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)

Macrophage migration inhibitory factor (MIF) has a key role in regulation of innate and adaptive immunity and is implicated in sepsis, tumorigenesis, and autoimmune disease. MIF deficiency or immunoneutralization leads to protection against fatal endotoxic, exotoxic, and infective shock, and anti-inflammatory effects in other experimental models of inflammatory disease. We report a novel regulatory role of MIF in type 1 IL-1R and p55 TNFR expression and function. Compared with wild-type cells, MIF-deficient cells were hyporesponsive to IL-1- and TNF-induced MAPK activity, AP-1 activity, and cellular proliferation, while NF-kappaB function was preserved. Hyporesponsiveness of MIF-deficient cells was associated with down-regulation of cytokine receptor expression, which was restored by reconstitution of either an upstream kinase of MAPK, MAPK/ERK kinase, or MIF. These data suggest that endogenous MIF is required for cytokine activation of MAPK/AP-1 and cytokine receptor expression. This autocrine regulatory pathway defines an important amplifying role of endogenous MIF in cytokine-mediated immune and inflammatory diseases and provides further molecular evidence for the critical role of MIF in cellular activation.
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PMID:Regulation of IL-1 and TNF receptor expression and function by endogenous macrophage migration inhibitory factor. 1698 23

Research using mammalian burn models has defined significant cardiac deficits after burn injury. The physiologic response to burn and burn complicated by sepsis, including the cardiac dysfunction associated with these insults, remains a very complex physiologic process which, despite active study, remains unclear. The well-characterized inflammatory mediators such as tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6 continue to play an active role in mediating cardiac dysfunction. However, perhaps of greater interest are the late mediators, high mobility group box 1 and macrophage migration inhibitory factor, because they offer a very realistic window for therapeutic intervention for controlling the inflammatory response. In addition, several other mediators of cardiac dysfunction have been identified and include the heat shock proteins, apoptosis, and the inflammatory caspases. These new mediators provide opportunities for therapeutic intervention, but further research is needed to clarify the importance of their mechanisms of action and the complex interactions between these various signaling pathways.
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PMID:Cardiac molecular signaling after burn trauma. 1699 99

The chemokine monocyte chemoattractant protein 1/CC chemokine ligand 2 (MCP-1/CCL2) is a potent chemoattractant of mononuclear cells and a regulatory mediator involved in a variety of inflammatory diseases. In the present study, we demonstrate that mcp-1/ccl2-deficient mice are more susceptible to systemic inflammatory response syndrome induced by lipopolysaccharide and to polymicrobial sepsis induced by cecum ligation and puncture (CLP) when compared with wild-type mice. Interestingly, in the CLP model, mcp-1/ccl2-deficient mice efficiently cleared the bacteria despite an impaired recruitment of leukocytes, especially mononuclear cells. The increased lethality rate in these models correlates with an impaired production of interleukin (IL) 10 in vivo. Furthermore, macrophages from mcp-1/ccl2-deficient mice activated with lipopolysaccharide also produced lower amounts of IL-10 and similar tumor necrosis factor compared with wild-type mice. We observed a drastic increase in the amounts of macrophage migration inhibitory factor at 6 and 24 h after CLP in mcp-1/ccl2-deficient mice. These results indicate that endogenous MCP-1/CCL2 positively regulates IL-10 but negatively controls macrophage migration inhibitory factor during peritoneal sepsis, thus suggesting an important immunomodulatory role for MCP-1/CCL2 in controlling the balance between proinflammatory and anti-inflammatory factors in sepsis.
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PMID:Increased susceptibility to septic and endotoxic shock in monocyte chemoattractant protein 1/cc chemokine ligand 2-deficient mice correlates with reduced interleukin 10 and enhanced macrophage migration inhibitory factor production. 1704 15

A series of phenolic hydrazones were synthesized and evaluated for their inhibition of macrophage migration inhibitory factor (MIF) tautomerase activity. Compound 7 emerged as a potent inhibitor of MIF with an IC50 of 130 nM. Compound 7 dose-dependently suppressed TNFalpha secretion from lipopolysaccharide stimulated macrophages. The therapeutic importance of the MIF inhibition by 7 is demonstrated by the significant protection from the lethality of sepsis when administration of the compound was initiated in a clinically relevant time frame.
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PMID:Phenolic hydrazones are potent inhibitors of macrophage migration inhibitory factor proinflammatory activity and survival improving agents in sepsis. 1738 48

