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)

Whether the gut alterations seen during sepsis are caused by microcirculatory hypoxia or disturbances in cellular metabolic pathways associated with mitochondrial respiration remains controversial. We hypothesized that hypoperfusion or hypoxia and local production of nitric oxide might play an important role in the development of gut mucosal injury during endotoxic shock and investigated their roles by using differing levels of fluid resuscitation and occlusion of the superior mesenteric artery (SMA). Anesthetized New Zealand rabbits were allocated to group I (sham, n = 8); group II [low-dose endotoxin (LPS, Escherichia coli-055:B5, 150 microg/kg)/fluid resuscitation (12 ml x kg(-1) x h(-1)); n = 8]; group III [high-dose LPS (1 mg/kg)/fluid resuscitation (12 ml x kg(-1) x h(-1)); n = 8]; group IV [high-dose LPS (1 mg/kg)/hypovolemia (4 ml x kg-1 x h(-1) fluids); n = 8]; and group V [SMA ligation/fluid resuscitation (12 ml x kg(-1) x h(-1)); n = 4]. Luminal gut lactate concentrations and PCO2 gap increased in groups IV and V (P < 0.05), reflecting alterations in gut perfusion. Interestingly, significant histological alterations were observed in all LPS groups but not in group V. Blood and luminal gut nitrate/nitrite concentrations increased only in group IV. The mechanism of gut injury in endotoxic shock seems unrelated to hypoxia and release of nitric oxide. Gut dysfunction may occur as a result of so-called "cytopathic hypoxia."
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PMID:Gut mucosal damage during endotoxic shock is due to mechanisms other than gut ischemia. 1292 22

Sepsis precipitates a systemic inflammatory stimulus that causes systemic release of cytokines and sequestration of polymorphonuclear neutrophils, resulting in degranulation of matrix metalloproteinases (MMPs), which causes extracellular matrix basement membrane degradation. One of the important anti-inflammatory properties of tetracyclines is their ability to inhibit MMPs. In this study, we focused on the regulation of MMPs in sepsis and their reduction by treatment with nonantimicrobial chemically modified tetracyclines (CMTs), which retain their anti-inflammatory activity. Sepsis was induced by cecal ligation and puncture (CLP) method. At 24 h and 1 h before CLP, some rats received CMT-3 (25 mg/kg), another group of rats received hydroxamate (H; an inhibitor of MMP; 25 mg/kg), and untreated rats received saline by gavage. At 0 h, 0.5 h, 1.5 h, and 24 h after CLP, blood and liver samples were collected. Plasma and liver MMP-9 by zymography and Western immunoblotting, plasma nitric oxide by measuring nitrate level, plasma glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) by enzymatic method, and liver gelatinase by radiolabeled gelatin lysis assay and 24 h mortality were determined. Plasma MMP-9 (92 kDa), nitrate, and GOT and GPT levels were elevated compared with the time 0 level and reached peak at 1.5 h CLP and remained high for 24 h. Both CMT-3 and H treatment reduced GOT,GPT, 92-kDa gelatinase, and nitrate levels throughout the 24 h. CMT-3 and H are equally effective in sepsis treatment. The 24-h mortality for CLP rats was 30%, whereas pretreatment with CMT-3 and H resulted in 0% mortality. Hepatic MMP-9 and gelatinase activity increased significantly after CLP, and pretreatment with CMT-3 and H inhibited these expressions. These results indicate the beneficial effect of CMT-3 in preventing the increase in GOT, GPT, NO, MMP-9, gelatinase activity, and the ensuing septic shock.
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PMID:Inhibition of matrix metalloproteinases by chemically modified tetracyclines in sepsis. 1292 2

