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)

The role of the macrophage system in shock pathogenesis now embraces both classic endocytic functions as well as the more recently discovered function of the macrophages as a multifaceted secretory apparatus. Among the major macrophage secretory products are the monokines, regulatory proteins that mediate via both local or paracrine and systemic or endocrine mechanisms, the nonspecific host defense and metabolic responses to inflammation and sepsis. Evidence is reviewed for a monokine involvement in the alterations of protein, fat, and carbohydrate metabolism in sepsis and/or endotoxicosis, viz., enhanced muscle proteolysis, enhanced hepatic acute phase protein synthesis, depressed lipogenesis and lipoprotein lipase function, enhanced peripheral glucose oxidation, and depression of hepatic gluconeogenesis. Monokines are also related to the disturbed endocrine mechanisms of sepsis, viz., enhanced insulin secretion and depressed adrenal steroidogenesis. It is suggested that the macrophage system mediates via secretion of monokines an integrated fuel substrate and hormonal adjustment to sepsis, which on the one hand may provide optimal metabolic homeostasis for systemic host defense, but on the other hand, if allowed to act unchecked, may contribute to the metabolic dyshomeostasis of septic shock.
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PMID:Monokines and the metabolic pathophysiology of septic shock. 388 Dec 89

The chemokines are a superfamily of small proteins secreted primarily by leukocytes and related by a conserved four-cystein motif. In the present study we investigated the serum levels of macrophage inflammatory protein 1 alpha (MIP-1 alpha) and interleukin-8 (IL-8). MIP-1 alpha is a neutrophil chemotactic protein important in acute and chronic inflammation. Recent studies demonstrated that MIP-1 alpha may also act as potent inhibitor of hemopoetic stem cell proliferation, which may be important in the development of prolonged anemia in patients suffering from Plasmodium falciparum malaria. IL-8 serum concentrations correlate with severity and outcome of infectious diseases. Moreover, recent reports indicate that IL-8 plays a major role in fatal gram-negative sepsis. It was the aim of this study to investigate the time course of MIP-1 alpha and IL-8 concentrations in patients suffering from acute P. falciparum infection. Blood samples of 20 patients suffering from severe P. falciparum malaria were investigated. MIP-1 alpha and IL-8 concentrations were determined using ELISA technique at admission, on Days 7, 14, 21, and 28. Maximal concentrations of MIP-1 alpha and IL-8 were found on Day 14, at a time when parasites were not detected in the smears. The serum levels of IL-8 on the day of admission were correlated to the parasite count. No correlation was seen between the hematokrit values and the MIP-1 alpha concentrations at any time.
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PMID:Serum concentrations of MIP-1 alpha and interleukin-8 in patients suffering from acute Plasmodium falciparum malaria. 760 66

Tumor necrosis factor-alpha (TNF-alpha), a monokine that contributes to vascular dysfunction accompanying the host response to gram-negative sepsis, has been shown to increase vascular permeability in vivo and to diminish the barrier function of cultured endothelial cell (EC) monolayers. The studies reported here indicate that a mechanism through which TNF alters EC barrier function involves a reduction in intracellular adenosine 3',5'-cyclic monophosphate (cAMP) content, due in part to increased cyclic nucleotide phosphodiesterase (CNPDE) activities. TNF increased the diffusional transit of [3H]sorbitol, [3H]inulin, and 125I-labeled albumin across confluent bovine aortic EC monolayers. This effect of TNF was both time and dose dependent and occurred in parallel with a fall in EC cAMP. cAMP analogues, such as dibutyryl cAMP (DBcAMP), prevented TNF-induced perturbation of EC barrier function. TNF also mediated another important alteration in the EC phenotype, in that both mRNA and activity of the anticoagulant cofactor thrombomodulin were reduced after exposure of EC to TNF and were normalized by the addition of DBcAMP. EC monolayers exposed to TNF-alpha showed increased cAMP levels when exposed to 3-isobutyl-1-methylxanthine, a nonspecific CNPDE inhibitor. Ion exchange chromatography of cytosol derived from TNF-treated EC consistently showed an approximately 245% increase in phosphodiesterase (PDE) IV (high-affinity, cAMP-specific PDE) activity as identified by rolipram inhibition. PDE II activity was increased by 150% after TNF-alpha treatment of early passage EC, which was identified by cGMP-activated hydrolysis of cAMP. Western and Northern analyses, as well as activity studies, revealed that TNF treatment did not change the amount of PDE IV protein or mRNA but rather increased the specific activity of the isozyme, suggesting that a posttranslational modification had occurred. These data indicate that activation of EC CNPDE activity and decreased intracellular cAMP may represent a mechanism by which TNF increases EC permeability and promotes a procoagulant EC phenotype.
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PMID:TNF modulates endothelial properties by decreasing cAMP. 776 2

