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)

Excessive nitric oxide (NO) production has been implicated to be responsible for the development of septic shock. To determine whether plasma nitrite/nitrate (NOx) levels are related to the severity of systemic inflammatory response syndrome (SIRS) and the degree of multiple organ dysfunction, we studied plasma NOx levels in 70 patients with SIRS consisting of noninfectious SIRS (n = 32), sepsis (n = 23), and septic shock (n = 15). Infection is a microbial phenomenon characterized by an inflammatory response to the presence of microorganism. Positive culture for microorganism is regarded as infectious SIRS (sepsis and septic shock) and negative culture is regarded as noninfectious SIRS. Plasma samples collected from each patient within 24 h from admission to the intensive care unit were subjected for measurement of NOx levels, the stable end products of NO, by the high performance liquid chromatography-Greiss system. Mean plasma NOx levels in patients with SIRS were 52.8 +/- 44 microM/L, ranging from 8.1 to 186.2 microM/L. Plasma NOx levels were positively correlated with Acute Physiology, Age, and Chronic Health Evaluation (APACHE) III score (r = 0.414, P < 0.01) and sequential organ failure assessment (SOFA) score (r = 0.433, P < 0.01). Plasma NOx levels in patients with sepsis (51.0 +/- 38.5 microM/L) and septic shock (94.5 +/- 53.7 microM/L) were significantly (P < 0.01) higher than those in patients with noninfectious SIRS (25.8 +/- 16.9 microM/L) and healthy subjects (29.6 +/- 8.9 microM/L). Our study shows that plasma NOx levels are increased in patients with infectious, but not noninfectious SIRS, which increase as the severity of SIRS and the development of multiple organ dysfunction syndrome, suggesting its possible pathogenic role in SIRS.
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PMID:Relationships of circulating nitrite/nitrate levels to severity and multiple organ dysfunction syndrome in systemic inflammatory response syndrome. 1268 39

Apoptotic loss of parenchymal cells may lead to organ dysfunctions in critically ill patients with septic states. As an antioxidant, the protective effects of N-acetylcysteine (NAC) are documented in many experimental and clinical studies. In this experimental study, we investigated the role of chronically used NAC in septic lung injury on a cecal ligation and puncture (CLP) model. To evaluate this, 30 male Wistar rats were randomly divided into four groups as sham (n = 7), CLP (n = 8), sham + NAC (n = 7) and CLP + NAC (n = 8) groups. NAC was administered 150 mg kg(-1) day through intramuscular route beginning 6 h after the operations and lasting for a period of 1 week. One week later, histopathology and epithelial apoptosis were assessed by hematoxylin-eosin and immunohistochemically by M30 and caspase 3 staining to demonstrate septic lung injury. Additionally, lung tissue myeloperoxidase (MPO) activity, malondialdehyde (MDA), and nitrite/nitrate levels were measured. The MPO activity and MDA levels in lung homogenates were found to be increased in CLP group and the administration of NAC prevented their increase significantly (P < 0.05). However, there were no significant differences among the groups regarding nitrite/nitrate levels. The number of apoptotic cells was significantly lower in CLP+NAC group than CLP group, and this finding was supported by M30 and caspase 3 expression in lung (P < 0.05). Lung histopathology was also protected by NAC in CLP-induced sepsis. In conclusion, the chronic use of NAC inhibited MPO activity and lipid peroxidation, which resulted in reduction of apoptosis in lung in this CLP model. Because lung tissue nitrite/nitrate levels did not change significantly, organs other than the lungs may be responsible for producing the increased nitric oxide during sepsis. The chronic use of NAC needs further investigation for its possible antiapoptotic potential in septic states besides its documented antioxidant and antiinflammatory effects.
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PMID:The protective effect of N-acetylcysteine on apoptotic lung injury in cecal ligation and puncture-induced sepsis model. 1268 49