Glucocorticoids can reverse hemodynamic disturbances and dependence on catecholamines in septic shock. The relevant beneficial mechanisms of steroids in septic shock are unknown, although inducible nitric oxide synthase could account for them. The aim of this study was to compare the effects of dexamethasone, a glucocorticoid and L-canavanine, a selective inhibitor of inducible nitric oxide synthase, in a rodent model of sepsis. Mean arterial pressure was restored by dexamethasone and L-canavanine administration at 24 h, no longer at 30 h. Dexamethasone but not L-canavanine improved aortic blood flow at 24 and 30 h. Although both dexamethasone and L-canavanine administration significantly reduced nitrite/nitrate production, and improved survival, steroids did better for survival. In conclusion, dexamethasone and L-canavanine displayed similar vasopressor effects. In addition, steroids improved blood flow suggesting that steroid-induced hemodynamic improvement in sepsis is not solely due to inhibition of inducible nitric oxide synthase.
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PMID:Comparative effects of dexamethasone and L-canavanine in experimental septic shock. 1295 60

Sepsis-induced nitric oxide (NO) overproduction has been implicated in a redistribution of flow from the pancreas making it vulnerable to ischemic injury in septic shock. To test this hypothesis in a remote injury model of normotensive sepsis, we induced Pseudomonas pneumonia in the rat and used intravital video microscopy (IVVM) of the pancreas to measure functional capillary density, capillary hemodynamics [red blood cell (RBC) velocity, lineal density, and supply rate], and lethal cellular damage (propidium iodine staining) at 6 and 24 h after the induction of pneumonia. With pneumonia, plasma nitrite/nitrate [NO2(-)/NO3(-)(NOx(-))] levels were doubled by 21 h (P < 0.05). To assess the effect of NO overproduction on microvascular perfusion, N6-(1-iminoethyl)-L-lysine (L-NIL) was administered to maintain NOx(-) levels at baseline. Pneumonia did cause a decrease in RBC velocity of 23% by 6 h, but by 24 h RBC velocity and supply rate had increased relative to sham by 22 and 38%, respectively (P < 0.05). L-NIL treatment demonstrated that this increase was due to NO overproduction. With pneumonia, there was no change in functional capillary density and only modest increases in cellular damage. We conclude that, in this normotensive pneumonia model of sepsis, NO overproduction was protective of microvascular perfusion in the pancreas.
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PMID:Effect of nitric oxide on capillary hemodynamics and cell injury in the pancreas during Pseudomonas pneumonia-induced sepsis. 1296 89

Both, burn trauma and sepsis induce the generation of reactive oxygen intermediates which often coincides with increased nitric oxide (NO) levels. NO takes part in both circulatory disorders and cell protection. Therefore, in a prospective (pre-)clinical study we focused on the detection of NO in polytrauma patients (pts) starting as early as at the scene of accident. Upon approval of the local ethics committee, pts with an injury severity score (ISS) ranging from 9 to 75 (mean 22) were enrolled. Subsets were performed according to the different injury pattern (long bone fractures, head injury, polytrauma with and without damage to the thorax, isolated chest trauma). The first blood sample was obtained at the scene of accident. Then, blood was collected in hourly to daily intervals. NO production was assessed by the nitrate + nitrite plasma levels. To eliminate dilution effects following volume substitution, all values were recalculated on the plasma protein content. Immediately after trauma, NO plasma levels were elevated. This was most pronounced in pts that have experienced thoracic injuries irrespective of with or without additional polytrauma. There is evidence that NO production always starts immediately after major trauma but depends on the individual trauma pattern. In addition, the results reveal that lethal outcome is associated with an increased NO generation in the early post-injury period. We conclude that NO overproduction does not necessarily prime an overall protection in patients that have suffered from mechanical trauma. The role of NO after severe trauma and especially in thoracic injury should further be elucidated in a specific study on that topic.
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PMID:[Detection of NO liberation in the early phase of trauma]. 1451 7

