UMLS:C0036690 - FACTA Search

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

Previous investigations have shown that sepsis, while causing cardiac dysfunction, can protect the heart from ischemia-reperfusion injury. Sepsis-induced protection may be due to nitric oxide produced by an inducible form of nitric oxide synthase generated in response to cytokines released during sepsis. The glucocorticoid dexamethasone has been shown to inhibit the synthesis of the inducible form of nitric oxide synthase (iNOS). The goals of this study were to determine if dexamethasone would prevent sepsis-induced cardiac dysfunction and sepsis-induced protection of the heart from ischemia-reperfusion injury. In this experiment, rats were made septic by injecting Escherichia coli into the dorsal subcutaneous space. Control rats were injected with sterile saline. At the time of surgery, some of the control and septic animals were injected intraperitoneally with dexamethasone (3 mg/kg). The next day, 24-26 hr after injection of the first dose of E. coli, animals were anesthetized, and hearts were removed and studied in the isovolumic beating-heart preparation. Left ventricular end diastolic pressure was set to 5 mmHg, and left ventricular pressure was measured continuously throughout the protocol. Left ventricular developed pressure (LVDP) was used as an index of LV function. After stabilization, hearts were made globally ischemic for 35 min and then reperfused for 25 min. As has been shown previously, sepsis depressed LVDP but also protected the heart from further depression of LVDP by ischemia and reperfusion. Dexamethasone prevented both sepsis-induced cardiac dysfunction and sepsis-induced protection of the heart from ischemia-reperfusion injury. In addition plasma nitrite/nitrate levels were not different from control levels in the dexamethasone-treated septic rats whereas levels were elevated in the septic animals. The dexamethasone mediated abrogation of sepsis-induced cardiac dysfunction and protection during ischemia-reperfusion injury may be due to suppression of nitric oxide production.
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PMID:Dexamethasone blocks sepsis-induced protection of the heart from ischemia reperfusion injury. 1063 65

The activation of inducible form of nitric oxide (NO) synthase (iNOS, type II, or macrophage NOS) and subsequent production of free radical gas NO is an important anti-infectious and anti-tumor mechanism of innate immunity. On the other hand, high amounts of iNOS-derived NO have been implicated in self-tissue destruction during autoimmune diseases, allograft rejection, sepsis, and other disorders accompanied by excessive activation of the immune system. It is generally accepted that beneficial effects of some recently designed immunosuppressive agents primarily stem froin their ability to interfere with the function of T and/or B cells, thus preventing deleterious consequences of specific immunity-innate immunity positive feedback, with high NO production being one of them. However, it has been recently observed that drugs like cyclosporin A, FK506, leflunomide, mycophenolate mofetil, pentoxifylline, and linomide can directly modulate cytokine and/or LPS-induced NO production in various cell types in vitro, probably by interfering with iNOS gene transcription or catalytic activity of iNOS enzyme. Interestingly, some of these drugs exhibited cell-specific pattern of iNOS modulation, thus indirectly revealing distinct requirements for iNOS induction in different cell types. Possible impact of this direct and cell-selective interference with iNOS activation on the therapeutic effectiveness of immunosuppressive drugs is discussed.
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PMID:Modulation of inducible nitric oxide synthase activation by immunosuppressive drugs. 1151 33

