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)

Polymicrobial sepsis induces suppression of macrophage function as determined by a reduction of pro-inflammatory cytokine production upon re-exposure to lipopolysaccharide (LPS) in vitro. We examined whether macrophages were refractory to only LPS challenge or if they were immunoparalyzed and unable to respond to other stimuli such as lipoteichoic acid (LTA) or zymosan (ZYM). This study evaluated the capacity of peritoneal macrophages to produce pro-inflammatory and anti-inflammatory cytokines as well as chemokines following mild or severe sepsis induced by cecal ligation and puncture (CLP). Peritoneal macrophages were isolated 29 h after CLP and challenged with different stimuli. LPS was a more potent stimulus for cytokine induction than LTA or ZYM in both mild and severe sepsis. In mild sepsis, the macrophage cytokine response to LPS was selective and less refractory than in severe sepsis. While production of IL-6 and KC was reduced, secretion of TNF-alpha and MIP-1alpha was enhanced in those cells isolated from mice with mild sepsis. Production of IL-10 and the IL-1 receptor antagonist , MIP-2, and MCP-1 in response to LPS stimulation was equivalent to the amount produced by naive macrophages. Our results indicate that macrophages are not immunoparalyzed during sepsis and may still be induced to secrete some inflammatory mediators.
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PMID:Selective macrophage suppression during sepsis. 1591 75

Neutrophil associated lung injury is identified with a variety of local and systemic priming insults. In vitro studies have shown that TNF-alpha mediated suppression of neutrophil apoptosis is due to the secretion of interleukin-8 (IL-8), a human chemokine shown to alter neutrophil chemotaxis. Our initial in vitro antibody neutralization studies with neutrophil chemotactic proteins, keratinocyte-derived chemokine (KC) and macrophage inflammatory protein-2alpha (MIP-2alpha), mouse IL-8 homologues, indicate that MIP-2alpha but not KC appears to mediate TNF-alpha suppression of mouse neutrophil apoptosis. Therefore, we hypothesized that in vivo neutralization of KC or MIP-2alpha during an initial priming insult would produce differential effects on the extent of lung injury by restoring normal neutrophil apoptotic function. To assess this, mice were hemorrhaged followed with septic challenge at 24 h. Antibody against KC or MIP-2alpha or a nonspecific IgG was given during resuscitation immediately following hemorrhage. Anti-MIP-2alpha treatment resulted in a significant reduction in lung tissue IL-6 and myeloperoxidase levels. Percentage of neutrophil apoptosis increased significantly in the anti-KC group. Tissue and plasma KC and MIP-2alpha were reduced in their respective treatment groups. These data suggest that KC and MIP-2alpha differ in their mediation of neutrophil function (apoptosis and chemotaxis) and contribution to the pathogenesis of lung injury following hemorrhage subsequent to sepsis.
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PMID:Divergent roles of murine neutrophil chemokines in hemorrhage induced priming for acute lung injury. 1596 14

In sepsis, and in models of sepsis including endotoxemia, impaired neutrophil recruitment and chemotaxis have been reported. The inability of the endotoxemic neutrophil to chemotax could be attributed to the fact that intracellular signaling via LPS overrides signals from endogenous chemokines or, alternatively, that sequestration of neutrophils into lungs prevents access to peripheral tissues. Using both in vitro and in vivo chemotaxis assays the authors established that neutrophils from healthy mice chemotaxed in vivo toward MIP-2, whereas endotoxemic neutrophils did not. Since LPS activates leukocytes via the p38 MAPK pathway, SKF86002, a p38 MAPK inhibitor, was given to endotoxemic animals. SKF86002 significantly reversed the LPS-induced impairment in emigration of endotoxic neutrophils in response to MIP-2. Neutrophil chemotaxis in vitro was also impaired by LPS, via a p38 MAPK-dependent pathway, and this impairment could be reversed via p38 MAPK inhibition. Although neutrophil numbers dropped in the circulation and trapped in lungs during endotoxemia, SKF86002 did not reverse these parameters, demonstrating that p38 MAPK inhibition did not release trapped neutrophils from the lungs. In conclusion, the data suggest that the impaired emigration and chemotaxis of neutrophils at peripheral sites during endotoxemia may be partially due to a p38 MAPK-mediated inhibition of neutrophil responses to endogenous chemokines.
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PMID:Lipopolysaccharide: a p38 MAPK-dependent disrupter of neutrophil chemotaxis. 1602 Mar 90

