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)

Extensive research has been done to elucidate the cellular and biochemical events of a healing wound. Similarly, new techniques are continually being investigated which would stimulate and augment the reparative process. This paper describes the uses and biochemistry of povidone-iodine which has gained widespread acceptance as a surgical preparation. However, its use as a topical agent for treating head and neck wound infections, dehiscences, and salivary fistulas has gained little recognition. Povidone-iodine is a unique compound formed by binding free iodine to polyvinylpyrrolidone. Previously, the toxic effects of iodine limited its use to preparation of the skin for surgery. When bound to the pyrrolidine molecule, iodine becomes water soluble and markedly less toxic. As a result, the broad antimicrobial spectrum of iodine may be used topically to control wound sepsis. It can be applied to mucosal surfaces without producing burns. The brown color acts as an indicator of its clinical effectiveness. When the dressings become light yellow or pale, free iodine is no longer being released and the dressing should be changed. Povidone-iodine is not a panacea for correcting interruption in the healing process during the postoperative period. The basic management of wound infections, dehiscences, and fistulas remains unchanged. Incision and drainage, debridement and flap contracture, lateralization, and diversion are necessary to initiate the healing process. Familarity with each phase of healing provides the basis for managing each of these surgical problems. Topical povidone-iodine not only controls wound sepsis but augments wound healing. The physiologic correlation with each phase of wound healing for these various surgical problems is elaborated and clinical cases presented.
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PMID:Povidone-iodine: an adjunct in the treatmen of wound infections, dehiscences, and fistulas in head and neck surgery. 85 82

Tissue factor (TF), a 46-kD glycoprotein receptor for coagulation factors VII and VIIa, is expressed on the surface of endothelial cells in response to a variety of agonists and is thought to play an important role in initiating the thrombosis associated with inflammation during infection, sepsis, and organ transplant rejection. The induction of TF activity by lipopolysaccharide (LPS) is regulated, at least partially, at a transcriptional level and an LPS response element containing two activator protein-1 sites and a nuclear factor-kappa B (NF kappa B)-like site has been localized to the 5' flanking region of the TF gene by transfection studies of TF promoter/reporter gene constructs. We have examined the effect of pyrrolidine dithiocarbamate (PDTC), a specific inhibitor of the NF kappa B pathway on the expression of the endogenous TF gene in human umbilical vein endothelial cells (HUVEC). Preincubation of HUVEC for 60 minutes with PDTC inhibited LPS induction of TF activity on the cell surface in a dose-dependent manner, with 50% inhibition occurring at 10 mumol/L PDTC and 100% inhibition at higher concentrations (> or = 100 mumol/L). Furthermore, PDTC inhibited TF expression in response to tumor necrosis factor-alpha, interleukin-1 beta, and phorbol 12-myristate 13-acetate. The effect of PDTC was at the mRNA level, as seen by the complete abrogation of the large increase in TF mRNA observed in LPS-treated HUVEC. These results suggest that endothelial cell activation by diverse agonists initiates intracellular signaling events that converge upon a common pathway involving NF kappa B and, furthermore, that NF kappa B activation is an obligatory step induction of TF.
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PMID:Pyrrolidine dithiocarbamate abrogates tissue factor (TF) expression by endothelial cells: evidence implicating nuclear factor-kappa B in TF induction by diverse agonists. 760 83

During sepsis or inflammation, the liver expresses various protective phenotypes such as the acute phase response or the heat shock response (HSR). Inducible nitric oxide synthase (NOS2) is also expressed in the liver in these conditions and may protect the liver under some circumstances and promote injury in others. We have previously reported that the acute phase response and NOS2 expression are differentially regulated, though both can be expressed simultaneously. The HSR is known to prevent expression of other genes, but its effects on NOS2 expression in the liver is unknown. Therefore, we examined how the HSR influences NOS2 expression in primary rat hepatocytes. Sodium arsenite (Ars) or hyperthermia (43 degrees C) induced the synthesis of hsp72 messenger RNA (mRNA) and protein in hepatocytes, indicating activation of the HSR. In the absence of the HSR, combinations of interleukin-1beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha), and interferon gamma (IFN-gamma) stimulated high levels of NOS2 mRNA and nitric oxide (NO) synthesis. However, treatment with Ars or heat shock significantly attenuated cytokine-induced NOS2 mRNA and NO production. The addition of the nuclear factor kappaB (NF-kappaB) inhibitor pyrrolidine dithiocarbamate also inhibited NOS2 expression, suggesting a role for NF-kappaB in the cytokine induction of NOS2 in hepatocytes. Cytokines induced the appearance of an NF-kappaB complex as shown in gel retardation assays; however, induction of the HSR by Ars partially prevented cytokine-induced formation of this band while hyperthermia had a more complete inhibition. Furthermore, preinduction of the HSR prevented the activation of the NOS2 promoter construct in hepatocytes transfected with a 1.6 kilobase NOS2 promoter linked to luciferase. These findings show that NO production in stressed cells can be modulated by the HSR, possibly through repression of NOS2 gene transcription via the inhibition of NF-kappaB.
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PMID:Heat shock response inhibits cytokine-inducible nitric oxide synthase expression in rat hepatocytes. 890 4