The production of large amounts of nitric oxide (NO) by the inducible form of nitric oxide synthase (iNOS) and the subsequent production of peroxynitrite (OONO-) are believed to be major factors in the hemodynamic abnormalities of sepsis. This finding is based on data from rats and mice but has not been established in other species. Therefore, we examined the role of iNOS in lipopolysaccharide (LPS)-treated pigs, which have a hemodynamic pattern with sepsis that is more similar to humans than rats. Pigs were anesthetized, ventilated, and given LPS (n = 12), 20 microg/kg over 2 h, or saline (n = 7). They were killed after 2 (n = 8 LPS, 7 control) or 4 h (4 LPS). We measured cardiac output (CO), mean arterial (Part), and pulmonary and central venous pressures. We evaluated NO production by measuring expired NO, and plasma nitrate/nitrite concentration, NOS activity (in lung tissue), and iNOS protein by Western analysis, and immunohistochemistry (lung and liver), as well as iNOS mRNA by Northern analysis (liver and lung). We also measured nitrotyrosine as evidence of OONO- production by slot blot, Western analysis, and immunohistochemistry. By 2 h, Part fell and CO did not change so that systemic vascular resistance decreased from 21.5+/-2.9 to 12.7+/-3.1 mmHg x L(-1) x min (P < 0.05) and remained at 11.3+/-1.7 mmHg x L(-1) x min in the animals observed for 4 h. Plasma nitrate/nitrite, expired NO, and NOS activity did not change. We found no iNOS in tissues by Western analysis with 5 different antibodies but detected a small amount of iNOS by immunohistochemistry in inflammatory cells and small vessels. There was a small increase in iNOS mRNA in liver and lung. Despite the minimal increase in iNOS, nitrotyrosine was increased in small vessels and in inflammatory cells. In conclusion, caution should be used when extrapolating the septic response in rodents to other species, for the pattern of iNOS induction is very different.
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PMID:Presence of nitrotyrosine with minimal inducible nitric oxide synthase induction in lipopolysaccharide-treated pigs. 1158 Jan 15

Antithrombin (AT) prevents Escherichia coli-induced hypotension in animal models of sepsis, and it further reduces the mortality of patients with septic shock. In the present study, we examined whether AT may prevent the endotoxin (ET)-induced hypotension by promoting the endothelial release of prostacyclin (PGI(2)) in rats. Intravenous administration of AT (250 U/kg) prevented both hypotension and the increases in plasma levels of NO(2)(-)/NO(3)(-) in rats given ET. Lung expression of messenger RNA (mRNA) for tumor necrosis factor-alpha (TNF-alpha) was transiently increased after ET administration, followed by the increases in lung tissue levels of TNF-alpha. Both the lung activity of the inducible form of nitric oxide synthase (iNOS) and the lung expression of iNOS mRNA in animals administered ET were gradually increased after the TNF-alpha mRNA expression had peaked. Administration of AT significantly inhibited these increases. Neither DEGR-F.Xa, a selective inhibitor of thrombin generation, nor Trp(49)-modified AT, which is not capable of promoting the endothelial release of PGI(2), showed any effects on these changes induced by ET. Administration of antirat TNF-alpha antibody produced effects similar to those induced by AT. Indomethacin pretreatment abrogated the effects induced by AT. Iloprost, a stable derivative of PGI(2), produced effects similar to those of AT. These findings suggested that AT prevents the ET-induced hypotension by inhibiting the induction of iNOS through inhibiting TNF-alpha production. These effects of AT could be mediated by the promotion of endothelial release of PGI(2) and might at least partly explain the therapeutic effects for septic shock.
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PMID:Antithrombin prevents endotoxin-induced hypotension by inhibiting the induction of nitric oxide synthase in rats. 1186 Dec 78

Fifteen years after its discovery, NO has fully reached an established position in physiology, medicine and therapeutics. It is difficult to find a biological function or a pathological condition where NO does not play a relevant role. Discoveries in the NO field have historically evolved from cardiovascular research, although its influences have already covered nearly all the medical specialties. This review analyzes, step by step, the pathway through which NO is synthesized in the cells of the cardiovascular system and the main physiological and pathological routes it undergoes once it is released. We focus on various diseases affecting the cardiovascular system (atherosclerosis, hypertension, diabetes mellitus and septic shock). We describe in detail those steps of the NO pathway in which anomalies have been detected and may account for the pathophysiology of these diseases. In atherosclerosis, hypertension and diabetes mellitus, the endothelial form of NOS is upregulated, but is very sensitive to environmental conditions, such as substrate or cofactor deficiencies or increases in LDL or glucose. In this situation NOS synthesizes superoxide anion instead of NO leading to oxidative and nitrosative stress. In diabetes mellitus and, very importantly, in septic shock, the inducible form of NOS is highly upregulated. Overproduction of NO appears to underlie the hypotension and tissue damage of septicemia and the destruction of beta-cells in diabetes mellitus. New knowledge of the role of NO in these diseases has started to influence therapeutic design. We also review the current status of research on NO-based therapies.
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PMID:Cardiovascular diseases and the nitric oxide pathway. 1532 Apr 80