The homeostasis of nitric oxide (NO) is attained through a balance between its production and consumption. Shifts in NO bioavailability have been linked to a variety of diseases. Although the regulation of NO production has been well documented, its consumption is largely thought to be unregulated. Here, we have demonstrated that under hypoxic conditions, NO accelerates its own consumption by increasing its entry into RBCs. When RBCs were exposed to NO (1:400 NO/heme ratio) under hypoxic conditions to form HbFe(II)NO, the consumption rate of NO increased significantly. This increase in NO consumption converted the bioactivity of serotonin from a vasodilator to a vasoconstrictor in isolated coronary arterioles. We identified HbFe(II)NO as a potential mediator of accelerated NO consumption. Accelerated NO consumption by HbFe(II)NO-bearing RBCs may contribute to hypoxic pulmonary vasoconstriction and the rebound effect seen on termination of NO inhalation therapy. Furthermore, accelerated NO consumption may exacerbate ischemia-mediated vasospasm and nitrate tolerance. Finally, this phenomenon may be an evolved mechanism to stabilize the vasculature in sepsis.
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PMID:Regulation of nitric oxide consumption by hypoxic red blood cells. 1452 33

We have recently demonstrated that selective inducible nitric oxide (NO) synthase (iNOS) inhibition with 1400W attenuated the hemodynamic and metabolic alterations affiliated with hyperdynamic porcine endotoxemia. In contrast to endotoxemia, limited evidence is available to document a relationship between NO and organ dysfunction in large animal bacteremic models. Therefore, using the same experimental setup, we investigated the role of selective iNOS blockade in porcine bacteremia induced and maintained for 24 h with a continuous infusion of live Pseudomonas aeruginosa. After 12 h of sepsis, animals received either vehicle (Control, n = 8) or continuous infusion of selective iNOS inhibitor, L-N6-(1-iminoethyl)-lysine (L-NIL; n = 8). Measurements were performed before, and 12, 18, and 24 h after P. aeruginosa infusion. L-NIL inhibited sepsis-induced increase in plasma nitrate/nitrite concentrations and prevented hypotension without affecting cardiac output. Despite comparable hepatosplanchnic macrocirculation, L-NIL blunted the progressive deterioration in ileal mucosal microcirculation and prevented mucosal acidosis. L-NIL largely attenuated mesenteric and hepatic venous acidosis, significantly improved P. aeruginosa-induced impairment of hepatosplanchnic redox state, and mitigated the decline in liver lactate clearance. Furthermore, the administration of L-NIL reduced the hepatocellular injury and prevented the development of renal dysfunction. Finally, treatment with L-NIL significantly attenuated the formation of 8-isoprostane concentrations, a direct marker of lipid peroxidation. Thus, selective iNOS inhibition with L-NIL prevented live bacteria from causing key features of metabolic derangements in porcine hyperdynamic sepsis. Underlying mechanisms probably include reduced oxidative stress with improved microcirculatory perfusion and restoration of cellular respiration.
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PMID:Selective inducible nitric oxide synthase inhibition during long-term hyperdynamic porcine bacteremia. 1508 23

Excessive activation of calpains has been implicated in the pathophysiology of inflammation, trauma, and ischemia reperfusion injury. Here, we investigated the effects of calpain inhibition on myocardial dysfunction and inflammation induced by endotoxin in rats. Rats were treated i.v. with endotoxin (10 mg/kg) or endotoxin plus calpain inhibitors and were then prepared after 4 h for myocardial contractility assessment, detection of endothelium leukocyte interactions, and plasma TNF-alpha, nitrite/nitrate, and endocan levels. Compared with vehicle-treated rats, hearts from endotoxin-treated rats had reduced systolic performance that was partially prevented by calpain inhibitors, i.e., acetyl-leucyl-leucyl-arginal (leupeptin), carbobenzoxy-valyl-phenylalanial (calpain inhibitor III), and N-acetyl-leucinyl-leucinyl-norleucinal (ALLN). Leupeptin and calpain inhibitor III reduced plasma TNF-alpha levels in endotoxin-treated rats. ALLN reduced plasma TNF-alpha and nitrite/nitrate levels in endotoxin-treated rats. Endotoxin treatment increased mesenteric venule leukocyte rolling (10 +/- 3 leukocytes/min vs. 44 +/- 10 leukocytes/min; P < 0.01) and adhesion (2 +/- 2 leukocytes/min vs. 15 +/- 3 leukocytes/min; P < 0.01), which was reduced by calpain inhibitors. Attenuation of leukocyte endothelium interactions observed in calpain inhibitor-treated rats with sepsis was associated with increases in plasma anti-adhesion molecule endocan. In conclusion, calpain inhibitors improved endotoxin-induced cardiac dysfunction, which may be attributed to the modulation of endothelium leukocyte interactions in the inflamed vasculature.
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PMID:Calpain inhibitors improve myocardial dysfunction and inflammation induced by endotoxin in rats. 1517 36