The tissue-fixed macrophage (Mphi) plays a key role in coordinating the excessive inflammatory response following shock or sepsis. Reactive oxygen intermediates have been recently described as second messengers involved in signal transduction in these cells, including the activation of the transcription factors NF-kappaB and AP-1. The dithiocarbamates are potent antioxidants that inhibit NF-kappaB activation. We postulated that dithiocarbamates would inhibit Mphi activation via inhibition of NF-kappaB. Rabbit alveolar Mphi were obtained by bronchoalveolar lavage and exposed to either pyrrolidine dithiocarbamate (PDTC) or diethyl dithiocarbamate (DDTC) followed by stimulation with LPS (10 ng/mL). Supernatants were analyzed for TNF and prostaglandin E2, (PGE2) and F2-isoprostane (ISP), a marker of membrane lipid peroxidation, production at 18 h. PDTC and DDTC significantly enhanced production of TNF while inhibiting PGE2 and ISP production compared with LPS alone (p < .05). Northern blots revealed increased mRNA for TNF after pretreatment with PDTC, compared with LPS alone. Western blots and oligonucleotide gel shifts of nuclear proteins revealed inhibition of NF-kappaB activation by both PDTC and DDTC. AP-1 activity was shifted to earlier time points by PDTC pretreatment. These results demonstrate transcriptional and functional enhancement of TNF production despite inhibition of NF-kappaB activation. This may be due in part to a loss of autocrine feedback inhibition by PGE2 and enhancement of AP-1 activity. On the basis of these results, we conclude NF-kappaB may be necessary but, in contrast to prior analyzes, is not sufficient for optimal response of the alveolar Mphi to endotoxin.
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PMID:Dithiocarbamates enhance tumor necrosis factor-alpha production by rabbit alveolar macrophages, despite inhibition of NF-kappaB. 964 90

Lipopolysaccharide (LPS) is a key mediator of multiple organ injury observed in septic shock. The mechanisms responsible for LPS-induced multiple organ injury remain obscure. In the present study, we tested the hypothesis that the LPS-induced injury occurs through activation of the transcription factor, nuclear factor-kappaB (NF-kappaB). We examined the effects of inhibiting NF-kappaB activation in vivo in the rat on LPS-induced: 1) gene and protein expression of the cytokine-inducible neutrophil chemoattractant (CINC) and intercellular adhesion molecule-1 (ICAM-1); b) neutrophil influx into lungs, heart, and liver; and c) increase in microvascular permeability induced by LPS in these organs. LPS (8 mg/kg, i.v.) challenge of rats activated NF-kappaB and induced CINC and ICAM-1 mRNA and protein expression. Pretreatment of rats with pyrrolidine dithiocarbamate (50, 100, and 200 mg/kg, i.p.), an inhibitor of NF-kappaB activation, prevented LPS-induced I-kappaBalpha degradation and the resultant NF-kappaB activation and inhibited, in a dose-related manner, the LPS-induced CINC and ICAM-1 mRNA and protein expression. Pyrrolidine dithiocarbamate also markedly reduced the LPS-induced tissue myeloperoxidase activity (an indicator of tissue neutrophil retention) and the LPS-induced increase in microvascular permeability in these organs. These results demonstrate that NF-kappaB activation is an important in vivo mechanism mediating LPS-induced CINC and ICAM-1 expression, as well as neutrophil recruitment, and the subsequent organ injury. Thus, inhibition of NF-kappaB activation may be an important strategy for the treatment of sepsis-induced multiple organ injury.
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PMID:Pyrrolidine dithiocarbamate prevents I-kappaB degradation and reduces microvascular injury induced by lipopolysaccharide in multiple organs. 1010 Oct 23