Oxidative stress triggered by septic insult may be the major cause of multiple organ dysfunction syndrome (MODS) in intensive unit care patients. The inducible form of heme oxygenase-1 (HO-1) can be induced by cytokines, lipopolysaccharide, and reactive oxygen species during sepsis. These facts raise the question of whether the expression of HO-1 in leukocytes can indicate the level of oxidative stress of multiple organs in sepsis. Clinical peritonitis was simulated in an animal model by cecal ligation and puncture (CLP). The level of oxidative stress was examined by plasma lipid peroxidation (LPO). Liver function was analyzed by plasma aspartate aminotransferase, alanine aminotransferase, total bilirubin, and direct bilirubin. Lung function was evaluated by severity of edema. Renal function was measured by blood urea nitrogen and creatinine. The correlation between early HO-1 induction and LPO level or organ functional indicators of the same rat at late sepsis was analyzed by linear regression. The results showed that the protein content of HO-1 increased at 9 h after CLP, whereas expression of HO-1 mRNA in leukocytes was significantly increased (P < 0.01) at 6 h after CLP. Plasma level of LPO and the indices of hepatic, pulmonary, and renal function were significantly increased at 18 h after CLP. Moreover, highly negative correlations were observed between HO-1 mRNA expression at 6 h after CLP and level of LPO or severity of hepatic/renal dysfunction at 18 h after CLP. These results suggest that early HO-1 mRNA expression in leukocytes may represent oxidative stress and may predict the severity of liver and renal dysfunction during sepsis.
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PMID:Early expression of heme oxygenase-1 in leukocytes correlates negatively with oxidative stress and predicts hepatic and renal dysfunction at late stage of sepsis. 1583 14

Melatonin is a product of the amino acid tryptophan in the pineal gland. Once synthesized, the specific mechanisms governing the release of melatonin from the pineal gland and its functions are largely unknown. Besides its regulatory role in circadian rhythms in mammals, because of its widespread subcellular distribution, melatonin contributes to the reduction of oxidative damage in both the lipid and the aqueous environments of the cell. This postulate is widely supported by the experimental observations showing that melatonin protects lipids in membranes, proteins in the cytosol, and DNA in the nucleus and mitochondria from free radical damage. Melatonin thus reduces the severity of disease conditions where free radicals are implicated. The direct free radical scavenging effects of melatonin are receptor independent. It has recently been shown that it has an ability to scavenge free radicals, including hydroxyl radicals, hydrogen peroxide, peroxyl radicals, singlet oxygen and nitric oxide (NO) and peroxynitrite anion. An excessive amount of NO, a free radical which is generated by the inducible form of NO synthase, is known to cause cytotoxic changes in cells. Hence, NO synthase is considered a pro-oxidative enzyme, and any factor that reduces its activity would be considered an antioxidant. Recent studies have shown that melatonin inhibits the activity of NO synthase, beside its NO and peroxynitrite scavenging activity. Thus, inhibition of NO production may be another means whereby melatonin reduces oxidative damage under conditions, such as ischemia-reperfusion, sepsis, etc, where NO seems to be important in terms of the resulting damage.
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PMID:Melatonin and nitric oxide. 1668 46

Carbon monoxide (CO) can exert potent anti-inflammatory effects in animal and cell culture models of sepsis, despite well-known lethal effects at high concentration. Endogenous biological CO arises from the enzymatic degradation of haem, mainly from haemoglobin turnover, catalysed by haem oxygenases (HO). The inducible form of HO, haem oxygenase 1 (HO-1) participates in endogenous cellular defence against oxidative stress. HO-1 confers cytoprotection in many models of organ and tissue injury where inflammatory processes are implicated, including sepsis. When applied exogenously at low concentration, CO mimics the cytoprotective potential of HO-1 induction in these models. CO confers protection against endotoxin shock in vitro and in vivo by inhibiting the production of pro-inflammatory cytokines, in a mechanism involving the modulation of p38 mitogen activated protein kinase. CO protection against vascular injury may involve both anti-inflammatory and antiproliferative effects. The protection afforded by CO against liver failure and inflammatory lung injury was associated with the modulation of inducible nitric oxide synthase. Recent in vitro studies indicate that CO inhibits proinflammatory signalling by differentially inhibiting the trafficking of toll-like receptors (TLRs) to lipid rafts. Additional candidate mechanisms in anti-inflammatory effects of CO include the increased expression of heat shock proteins and the tumour suppressor protein caveolin 1.
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PMID:Cytoprotective and anti-inflammatory actions of carbon monoxide in organ injury and sepsis models. 1738 Jul 94

