor-alpha, interleukin-1, and interleukin-6. Studying the mechanisms that control alveolar macrophage cytokine production may lead to better therapies for conditions involving inflammatory lung injury. We and others have noted significant differences between alveolar macrophages and peritoneal macrophages, but large numbers of human or murine alveolar macrophages are rarely available for detailed mechanistic studies. We have obtained three murine alveolar macrophage cell lines (AMJ2C8, AMJ2C11, and AMJ2C20) and have begun to characterize their cytokine responses to proinflammatory stimuli. We measured the effects of endotoxin, interferon gamma, and the combination of the two on production of tumor necrosis factor, interleukin-1 beta, and interleukin-6 in each line. We also studied the expression of the endotoxin receptor CD14 by these cells, and investigated the effect of serum on their endotoxin responsiveness. We show here that all three of the cell lines responded in a manner comparable to that of primary murine alveolar macrophages. Observed variations between these lines may reflect the documented heterogeneity seen in populations of primary alveolar macrophages. These cell lines should expand the repertoire of tools available to investigators studying regulation of murine alveolar macrophage responses.
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PMID:Characterization of proinflammatory cytokine production and CD14 expression by murine alveolar macrophage cell lines. 933 48

Exaggerated responses by phagocytes to bacterial endotoxin [lipopolysaccharide (LPS)] may result in the sepsis syndrome. While a number of LPS-binding proteins have been identified on immune cells, only CD14 has been definitively shown to be involved in signal transduction in response to LPS. The beta2 leukocyte integrins are a family of transmembrane receptors whose expression is restricted to leukocytes. Among their many functions, the beta2 integrins are phagocytic receptors that bind a variety of bacterial products, including LPS. We hypothesize that this binding results in signal transduction. Chinese hamster ovary (CHO) fibroblast cell lines expressing the CD11a/CD18 or CD11b/CD18 antigen were engineered by gene transfection. The cell lines were stimulated with LPS. LPS-induced nuclear translocation of nuclear factor kappa B (NF-kappaB) was analyzed by electrophoretic mobility shift assay. Heterologous expression of CD11a/CD18 and CD11b/CD18 in otherwise LPS-nonresponsive fibroblasts imparted the ability to respond to LPS. Responses to LPS were observed at levels of LPS of 100 ng/ml, as were responses to whole Gram-negative bacteria. The CD11/CD18 leukocyte integrins mediate cellular responses to the LPS component of Gram-negative bacteria. CD11/CD18-mediated responses of cells to LPS are likely to affect the phagocytosis, intracellular trafficking, and killing of invading bacteria as well as to help mediate cytokine responses during endotoxemia. The development of novel therapies to prevent the end-organ damage frequently observed during sepsis will require an understanding of these complex cellular events.
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PMID:CD11/CD18 leukocyte integrins: new signaling receptors for bacterial endotoxin. 944 98

Cell wall compounds of gram-positive bacteria are capable of inducing the biosynthesis of proinflammatory cytokines in CNS cells in a similar way as lipopolysaccharide (LPS) of gram-negative bacteria does. Astrocytes, which lack the CD14 LPS receptor, have also been shown to respond to LPS-stimulation by increased cytokine synthesis. However, almost nothing is known about signaling steps involved in this process. We have therefore examined signaling events in primary cultures of rat astrocytes and the human astrocytoma cell line U373MG, brought about by LPS and pneumococcal cell walls (PCW). Of particular interest to us was the tyrosine phosphorylation patterns and activation states of three members of the mitogen activated protein kinase (MAPK) family, i.e., extracellular signal-regulated protein kinase (erk)-1, erk-2, and the recently identified p38. We show that LPS and PCW initiate tyrosine phosphorylation and activation of erk-1, erk-2, and p38 in a dose-dependent fashion. Inhibitors of tyrosine phosphorylation were able to alleviate this effect and also blocked cytokine production of astrocytes. Both, LPS- and PCW-induced responses of astrocytic cells required the presence of soluble CD14 (sCD14) present in serum. Unraveling the signaling steps induced by bacterial compounds in cells of the CNS may potentially help to elucidate the pathomechanisms of meningitis and central nervous complications of sepsis and may offer options for novel treatment strategies.
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PMID:Lipopolysaccharide and pneumococcal cell wall components activate the mitogen activated protein kinases (MAPK) erk-1, erk-2, and p38 in astrocytes. 948 15