In this study, we evaluated the time course of changes in inducible nitric oxide synthase (iNOS) in the brain by using the rat model of sepsis induced by cecal ligation and puncture (CLP) and examined whether selective iNOS inhibition can prevent the hemodynamic and neurological changes induced by sepsis. Male Wistar rats were randomly divided into four groups: control, sham, CLP, and CLP + the selective iNOS inhibitor L-N6-(1-iminoethyl)-lysine (L-NIL). Septic shock was induced in the rats by CLP under pentobarbital anesthesia, and then we measured hemodynamic variables, neurological indicators, blood gases, plasma levels of nitrate/nitrite (an indicator of the biosynthesis of NO), and brain iNOS activity and nitrotyrosine levels after 1, 6, 12, and 24 h. Plasma nitrite was increased at 12 and 24 h in the CLP group. The activity of iNOS in the brain was increased at 12 and 24 h after CLP (at 12 h: control, 0.3 +/- 0.05; sham, 0.3 +/- 0.1; CLP, 1.3 +/- 0.08*; CLP + L-NIL, 0.33 +/- 0.1 fmol x mg(-1) x min(-1); at 24 h: control, 0.27 +/- 0.08; sham, 0.31 +/- 0.1; CLP, 1.0 +/- 0.3*; CLP + L-NIL, 0.34 +/- 0.1 fmol x mg(-1) x min(-1); mean +/- SD; *P < 0.05). Brain nitrotyrosine was increased at 24 h after CLP (at 24 h: control, 6.7 +/- 0.4; sham, 6.7 +/- 0.5; CLP, 11.2 +/- 2.8*; CLP + L-NIL, 7.52 +/- 0.5 densitometric units; means +/- SD; *P < 0.01). In contrast, in both the CLP and CLP + L-NIL groups, the consciousness reflex was significantly decreased at 24 h after CLP. Selective iNOS inhibition restored the hemodynamic changes induced by sepsis but could not improve neurological dysfunction.
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PMID:Selective inducible nitric oxide inhibition can restore hemodynamics, but does not improve neurological dysfunction in experimentally-induced septic shock in rats. 1528 32

Compromised microvascular responsiveness is one of the key factors associated with mortality of septic patients. The present study addresses the mechanism of protection by ascorbate against impaired vasoconstriction in septic mice. Sepsis (i.e., cecal ligation and puncture (CLP) model) elevated both plasma protein carbonyl (i.e., an index of oxidative stress) and plasma nitrite/nitrate (NOx) levels, reduced baseline mean arterial blood pressure (MABP), and inhibited the MABP pressor response to angiotensin II (Ang II) at 6 h post-CLP. At the microvascular level, sepsis increased the inducible nitric oxide synthase (iNOS) mRNA level in cremaster muscle arterioles (18-25 microm diameter) at 3 h post-CLP, and impaired vasoconstriction to Ang II in these arterioles at 6 h post-CLP. At 24 h post-CLP, sepsis resulted in 9% survival. An intravenous bolus of ascorbate (200 mg/kg body wt) given 30 min prior to CLP prevented the protein carbonyl and NOx increases, partially restored the baseline arterial pressure, and completely protected against all arteriolar iNOS mRNA increases, arteriolar constriction hyporesponsiveness, and pressor response impairment. Survival increased to 65%. In septic mice, iNOS gene knockout resulted in protection of arteriolar constriction and pressor responses identical to that provided by ascorbate. Ascorbate bolus given 3 h post-CLP protected against the increase in plasma NOx concentration and against the pressor response impairment. We conclude that ascorbate may protect arteriolar vasoconstrictor responsiveness in sepsis by inhibiting excessive NO production.
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PMID:Ascorbate protects against impaired arteriolar constriction in sepsis by inhibiting inducible nitric oxide synthase expression. 1545 Oct 67


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