Biglycan, a small leucine-rich proteoglycan, is a ubiquitous ECM component; however, its biological role has not been elucidated in detail. Here we show that biglycan acts in macrophages as an endogenous ligand of TLR4 and TLR2, which mediate innate immunity, leading to rapid activation of p38, ERK, and NF-kappaB and thereby stimulating the expression of TNF-alpha and macrophage inflammatory protein-2 (MIP-2). In agreement, the stimulatory effects of biglycan are significantly reduced in TLR4-mutant (TLR4-M), TLR2-/-, and myeloid differentiation factor 88-/- (MyD88-/-) macrophages and completely abolished in TLR2-/-/TLR4-M macrophages. Biglycan-null mice have a considerable survival benefit in LPS- or zymosan-induced sepsis due to lower levels of circulating TNF-alpha and reduced infiltration of mononuclear cells in the lung, which cause less end-organ damage. Importantly, when stimulated by LPS-induced proinflammatory factors, macrophages themselves are able to synthesize biglycan. Thus, biglycan, upon release from the ECM or from macrophages, can boost inflammation by signaling through TLR4 and TLR2, thereby enhancing the synthesis of TNF-alpha and MIP-2. Our results provide evidence for what is, to our knowledge, a novel role of the matrix component biglycan as a signaling molecule and a crucial proinflammatory factor. These findings are potentially relevant for the development of new strategies in the treatment of sepsis.
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PMID:The matrix component biglycan is proinflammatory and signals through Toll-like receptors 4 and 2 in macrophages. 1602 56

Acute lung injury (ALI) is identified with the targeting/sequestration of polymorphonuclear leukocytes (PMN) to the lung. Instrumental to PMN targeting are chemokines [e.g., macrophage inflammatory protein-2 (MIP-2), keratinocyte-derived chemokine (KC), etc.] produced by macrophage, PMN, and other resident pulmonary cells. However, the relative contribution of resident pulmonary macrophages as opposed to PMN in inducing ALI is poorly understood. We therefore hypothesize that depletion of peripheral blood PMN and/or the oblation of a macrophage-mediated PMN chemokine signal (via macrophage deficiency) will reduce the inflammation and ALI observed in mice following hemorrhage (Hem) and subsequent sepsis (CLP) in our murine model of ALI. To examine this we pretreated mice with either 500 microg anti-mouse Gr1 antibody/animal (to deplete PMN) or subjected mice deficient in mature macrophage (B6C3Fe-a/a-CsF1op) to Hem (90 min at 35 +/- 5 mmHg) followed by resuscitation. Twenty-four hours post-Hem, mice were subjected to CLP and killed 24 h later, and lung tissue samples were collected. Our data showed that in the absence of either peripheral blood PMN or mature tissue macrophages there was a suppression of IL-6, KC, and MIP-2 levels in lung tissue from Hem/CLP mice as well as a reduction in PMN influx to the lung and lung injury (bronchoalveolar lavage fluid protein). In contrast, lung tissue IL-10 and TNF-alpha levels were suppressed in the macrophage-deficient Hem/CLP mice compared with PMN-depleted Hem/CLP mice. Together, these data suggest that both the PMN and the macrophage are required to induce inflammation seen here, however, macrophage not PMN regulate the release of IL-10, independent of local changes in TNF.
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PMID:Role of alveolar macrophage and migrating neutrophils in hemorrhage-induced priming for ALI subsequent to septic challenge. 1615 17