Monocytes (MO) and macrophages (MAC) are important producers of cytokines involved in the pathophysiology of bacterial sepsis. Most studies concentrate on the effects of bacterial lipopolysaccharides (LPS) regarding the induction of cytokine gene expression and secretion in MO/MAC. Here we report that besides LPS, the synthetic lipoprotein analogue lipopeptide N-palmitoyl-S-(2,3-bis(palmitoyl)-(2RS)-propyl)-(R)-cysteinyl-alanyl- glycine (Pam3-Cys-Ala-Gly), another component of the outer membrane of Gram-negative bacteria, as well as heat-killed Staphyloccocus aureus (S. aureus/SAC) are potent stimuli for cytokines in human MO. For all three investigated stimuli we found an individual pattern of cytokine induction: LPS was most potent in inducing interleukin-6 (IL-6) synthesis, whereas for tumour necrosis factor-alpha (TNF-alpha) secretion SAC was the best stimulus. Comparable amounts of IL-8 were induced by either LPS or Pam3-Cys-Ala-Gly, with SAC being less effective even at higher concentrations. The addition of serum led to an increase in LPS-, SAC- and Pam3-Cys-Ala-Gly-stimulated TNF-alpha secretion, indicating that the presence of serum is critical not just for LPS stimulation. Furthermore, as is known for LPS, Pam3-Cys-Ala-Gly and SAC rendered MO refractory to a second bacterial stimulus. Pam3-Cys-Ala-Gly and SAC induced tolerance for itself, but LPS could partially overcome this effect. As the CD14 molecule is discussed as a common receptor for different bacterial components, we investigated whether the TNF-alpha response of MO could be blocked by anti-CD14 antibodies. MY4, a CD14 antibody, selectively blocked the TNF-alpha secretion induced by LPS but not by Pam3-Cys-Ala-Gly or SAC. In summary, we conclude that besides LPS, lipopeptide Pam3-Cys-Ala-Gly and SAC are potent stimuli for human MO, while the mechanisms of activation seem to be partially different from LPS.
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PMID:A comparative analysis of cytokine production and tolerance induction by bacterial lipopeptides, lipopolysaccharides and Staphyloccous aureus in human monocytes. 948 14

Little is known about the role of peripheral blood mononuclear cells (PBMCs) in lipopolysaccharide (LPS) elimination. We studied the endotoxin elimination capacities (EEC) of PBMCs of 15 healthy volunteers, 13 patients with sepsis, and 1 patient suffering from paroxysmal nocturnal hemoglobinuria (PNH). Although expression of CD14, the best-characterized receptor for LPS to date, was reduced from 93.6% +/- 0.8% in healthy subjects to 50.5% +/- 6.5% in patients with sepsis and was 0.3% in a patient with septic PNH, EEC were found to be unchanged. There was no difference in the amount of tumor necrosis factor alpha (TNF-alpha) released by PBMCs of healthy donors and patients with sepsis. Anti-CD14 antibodies (MEM-18) completely suppressed EEC, binding of fluorescein isothiocyanate-labeled LPS to monocytes as determined by FACScan analysis, and TNF-alpha release in all three groups studied. The concentrations of soluble CD14 (sCD14) secreted by endotoxin-stimulated PBMCs from healthy donors and patients with sepsis amounted to 4.5 +/- 0.4 and 20.1 +/- 1.8 ng/ml, respectively. Based on our results, we suggest that PBMCs eliminate LPS by at least two different mechanisms; in healthy subjects, the membrane CD14 (mCD14) receptor is the most important factor for LPS elimination, while in patients with sepsis (including the septic state of PNH), increased sCD14 participates in LPS elimination. Secretion of sCD14 is strongly enhanced under conditions of low expression of mCD14 in order to counteract the reduction of mCD14 and maintain the function of monocytes. This sCD14 may substitute the role of mCD14 in LPS elimination during sepsis. The elimination of LPS by PBMCs correlates with the binding reaction and the secretion of TNF-alpha.
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PMID:Endotoxin binding and elimination by monocytes: secretion of soluble CD14 represents an inducible mechanism counteracting reduced expression of membrane CD14 in patients with sepsis and in a patient with paroxysmal nocturnal hemoglobinuria. 948 6

The identification of lipopolysaccharide binding protein (LBP) and CD14 as key molecules in the cellular response to endotoxin has been a major advance in unravelling the pathophysiological basis of Gram-negative sepsis. Much interest has focused on developing effective anti-endotoxin treatments to abrogate the inflammatory consequences of Gram-negative infection. The therapeutic options can be divided into those aimed at neutralizing or clearing circulating endotoxin, including anti-endotoxin antibodies and endotoxin neutralizing proteins, and those that antagonize the effects of endotoxin on human cells--for example, lipid A analogues. Initial experiences with anti-lipopolysaccharide antibodies have been disappointing but a new generation of anti-endotoxin agents is about to enter clinical trials. Whether these will prove sufficiently effective to reduce the morbidity and mortality of Gram-negative sepsis remains to be seen.
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PMID:Anti-endotoxin therapeutic options for the treatment of sepsis. 951 Oct 89