Interleukin 10 (IL-10) decreases production of IL-1, IL-6, and tumor necrosis factor alpha (TNF-alpha) in vitro, and neutralization of IL-10 in mice leads to elevation of the same monokines. We test here whether this monokine-suppressing property of IL-10 confers on it the capacity to protect mice from lipopolysaccharide-induced shock, a monokine-mediated inflammatory reaction. A single injection of 0.5-1 microgram of recombinant murine IL-10 reproducibly protected BALB/c mice from a lethal intraperitoneal injection of endotoxin. This result was obtained whether the IL-10 was administered concurrently with, or 30 min after the injection of endotoxin. The protective effect of IL-10 was reversed by prior injection of neutralizing anti-IL-10 antibodies, and correlated with a substantial decrease in endotoxin-induced TNF-alpha release. These data implicate IL-10 as a candidate for treatment of bacterial sepsis, and more generally as an effective antiinflammatory reagent.
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PMID:Interleukin 10 protects mice from lethal endotoxemia. 845 15

Elevated zinc serum concentrations have been shown to restore impaired immune response. Therefore, pharmacologic zinc supplementation has been used to improve immune function, particularly in intensive care patients. In these patients, Gramnegative sepsis, the symptoms of which are predominantly caused by LPS-induced release of monokines, represents a serious problem. We have recently shown that zinc enhances induction of TNF-alpha and IL-1 beta in cultures of PBMC by LPS. By fluorescence polarization and infrared spectroscopic measurements we found that zinc addition leads to decreased fluidity of the hydrocarbon chains of LPS. Experiments at different temperatures showed that the less fluid gel (beta) phase of LPS is more effective in cytokine induction than the more fluid liquid-crystalline (alpha) phase. Our studies suggest that the synergistic effect of zinc on monokine induction by LPS is caused by direct interaction of zinc with LPS altering the fluidity of the hydrocarbon chains. Although this effect is zinc specific, other divalent ions, like cobalt and nickel, with a complex structure and size comparable to those of zinc also enhance LPS-induced monokine secretion but to a much lesser extent. Our data indicate that the zinc level represents a relevant clinical parameter in the treatment of Gram-negative infection. This reveals potential risks in the therapeutic application of zinc.
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PMID:Zinc enhances lipopolysaccharide-induced monokine secretion by alteration of fluidity state of lipopolysaccharide. 881 25

Thrombosis and disseminated intravascular coagulation (DIC) are common complications of infections. Abnormal activation of coagulation is due in part of expression of tissue factor on intravascular cells in response to cytokines, including interleukin-1 beta (IL1 beta ) and tumor necrosis factor (TNF). Both TNF and IL1 beta are thought to play significant roles in producing the pathologic manifestations of sepsis. Therefore, we examined the effects of thrombin on TNF and IL1 beta secretion of monocytes, and the ability of monocyte products to promote tissue factor expression by endothelial cells. Human monocytes were treated with thrombin or a thrombin receptor agonist peptide (SFLLRN), and/or bacterial lipopolysaccharide (LPS). The agonists were removed, and monocytes cultured 18 hours. The monocyte-conditioned supernatants were assayed for TNF and IL1 beta antigen, and for their ability to induce tissue factor expression on human umbilical vein endothelial cells and the Ea.hy endothelial cell line. Thrombin alone did not promote monocyte TNF or IL-1 beta secretion. However, thrombin enhanced LPS-induced TNF and IL1 secretion. Supernatants from monocytes exposed to LPS plus thrombin promoted greater tissue factor expression on endothelial cells than supernatants from those treated with LPS only. SFLLRN did not increase TNF secretion in response to LPS, but did enhance LPS-induced IL1 beta secretion and tissue factor-inducing activity. Neither SFLLRN nor active thrombin augmented the level of mRNA for TNF above that induced by LPS alone. However, both increased the LPS-induced level of IL1 beta message. Thus, thrombin enhanced LPS-induced TNF and IL1 beta secretion by monocytes. Unexpectedly, the effects on these two cytokines were mediated by different mechanisms. Enhancement of LPS-induced IL1 beta secretion was largely mediated via the tethered ligand type thrombin receptor and correlated with an increase in the steady state level of mRNA. By contrast, enhanced TNF required proteolytically active thrombin, but was not mediated by the tethered ligand receptor. These data demonstrate that physiologically relevant amounts of thrombin can synergize with endotoxin to stimulate monokine release. Thrombin could thereby play a role in the complex network of mediators involved in the pathophysiology of sepsis. We speculate that limiting thrombin activity during DIC could be a beneficial adjunct in the management of sepsis.
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PMID:Thrombin enhances monocyte secretion of tumor necrosis factor and interleukin-1 beta by two distinct mechanisms. 884 45

Interleukin-10 (IL-10) has been shown to be protective in models of sepsis. This protection is mediated in part by inhibition of monokine-dependent processes. Because IL-10 can act on other cells to regulate inflammatory events, and because we have previously shown that clearance of inflammation is an active process, we examined whether IL-10 could regulate processes of resolution during pulmonary inflammation induced by lipopolysaccharide (LPS) challenge. Administration of 1 microgram of IL-10 with 6 micrograms LPS intratracheally to rats did not alter the time of onset or the magnitude of the initial response, as assessed by bronchoalveolar lavage (BAL) neutrophilia. However, the extent of the neutrophilia was markedly reduced at 18 h, and longer, after challenge. During ex vivo culture of cells obtained by BAL, neutrophils died by apoptosis and were engulfed by macrophages. Clearance of neutrophils was more rapid in the cultured BAL of rats treated with IL-10. In separate experiments, IL-10 did not reduce survival rates of untreated human neutrophils, but did inhibit LPS-induced increases in survival in a dose-dependent fashion. Thus IL-10 did not modulate the onset of, or peak of, neutrophil accumulation in response to LPS but did promote the clearance of recruited neutrophils in vivo. The mechanism of this anti-inflammatory action may be through the prevention of stimulated increases in neutrophil survival.
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PMID:IL-10 enhances resolution of pulmonary inflammation in vivo by promoting apoptosis of neutrophils. 889 3