This prospective study aimed to delineate the association between the serum levels of macrophage migration inhibitory factor (MIF) and the risks of early mortality in 112 patients who presented with clinically severe sepsis. Previous studies showed that elevated serum MIF levels on the first day are associated with an increased risk of 28-day mortality. Nonsurvivors may be the sickest population on arrival. Not all patients with severe sepsis follow the same clinical pathway, however, and the sequential change in MIF might be an important predictor of mortality. We hypothesized that, for septic patients, in addition to serum MIF levels on day 1, the percentage of change in MIF between days 1 and 2 after arriving in the emergency department predicts the probability of early mortality. Serum MIF levels were measured on days 1 (emergency department arrival) and 2 (24 h after arrival). Patients with a high percentage of increase between MIF levels on days 1 and 2 had higher 3-day (odds ratio, 1.8; 95% confidence interval, 1.2-2.6; P = 0.003) and 7-day mortalities (odds ratio, 1.4; 95% confidence interval, 1.0-1.9; P = 0.03) after adjusting for age and day-1 serum MIF levels. In conclusion, an increase in serum MIF from the first to second day of admission in patients with severe sepsis indicates a higher risk of early mortality; therefore, these patients need more aggressive therapeutic intervention.
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PMID:Increases in serum macrophage migration inhibitory factor in patients with severe sepsis predict early mortality. 1743 55

Pharmacophores are chemical scaffolds upon which changes in chemical moieties (R-groups) at specific sites are made to identify a combination of R-groups that increases the therapeutic potency of a small molecule inhibitor while minimizing adverse effects. We developed a pharmacophore based on a carbonyloxime (OXIM) scaffold for macrophage migration inhibitory factor (MIF), a protein involved in the pathology of sepsis, to validate that inhibition of a catalytic site could produce therapeutic benefits. We studied the crystal structures of MIF.OXIM-based inhibitors and found two opposite orientations for binding to the active site that were dependent on the chemical structures of an R-group. One orientation was completely unexpected based on previous studies with hydroxyphenylpyruvate and (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1). We further confirmed that the unexpected binding mode targets MIF in cellular studies by showing that one compound, OXIM-11, abolished the counter-regulatory activity of MIF on anti-inflammatory glucocorticoid action. OXIM-11 treatment of mice, initiated 24 h after the onset of cecal ligation and puncture-induced sepsis, significantly improved survival when compared with vehicle-treated controls, confirming that inhibition of the MIF catalytic site could produce therapeutic effects. The crystal structures of the MIF inhibitor complexes provide insight for further structure-based drug design efforts.
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PMID:Alternative chemical modifications reverse the binding orientation of a pharmacophore scaffold in the active site of macrophage migration inhibitory factor. 1752 94

To determine the relationship between macrophage migration inhibitory factor (MIF) and disseminated intravascular coagulation (DIC) in patients with systemic inflammatory response syndrome (SIRS) and sepsis, and their relationship to multiple organ dysfunction syndrome (MODS) and prognosis, we conducted a prospective cohort study. Forty-eight patients with SIRS or sepsis were classified as 20 DIC and 28 non-DIC patients. MIF, tumor necrosis factor-alpha (TNF-alpha), soluble fibrin, protein C activity (protein C), and plasminogen activator inhibitor-1 (PAI-1) were all measured within 24 h after the patients met the criteria of SIRS or sepsis (day 0), and on days 1 to 4. The number of SIRS criteria that the patients met and the DIC scores were determined simultaneously. In DIC patients, significantly higher levels of MIF, TNF-alpha, soluble fibrin, PAI-1 were found compared with non-DIC patients. We also found significantly lower protein C levels in the DIC patients than in the non-DIC patients. Significant correlations were found between the peak levels of MIF and soluble fibrin in the DIC patients (rs = 0.496, p < 0.0407). All DIC patients had MODS and also showed a higher number of dysfunctioning organs and a poorer prognosis than the non-DIC patients. A simple logistic regression analysis showed the peak MIF levels and DIC significantly to be related to the patients' death (odds ratio 1.016 and 40.5; p < 0.0409, p < 0.0009, respectively). In conclusion, DIC patients with elevated levels of MIF and TNF-alpha had more organ dysfunctions leading to a poor prognosis in a population of SIRS and sepsis patients. MIF may therefore play a role in the inflammatory and thrombotic processes in DIC patients.
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PMID:High macrophage migration inhibitory factor levels in disseminated intravascular coagulation patients with systemic inflammation. 1753 4

The macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine central to the response to endotoxemia, is a putative biomarker in acute lung injury (ALI). To explore MIF as a molecular target and candidate gene in ALI, the MIF gene and protein expression were examined in murine and canine models of ALI (high tidal volume mechanical ventilation, endotoxin exposure) and in patients with either sepsis or sepsis-induced ALI. MIF gene expression and protein levels were significantly increased in each ALI model, with serum MIF levels significantly higher in patients with either sepsis or ALI compared with healthy controls (African- and European-descent). The association of 8 MIF gene polymorphisms (single-nucleotide polymorphisms (SNPs)) (within a 9.7-kb interval on chromosome 22q11.23) with the development of sepsis and ALI in European-descent and African-descent populations was studied next. Genotyping in 506 DNA samples (sepsis patients, sepsis-associated ALI patients, and healthy controls) revealed haplotypes located in the 3' end of the MIF gene, but not individual SNPs, associated with sepsis and ALI in both populations. These data, generated via functional genomic and genetic approaches, suggest that MIF is a relevant molecular target in ALI.
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PMID:Macrophage migration inhibitory factor in acute lung injury: expression, biomarker, and associations. 1758 60

Inflammation provokes significant abnormalities in host metabolism that result from the systemic release of cytokines. An early response of the host is hyperglycemia and resistance to the action of insulin, which progresses over time to increased glucose uptake in peripheral tissue. Although the cytokine TNF-alpha has been shown to exert certain catabolic effects, recent studies suggest that the metabolic actions of TNF-alpha occur by the downstream regulation of additional mediators, such as macrophage migration inhibitory factor (MIF). We investigated the glycemic responses of endotoxemic mice genetically deficient in MIF (MIF(-/-)). In contrast to wild-type mice, MIF(-/-) mice exhibit normal blood glucose and lactate responses following the administration of endotoxin, or TNF-alpha. MIF(-/-) mice also show markedly increased glucose uptake into white adipose tissue in vivo in the endotoxemic state. Treatment of adipocytes with MIF, or anti-MIF mAb, modulates insulin-mediated glucose transport and insulin receptor signal transduction; these effects include the phosphorylation of insulin receptor substrate-1, its association with the p85 regulatory subunit of PI3K, and the downstream phosphorylation of Akt. Genetic MIF deficiency also promotes adipogenesis, which is in accord with a downstream role for MIF in the action of TNF-alpha. These studies support an important role for MIF in host glucose metabolism during sepsis.
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PMID:The proinflammatory cytokine macrophage migration inhibitory factor regulates glucose metabolism during systemic inflammation. 1791 26

Insulin is essential for glucose homeostasis. Insulin/glucose-insulin-potassium (GIK) regimen suppresses the production of tumor necrosis factor-alpha (TNF-alpha), interleukins-6 (IL-6), macrophage migration inhibitory factor (MIF) and other pro-inflammatory cytokines and reactive oxygen species (ROS), enhances the synthesis of endothelial nitric oxide (eNO), and anti-inflammatory cytokines interleukins-4 (IL-4) and interleukin-10 (IL-10). In subjects who are critically ill, monocyte HLA-DR expression was significantly decreased with a concomitant increase in plasma IL-10 and IL-4 concentrations. Large increases in the plasma concentrations of TNF-alpha, IL-6, sustained increase in the expression of leukocyte CD11b/CD18, and ROS generation following surgery and infections were found to be associated with increased mortality. By virtue of its actions on pro- and anti-inflammatory cytokines and ROS, insulin may have the ability to alter HLA-DR expression in the critically ill and thus bring about its beneficial actions in sepsis/septic shock, myocardial recovery following acute myocardial infarction, improve prognosis of those who are critically ill, and suppress inflammation.
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PMID:Insulin in the critically ill with focus on cytokines, reactive oxygen species, HLA-DR expression. 1792 13


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