The inducible form of nitric oxide synthase (NOS2) plays an important role in sepsis incurred as a result of infection with Gram-negative bacteria that elaborate endotoxin. The HMGA1 (high-mobility group A1) architectural transcription factor facilitates NOS2 induction by binding a specific AT-rich Oct (octamer) sequence in the core NOS2 promoter via AT-hook motifs. The small-molecule MGB (minor-groove binder) netropsin selectively targets AT-rich DNA sequences and can interfere with transcription factor binding. We therefore hypothesized that netropsin would improve survival from murine endotoxaemia by attenuating NOS2 induction through interference with HMGA1 DNA binding to the core NOS2 promoter. Netropsin improved survival from endotoxaemia in wild-type mice, yet not in NOS2-deficient mice, supporting an important role for NOS2 in the beneficial effects of MGB administration. Netropsin significantly attenuated NOS2 promoter activity in macrophage transient transfection studies and the AT-rich HMGA1 DNA-binding site was critical for this effect. EMSAs (electrophoretic mobility-shift assays) demonstrated that netropsin interferes with HMGA1 NOS2 promoter binding and NMR spectroscopy was undertaken to characterize this disruption. Chemical shift perturbation analysis identified that netropsin effectively competes both HMGA1 DNA-binding AT-hooks from the AT-rich NOS2 promoter sequence. Furthermore, NOESY data identified direct molecular interactions between netropsin and A/T base pairs within the NOS2 promoter HMGA1-binding site. Finally, we determined a structure of the netropsin/NOS2 promoter Oct site complex from molecular modelling and dynamics calculations. These findings represent important steps toward refined structure-based ligand design of novel compounds for therapeutic benefit that can selectively target key regulatory regions within genes that are important for the development of critical illness.
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PMID:Netropsin improves survival from endotoxaemia by disrupting HMGA1 binding to the NOS2 promoter. 1893 43

Inhibition of NOS is not beneficial in septic shock; selective inhibition of the inducible form (iNOS) may represent a better option. We compared the effects of the selective iNOS inhibitor BYK191023 with those of norepinephrine (NE) in a sheep model of septic shock. Twenty-four anesthetized, mechanically ventilated ewes received 1.5 g/kg body weight of feces into the abdominal cavity to induce sepsis. Animals were randomized into three groups (each n = 8): NE-only, BYK-only, and NE + BYK. The sublingual microcirculation was evaluated with sidestream dark-field videomicroscopy. MAP was higher in the NE + BYK group than in the other groups, but there were no significant differences in cardiac index or systemic vascular resistance. Mean pulmonary arterial pressure was lower in BYK-treated animals than in the NE-only group. PaO2/FiO2 was higher and lactate concentration lower in the BYK groups than in the NE-only group. Mesenteric blood flow was higher in BYK groups than in the NE-only group. Renal blood flow was higher in the NE + BYK group than in the other groups. Functional capillary density and proportion of perfused vessels were higher in the BYK groups than in the NE-only group 18 h after induction of peritonitis. Survival times were similar in the three groups. In this model of peritonitis, selective iNOS inhibition had more beneficial effects than NE on pulmonary artery pressures, gas exchange, mesenteric blood flow, microcirculation, and lactate concentration. Combination of this selective iNOS inhibitor with NE allowed a higher arterial pressure and renal blood flow to be maintained.
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PMID:Effects of a selective iNOS inhibitor versus norepinephrine in the treatment of septic shock. 2060 34

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