Macrolide antibacterials inhibit the production of various cytokines and the migration of inflammatory cells. These anti-inflammatory actions of macrolides may be beneficial in attenuating inflammatory processes involved in bacterial sepsis. Therefore, we investigated the ability of azithromycin to attenuate the deleterious effects of lipopolysaccharide (LPS), in three different LPS-induced inflammatory models. Our results show that azithromycin (10 and 100 mg/kg) significantly attenuated the intraperitoneal LPS-induced increase in plasma TNF-alpha concentration. It also increased survival rate in a septic shock model in mice challenged with intravenous LPS. Oral treatment with azithromycin (up to 300 mg/kg) was less effective in suppressing neutrophil infiltration into the lungs 24 h after intranasal LPS challenge, possibly because of a slower onset of action or inadequate dosing. In the same model, azithromycin given intraperitoneally significantly improved inflammatory markers (total cell number, neutrophil percentage and MIP-2 concentration) in bronchoalveolar lavage fluid. In conclusion, azithromycin exhibits significant anti-inflammatory properties but the potency of such effects varies depending on the experimental model and route of administration.
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PMID:Anti-inflammatory activity of azithromycin attenuates the effects of lipopolysaccharide administration in mice. 1669 12

Neutrophil accumulation in the lung plays a pivotal role in the pathogenesis of acute lung injury during sepsis. Directed movement of neutrophils is mediated by a group of chemoattractants, especially CXC chemokines. Local lung production of CXC chemokines is intensified during experimental sepsis induced by cecal ligation and puncture (CLP), as reflected by rising levels of MIP-2 and cytokine-induced neutrophil chemoattractant-1 in bronchoalveolar lavage fluids. Alveolar macrophages are primed and blood neutrophils are down-regulated for production of MIP-2 and cytokine-induced neutrophil chemoattractant production in response to LPS and C5a. Under these conditions of stimulation, activation of MAPKs (p38, p42/p44) occurs in sham neutrophils but not in CLP neutrophils, while under the same conditions phosphorylation of p38 and p42/p44 occurs in both sham and CLP alveolar macrophages. These data indicate that, under septic conditions, there is impaired signaling in neutrophils and enhanced signaling in alveolar macrophages, resulting in CXC chemokine production, and C5a appears to play a pivotal role in this process. As a result, CXC chemokines increase in lung, setting the stage for neutrophil accumulation in lung during sepsis.
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PMID:Divergent signaling pathways in phagocytic cells during sepsis. 1681 91

Group B streptococci (GBS) have been recognised as an ever-growing cause of serious invasive infections in non-pregnant adults, in particular in association with severe underlying diseases such as diabetes mellitus. In the present study we used mice rendered diabetic to gain further insights into host-pathogen interaction during induced GBS sepsis and septic arthritis. Type I diabetes was induced in adult CD-1 mice by low-dose streptozotocin treatment. Mice were then infected with different doses of GBS, and mortality, appearance of arthritis, growth of microorganisms in the organs and cytokine and chemokine profile were assessed in diabetic and control animals. The LD50 was significantly lower in diabetics than in controls, while both incidence and severity of arthritis were higher. A significantly higher number of microorganisms were recovered from the organs of diabetic mice than in controls. The worsening of sepsis and arthritis was associated with a significant increase in systemic and local production of IL-6, IL-1 beta, TNF-alpha, IL-10, macrophage inflammatory protein 1 alpha (MIP-1alpha), and MIP-2 and with a decrease in IFN-gamma production. Taken together, our results indicate an impaired host resistance to GBS infection in diabetics, likely due to a dysregulation of the cytokine network and prolonged local inflammatory response.
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PMID:Exacerbation of group B streptococcal sepsis and arthritis in diabetic mice. 1684 99