Nitric oxide (NO) is believed to be involved in the pathophysiology of sepsis. This study evaluated the activity of the NO pathway in a human endotoxin model. At baseline and after endotoxin, on-line measurements of exhaled NO (eNO) were made using a chemiluminescence technique with a single-breath method. NO-free air was inhaled prior to exhalation against a resistance. NO in orally and nasally exhaled air and in rectal gas was investigated. Plasma nitrite, nitrate, and guanosine 3', 5'-monophosphate (cGMP) and the events after diclophenac administration were also studied. Endotoxin infusion resulted in tachycardia and fever. An early increase in oral eNO concentration was observed and oral eNO decreased after diclophenac administration. NO exhaled nasally, NO in rectum gas and nitrite/nitrate levels remained unchanged over the study period, cGMP increased after 4 h. These findings suggest an early increase in nitric oxide production from the lungs, probably due to increased activity of the constitutive nitric oxide synthase upon endotoxin stimulation. In contrast, nitric oxide production in the upper airways, measured as nasally exhaled nitric oxide and nitric oxide in rectal gas, remained unchanged. Further studies will elucidate if exhaled nitric oxide is a valuable marker of sepsis-induced lung injury and if monitoring of treatment is possible.
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PMID:Exhaled NO and plasma cGMP increase after endotoxin infusion in healthy volunteers. 1276 41

Nitric oxide (NO) has been shown to play a major role in acute lung injury (ALI) after smoke inhalation. In the present study, we developed an ovine sepsis model, created by exposing sheep to smoke inhalation followed by instillation of bacteria into the airway, that mimics human sepsis and pneumonia. We hypothesized that the inhibition of neuronal NO synthase (nNOS) might be beneficial in treating ALI associated with this model. Female sheep (n = 26) were surgically prepared for the study and given a tracheostomy. This was followed by insufflation of 48 breaths of cotton smoke (40 degrees C) into the airway of each animal and subsequent instillation of live Pseudomonas aeruginosa [5 x 10(11) colony forming units (CFU)] into each sheep's lung. All sheep were mechanically ventilated using 100% O2. Continuous infusion of 7-nitroindazole (7-NI), an nNOS inhibitor, NG-monomethyl-l-arginine (l-NMMA), a nonspecific NOS inhibitor, or aminoguanidine (AG), an inducible NOS inhibitor, was started 1 h after insult. The administration of 7-NI improved pulmonary gas exchange (PaO2/FiO2; where PaO2 is arterial PO2 and FiO2 is fractional inspired oxygen concentration) and pulmonary shunt fraction and attenuated the increase in lung wet-to-dry weight ratio seen in the nontreated sheep. Histologically, 7-NI prevented airway obstruction. The increase in airway blood flow after injury in the nontreated group was significantly inhibited by 7-NI. The increase in plasma concentration of nitrate and nitrite (NOx) was inhibited by 7-NI as well. Posttreatment with l-NMMA improved the pulmonary gas exchange, but AG did not. The results of the present study show that nNOS may be involved in the pathogenesis of ALI after smoke inhalation injury followed by bacterial instillation in the airway.
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PMID:Inhibition of neuronal nitric oxide synthase by 7-nitroindazole attenuates acute lung injury in an ovine model. 1276 43

Increased nitric oxide (NO) production by inducible NO synthase (NOS2), an obligate homodimer, is implicated in the cardiovascular sequelae of sepsis. We tested the ability of a highly selective NOS2 dimerization inhibitor (BBS-2) to prevent endotoxin-induced systemic hypotension, myocardial dysfunction, and impaired hypoxic pulmonary vasoconstriction (HPV) in mice. Mice were challenged with Escherichia coli endotoxin before treatment with BBS-2 or vehicle. Systemic blood pressure was measured before and 4 and 7 h after endotoxin challenge, and echocardiographic parameters of myocardial function were measured before and 7 h after endotoxin challenge. The pulmonary vasoconstrictor response to left mainstem bronchus occlusion, which is a measure of HPV, was studied 22 h after endotoxin challenge. BBS-2 treatment alone did not alter baseline hemodynamics. BBS-2 treatment blocked NOS2 dimerization and completely inhibited the endotoxin-induced increase of plasma nitrate and nitrite levels. Treatment with BBS-2 after endotoxin administration prevented systemic hypotension and attenuated myocardial dysfunction. BBS-2 also prevented endotoxin-induced impairment of HPV. In contrast, treatment with NG-nitro-l-arginine methyl ester, which is an inhibitor of all three NOS isoforms, prevented the systemic hypotension but further aggravated the myocardial dysfunction associated with endotoxin challenge. Treatment with BBS-2 prevented endotoxin from causing key features of cardiovascular dysfunction in endotoxemic mice. Selective inhibition of NOS2 dimerization with BBS-2, while sparing the activities of other NOS isoforms, may prove to be a useful treatment strategy in sepsis.
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PMID:A selective inducible NOS dimerization inhibitor prevents systemic, cardiac, and pulmonary hemodynamic dysfunction in endotoxemic mice. 1290 25

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


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