Meningococcal sepsis is a good model to study the dynamic response of cytokines and other soluble factors in vivo in the early stages of the disease. Levels of soluble CD14, interleukin-6 (IL-6), IL-6 receptor (IL-6R), and C-reactive protein (CRP) have been measured in plasma from 26 children with septic shock (nine of whom had disseminated intravascular coagulation) and from ten control children. All samples were collected at the onset, before treatment, and, when possible, 24 and 48 hours later. At admission, patients had significantly higher levels of IL-6 (p < 0.001) and CRP (p < 0.001), and lower levels of IL-6R (p < 0.005) than normal controls. After 24 hours, there was a significant increase of sCD24 (p < 0.05) and CRP (p < 0.001). Although IL-6 showed a progressive decline since the onset, its levels were always higher than controls. There was an inverse correlation between IL-6 and both IL-6R (p < 0.001) and CRP (p < 0.001), probably due to the later increase of CRP. Nevertheless, sCD14 did not correlate with IL-6 levels. We have confirmed the finding of IL-6 as a sensitive and reliable inflammatory marker in septic shock. Moreover, the ratio IL-6/IL-6R may have a prognostic value, given a putative role of IL-6R in modulating the effects of IL-6 in meningococcal sepsis.
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PMID:Lack of correlation between soluble CD14 and IL-6 in meningococcal septic shock. 955 85

LPS-binding protein (LBP) recognizes bacterial LPS and transfers it to CD14, thereby enhancing host cell stimulation, eventually resulting in pathogenic states such as septic shock. Recently, LBP also was shown to detoxify LPS by transferring LPS into HDL particles in vitro. Thus, the predominant in vivo function of LBP has remained unclear. To investigate the biological activity of acute phase concentrations of recombinant murine LBP, high concentrations of LBP were investigated in vitro and in vivo. Although addition of low concentrations of LBP to a murine macrophage cell line enhanced LPS-induced TNF-alpha synthesis, acute phase concentrations of LBP blocked this effect in comparison to low-dose LBP. When injected into mice intraperitoneally, LBP inhibited LPS-mediated cytokine release and prevented hepatic failure resulting in a significantly decreased mortality rate in LPS-challenged and D-galactosamine-sensitized mice, as well as in a murine model of bacteremia. These results complement a recent study revealing LBP-deficient mice to be dramatically more susceptible to an intraperitoneal Salmonella infection as compared with normal mice. We conclude that acute phase LBP has a protective effect against LPS and bacterial infection and may represent a physiologic defense mechanism against infection. Despite the limitations of any murine sepsis model, the results shown may imply that LBP could have beneficial effects during gram-negative peritonitis in humans.
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PMID:LPS-binding protein protects mice from septic shock caused by LPS or gram-negative bacteria. 959 62

Macrophage activation by gram-negative lipopolysaccharide (LPS) has been extensively studied in an attempt to define the mechanisms that underlie innate immunity against bacterial pathogens. Dysregulation of these same mechanisms contributes to the pathophysiological consequences of bacterial sepsis. The biological actions of LPS are mediated, at least in part, by both LPS-binding proteins and LPS receptors. Several LPS receptors (CD14, the macrophage scavenger receptor, and the beta2 integrins), as well as the serum LPS-binding protein LBP, have been cloned and studied in detail. In addition, insights gained through the use of LPS antagonists have led to a better understanding of a molecule believed to function in conjunction with LPS receptors to transduce signals from the membrane to the cytosol. More recently, the use of knockout mice has greatly expanded our knowledge of the biology of LPS receptors and binding proteins. This review will summarize various phenotypes of mice that lack genes encoding CD14, the scavenger receptor, and LBP. These knockout mice have revealed several unexpected features of LPS action in vivo. Together, these animal models may provide a means to develop and evaluate novel therapeutic approaches to the control of endotoxin shock.
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PMID:LPS-binding proteins and receptors. 966 71

Lipopolysaccharide released during bacterial sepsis causes acute lung injury and ARDS. Pulmonary microvascular injury is a feature of ARDS, and vascular remodeling develops, leading to pulmonary hypertension. Pericytes in the lung circulation proliferate and contribute to the remodeling seen in experimental sepsis. It is unknown whether endotoxin can directly stimulate pericyte growth or induce contraction. We show that lipopolysaccharide from Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae increases rat lung pericyte proliferation in vitro by up to 72% on day 7 of exposure (P < 0.001), with E. coli being most potent. Lipid A is the active portion of the lipopolysaccharide, with equal activity at one-tenth the dose of lipopolysaccharide. Endotoxin's mitogenic effect requires the presence of serum, consistent with the requirement for a soluble CD14 receptor in the serum. Using FACS analysis, the pericytes lack surface CD14 receptors. Lipopolysaccharide exposure rapidly increases intracellular calcium and induces contraction of pericytes plated onto silicone membranes. Thus, endotoxin is a direct mitogen for lung pericytes in vitro and also induces pericyte contraction. Endotoxin, present in lung tissue early during sepsis, might directly contribute to the vascular remodeling in sepsis-induced lung injury.
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PMID:Effects of endotoxin on lung pericytes in vitro. 975 30


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