Production and release of proinflammatory mediators such as tumour necrosis factor-alpha and neopterin are common events following the activation of the cellular immune system. Concerning inflammatory disorders of the lung, e.g. sepsis or sarcoidosis, high serum neopterin levels have been reported to correlate well with the severity of the disease. These situations are often associated with an increased expression of ICAM-1 reported to be induced in type II alveolar epithelial cells. In our study we investigated the potential effects of neopterin on ICAM-1 synthesis in the type II-like pneumocyte cell line L2. Detection of ICAM-1 gene expression by reverse transcriptase-polymerase chain reaction revealed a dose-dependent effect of neopterin, with maximum impact following 12-h incubations. Comparable results were obtained when ICAM-1 protein synthesis was measured via a cell-based ELISA. In a second set of experiments we were able to show that coincubation of L2 cells with pyrrolidine dithiocarbamate (PDTC) significantly suppressed neopterin-induced ICAM-1 synthesis. Since PDTC is known to be a potent inhibitor of NF-kappaB, the stimulating effects of neopterin on ICAM-1 gene expression and protein generation may be mediated by activation of this transcription factor. From these data we conclude that neopterin stimulates ICAM-1 production in L2 cells. In vivo, these effects may contribute to the prolongation of the inflammatory response, including cytotoxic cell host defence mechanisms that impair the functions of the airway epithelium.
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PMID:Neopterin-induced expression of intercellular adhesion molecule-1 (ICAM-1) in type II-like alveolar epithelial cells. 1059 64

IL-1beta stimulation of cultured epithelial cells induces the degradation of IkappaBalpha and the consequent nuclear translocation of NF-lambdaB, a critical proinflammatory transcription factor in the mucosal host immune response. The role of reactive oxygen intermediates, serine protease activity, and tyrosine kinase activity in the activation of NF-kappaB is weakly conserved across various cell lineages and has not been defined in human enterocytes, a major target of oxidant stress in sepsis, thermal injury, and hemorrhagic shock. We report here that in Caco-2BBe cells, a transformed human colon cancer cell line with features of small intestinal epithelial cells in culture, exposure to oxidant stress (hydrogen peroxide 1-10 mM) did not induce NF-kappaB activation. Similarly, scavenging of free radicals and oxidants by pyrrolidine dithiocarbamate and dimethyl sulfoxide did not block IL-1beta-induced IkappaBalpha degradation and NF-kappaB activation. Genistein, a nonspecific tyrosine kinase inhibitor, also had no effect on IL-1beta-mediated effects on NF-kappaB. Serine protease inhibition by tosyl-lysine-chloromethylketone and tosyl-phenylalanine-chloromethylketone inhibited IkappaBalpha degradation and NF-kappaB activation stimulated by IL-1beta. Our data highlight the strong divergence between epithelial and mononuclear cells in the signal transduction pathways relating IL-1beta stimulation and NF-kappaB nuclear translocation.
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PMID:IL-1beta induction of NF-kappaB activation in human intestinal epithelial cells is independent of oxyradical signaling. 1063 62