We hypothesized that chemokines may play important roles in a cecal ligation and puncture (CLP) model of septic peritonitis in CD-1 mice. Concentrations of C-X-C (macrophage inflammatory protein 2 [MIP-2] and ENA-78) and C-C (MIP-1alpha and JE) chemokines were measured (by enzyme-linked immunosorbent assay) in serum, peritoneal lavage fluid, lung, and liver at 4, 8, 24, 48, and 96 h after CLP. Significant elevations in all measured chemokines occurred in peritoneal fluid after CLP (P < 0.05). MIP-2, in particular, increased dramatically (>400-fold, P < 0.001) in peritoneal fluid, serum, and to a lesser extent lung and liver (P < 0.05). Increased MIP-2 was correlated with severity of sepsis (P < 0.001). To determine the significance of this finding, mice were passively immunized prior to CLP with polyclonal antibody to MIP-2, which decreased mortality from 85 to 38% at 96 h (P < 0.01). To further understand the mechanism of the effect of MIP-2, additional measurements demonstrated that anti-MIP-2 prior to CLP decreased the percent neutrophils in peritoneal fluid (55% +/- 12%, compared with 82% +/- 10% in controls), but no significant changes in tumor necrosis factor alpha, interleukin-6, or interleukin-10 occurred. MIP-2 contributes to the inflammatory response and overall mortality in this model of severe septic peritonitis, possibly by increasing recruitment of neutrophils, which clear bacteria but may also injure the host.
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PMID:Elevated levels of macrophage inflammatory protein 2 in severe murine peritonitis increase neutrophil recruitment and mortality. 928 62

Macrophage inflammatory protein (MIP)-1alpha and MIP-1beta regulate leukocyte activation and trafficking. To assess the role of MIP-1alpha and MIP-1beta in human inflammation, healthy subjects were studied during experimental endotoxemia with prior administration of ibuprofen, a cyclooxygenase inhibitor, or dimeric p75 tumor necrosis factor (TNF)-alpha receptor, a TNF antagonist; septic patients were also studied. Following endotoxin, blood levels of both MIP-1 molecules rose acutely and fell to baseline by 6 h (P=. 001). While MIP-1 mediates fever in animals independent of cyclooxygenase blockade, in subjects given endotoxin and ibuprofen, MIP-1 levels increased and fever was suppressed. MIP-1 levels were not diminished by inhibiting circulating TNF-alpha in humans. In septic patients, elevated levels of MIP-1alpha and MIP-1beta were detected within 24 h of sepsis and fell in parallel with TNF-alpha and interleukin-6 (P<.01). MIP-1alpha and MIP-1beta increase during acute inflammation but are not associated with fever in endotoxemic humans during cyclooxygenase blockade.
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PMID:Detection of macrophage inflammatory protein (MIP)-1alpha and MIP-1beta during experimental endotoxemia and human sepsis. 984 32

Sequestration of neutrophils and release of histotoxic mediators are considered important for the development of pathologic alterations of the lung defined as adult respiratory distress syndrome. Mechanisms of inflammatory lung injury caused by abdominal sepsis were investigated using the colon ascendens stent peritonitis (CASP) model that closely mimics the human disease. In the CASP model, a continuous leakage of intraluminal bacteria into the peritoneal cavity is induced by implantation of a stent in the ascending colon, generating a septic focus. In contrast to the cecal ligation and puncture model of peritonitis, survival of mice following CASP surgery is dependent on IFN-gamma, but independent of tumor necrosis factor (TNF). Here we show that the systemic inflammation induced by CASP surgery results in a rapid and profound increase of lung vascular permeability that was associated with the activation and recruitment of neutrophils to the lung. Activation of circulating granulocytes was characterized by increased production of serine proteinases and reactive oxygen metabolites, as well as elevated expression of cell surface Mac-1. Expression of MIP-2, KC, MIP-1alpha and E-selectin mRNA in lung was strongly increased within 3 h following CASP surgery, whereas up-regulation of IP-10, MCP-1 and P-selectin was delayed. In contrast, induction of RANTES, LIX, ICAM-1 and VCAM-1 mRNA was weak or not detectable after CASP surgery. Importantly, recruitment of leukocytes to the lung was normal in lipopolysaccharide-resistant mice, and was not affected by antibody neutralization of TNF or the chemokines MIP-2 and KC.
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PMID:Mechanisms of acute inflammatory lung injury induced by abdominal sepsis. 1006 20


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