Mortality in sepsis remains unacceptably high and attempts to modulate the inflammatory response failed to improve survival. Previous reports postulated that the sepsis-triggered immunological cascade is multimodal: initial systemic inflammatory response syndrome (SIRS; excessive pro-, but no/low anti-inflammatory plasma mediators), intermediate homeostasis with a mixed anti-inflammatory response syndrome (MARS; both pro- and anti-inflammatory mediators) and final compensatory anti-inflammatory response syndrome (CARS; excessive anti-, but no/low proinflammatory mediators). To verify this, we examined the evolution of the inflammatory response during the early phase of murine sepsis by repetitive blood sampling of septic animals. Increased plasma concentrations of proinflammatory (IL-6, TNF, IL-1beta, KC, MIP-2, MCP-1, and eotaxin) and anti-inflammatory (TNF soluble receptors, IL-10, IL-1 receptor antagonist) cytokines were observed in early deaths (days 1-5). These elevations occurred simultaneously for both the pro- and anti-inflammatory mediators. Plasma levels of IL-6 (26 ng/ml), TNF-alpha (12 ng/ml), KC (33 ng/ml), MIP-2 (14 ng/ml), IL-1 receptor antagonist (65 ng/ml), TNF soluble receptor I (3 ng/ml), and TNF soluble receptor II (14 ng/ml) accurately predicted mortality within 24 h. In contrast, these parameters were not elevated in either the late-deaths (day 6-28) or survivors. Surprisingly, either pro- or anti-inflammatory cytokines were also reliable in predicting mortality up to 48 h before outcome. These data demonstrate that the initial inflammatory response directly correlates to early but not late sepsis mortality. This multifaceted response questions the use of a simple proinflammatory cytokine measurement for classifying the inflammatory status during sepsis.
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PMID:Circulating cytokine/inhibitor profiles reshape the understanding of the SIRS/CARS continuum in sepsis and predict mortality. 1684 10

Antibody-based approaches to pneumococcal disease may hold promise for immunocompromised patients in whom vaccines are less immunogenic and/or in the context of antimicrobial resistance. Antibody-mediated protection against experimental pneumococcal pneumonia has been shown to depend on immunoregulation, but the relationship between antibody and protection against pneumococcal sepsis and immunoregulation has not been examined. Similarly, the requirement for B and T cells for antibody efficacy is not known. In this study, we determined the efficacy of the human pneumococcal capsular polysaccharide serotype 3-specific antibody, A7 (immunoglobulin M [IgM]), in secretory IgM (sIgM)(-/-), CD4(-/-), CD8(-/-), muMT(-/-), and SCID mice and investigated its effect on cytokine and chemokine expression in sera and spleens from mice with intact cellular immunity. A7 is known to be protective against systemic infection with serotype 3 and to require complement for efficacy. Compared to that of an isotype control antibody, A7 administration prolonged the survival of mice of each immunodeficient strain and was associated with a significant reduction in CFU in blood, lung, and spleen samples and a significantly reduced level of keratinocyte-derived chemokine (KC), interleukin-6 (IL-6), and macrophage inflammatory protein-2 (MIP-2) expression in normal and sIgM(-/-) mice. Studies with mice treated with penicillin revealed similar reductions in CFU and similar levels of IL-6, KC, or MIP-2 expression in A7- and penicillin-treated mice. These findings demonstrate that natural IgM and B and T cells are dispensable for A7-mediated protection against experimental pneumococcal sepsis and suggest that the efficacy of antibody-mediated protection depends on immunomodulation. Taken together, our data extend the association between antibody-mediated protection and immunomodulation to protection against systemic pneumococcal infection and to a clinically important serotype often responsible for pneumococcal sepsis.
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PMID:A human monoclonal immunoglobulin M reduces bacteremia and inflammation in a mouse model of systemic pneumococcal infection. 1730 Dec 14


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