Studies indicate that critically ill patients who succumb to sequela of sepsis/multiorgan failure, as well as septic animals, exhibit an apparently pathological increase in apoptosis (Ao) in the immune system. However, the mechanisms regulating these changes are unclear. Studies also indicate that, dependent on the cell population and the nature and/or duration of the stimuli, activation of the nuclear factor (NF)-kappaB can either suppress or enhance Ao. Thus, the aim of this study was to determine the contribution of NF-kappaB activation to the onset of Ao seen in divergent immune cell populations during sepsis, as produced by cecal ligation and puncture (CLP). To assess this, C3H/HeN mice were pretreated (for 1 h) subcutaneously with either 100 mg/kg body weight of pyrrolidine dithiocarbamate (PDTC), an NF-kappaB inhibitor, or with saline vehicle, prior to subjecting them to CLP or Sham-CLP (Sham). Thymocytes, phagocytes, and Peyers Patch cells were harvested 24 h later, and the extent of Ao was determined by flow cytometry. The results indicate that PDTC pretreatment had no marked effect on the increase in thymocyte or phagocyte Ao seen following CLP, but there was a significant decline in the extent of Ao observed in septic mouse Peyer's patch B cells. To the extent that this was a result of NF-kappaB inhibition, we demonstrate by Western analysis, electrophoretic mobility shift assay (EMSA) and transfactor assay that the translocation of c-Rel to septic mouse Peyer's patch B cell nuclei is attenuated by PDTC. PDTC pretreatment also markedly reduced the number of Peyer's patch B cells that were producing IgA as well as attenuated the increase of proinflammatory cytokines in the blood. Interestingly, PDTC pretreatment did not restore peritoneal macrophage function or improve animal survival. Taken together, the inability of PDTC pretreatment to alter the Ao response of thymocytes or phagocytes, while inhibiting the increase in Peyer's patch B cell Ao in septic mice, implies not only that the activation of NF-kappaB has highly tissue/cell-specific effects that must be discerned when trying to clarify the pathophysiological role of NF-kappaB in sepsis, but that the activation of NF-kappaB may contribute to the early adaptive responses required by the host to fend off septic challenge.
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PMID:NF-kappaB activation has tissue-specific effects on immune cell apoptosis during polymicrobial sepsis. 1239 84

Preadministration of antioxidants such as pyrrolidine dithiocarbamate (PDTC) and phenyl N-tert-butyl nitrone (PBN) protects animals from lethality in sepsis models. However, the requirement of preadministration greatly diminishes the clinical significance of these studies. Although the synthetic antioxidant PBN has been shown to effectively protect rodents from lethality in endotoxemia (lipopolysaccharide [LPS] model), preliminary screening indicates that pre- or postadministration of PBN does not protect in the rat cecal ligation and puncture (CLP) model. We show in this report that in a rat CLP model, the administration of PBN (150 mg/kg, 30 min after CLP) followed by the antibiotic imipenem (IMP; 10 mg/kg, 1 h after CLP) significantly increased survival compared with other single treatment groups. Previously, we have shown that PBN's protection in a rat LPS model is mediated by the overproduction of the anti-inflammatory cytokine interleukin (IL)-10. We show in this study that the increase in survival found in the PBN + IMP-treated group was abrogated by immunoneutralization with anti-IL-10 antibody, indicating that endogenous IL-10 is an effective protective factor. Plasma LPS levels were shown to be elevated after imipenem treatment, and the increased LPS level could have assisted to overproduce endogenous IL-10, as in the case of the PBN-treated LPS model. Statistical analysis indicated that the increase of IL-10 in PBN + IMP-treated group at early time period has significant association to the improvement of survival.
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PMID:Antioxidant amplifies antibiotic protection in the cecal ligation and puncture model of microbial sepsis through interleukin-10 production. 1263 May 25

The role of endothelin ETA receptors in sepsis-induced mortality and edema formation was evaluated with a selective antagonist ABT-627 [2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)amino carbonylmethyl)-pyrrolidine-3-carboxylic acid]. Sprague-Dawley rats received saline (control group), Escherichia coli endotoxin (10 mg/kg, sepsis group) or infusion of ABT-627 prior and immediately after saline and endotoxin injection. Mortality, edema formation (wet/dry ratios), and multiple tissue injury (indicated by serum concentrations of creatinine, urea, bilirubin, creatine kinase, lactate dehydrogenase, and aspartate aminotransferase) were monitored within 5 h. Endotoxin injection elicited 64% mortality, significantly augmented edema formation in liver, heart, lung, and kidney, and raised serum levels of tissue injury markers. Pretreatment with ABT-627 completely reversed endotoxin-induced mortality, significantly attenuated wet/dry ratios of the heart, liver, and kidney, but not lungs, and reduced serum levels of creatine kinase, creatinine, aspartate aminotransferase, and lactate dehydrogenase, but not that of urea and bilirubin. These results suggest that endothelin ETA receptors play a significant role in promoting mortality, edema formation (except in the lungs), and tissue injury in animals with severe sepsis.
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PMID:Role of endothelin ETA receptors in sepsis-induced mortality, vascular leakage, and tissue injury in rats. 1290 4


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