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)

1. The pulmonary vasculature is constantly exposed to oxygen and reactive oxygen species such as nitric oxide (NO) and superoxide anions which can combine at a near diffusion limited rate, to form the powerful, oxidant, peroxynitrite (ONOO-). When formed in large amounts, ONOO- is thought to contribute to tissue injury and vascular dysfunction seen in diseases such as the acute respiratory distress syndrome (ARDS) and septic shock. Recent studies have shown that ONOO- can cause vasodilatation and at higher concentrations can activate poly (adenosine 5'-diphosphoribose) synthase (PARS) leading to consumption of nicotinamide adenine dinucleotide (NAD+) and adenosine 5'-triphosphate (ATP). As the lung represents a prime site for ONOO- formation, we characterized its effects on pulmonary vascular tone and on endothelial function. In addition, we have assessed the role of PARS in producing the vasoactive properties of ONOO- on pulmonary artery rings. 2. Isolated pulmonary artery rings from rats were mounted in organ baths containing warmed and gassed (95% O2: 5% CO2) Krebs buffer. Force was measured with isometric force transducers. After equilibration, ONOO- (10 nM-100 microM) was added in a cumulative manner. In separate experiments designed to assess any vasodilator properties of ONOO-, tissues were pre-contracted with the thromboxane mimetic U46619 (1 microM). Once a stable base-line was achieved, ONOO- was added in a cumulative fashion. ONOO- had no significant effect on resting pulmonary artery tone but caused concentration-dependent relaxations of pre-contracted vessels in the range 1 microM to 100 microM. In some experiments the effects of freshly prepared ONOO- solutions were compared with those allowed to decay at 4 degrees C for 2 days. 3. In some experiments either vehicle or ONOO- (1, 10 or 100 microM) was added for 15 min before U46619 (1 microM). Concentration-response curves to the endothelium-dependent vasodilator, acetylcholine (10 nM-100 microM) were then constructed. In these experiments, ONOO- (1 microM or 10 microM) had no effect on the actions of acetylcholine. However, at the highest concentration tested (100 microM), ONOO- increased acetylcholine-induced relaxations. 4. The vasodilator actions of ONOO- were unaffected by the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME; 100 microM) or by removal of superoxide anions with superoxide dismutase (SOD) (30 units ml-1). However, the relaxations induced by ONOO- were significantly inhibited by the PARS inhibitor, 3-aminobenzamide (10 microM). In contrast to its effects on ONOO-, 3-aminobenzamide had no effect on the relaxation caused by acetylcholine or sodium nitrite, but actually increased that induced by sodium nitroprusside. 5. These data show that ONOO- causes vasodilatation of rat pulmonary arteries, probably via activation of PARS. Moreover, at concentrations where relaxation was achieved, ONOO- did not affect the ability of pulmonary artery rings to relax to acetylcholine. We propose that ONOO-, but not endothelially derived NO, activates PARS resulting in the rapid depletion of ATP and a consequent reduction in contraction as well as other active processes of vascular smooth muscle. The finding that 3-aminobenzamide inhibited the actions of ONOO- but not acetylcholine, suggests that NO and ONOO- cause relaxation by independent mechanisms. It has been suggested that ONOO- is responsible for the vascular hyporesponsiveness to constrictor agents seen in experimental sepsis. This observation together with our current finding, that 3-aminobenzamide inhibits the relaxation induced by ONOO- but not by acetylcholine, suggests that inhibitors of PARS may reduce the persistent hypotension seen in sepsis without affecting the actions of endothelium-derived NO. Thus, the use of PARS inhibitors may represent a novel therapeutic approach to the treatment of septic shock.
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PMID:Characterization of the vasodilator properties of peroxynitrite on rat pulmonary artery: role of poly (adenosine 5'-diphosphoribose) synthase. 917 90

Intracellular enterocytic levels of the immunomodulator taurine decrease significantly in response to trauma and surgical insult. The effect of physiological stress on enterocyte taurine uptake is unknown. The aim of this study was to compare taurine transport under basal and stressed conditions using the human intestinal Caco-2 cell line in vitro. Caco-2 cells were incubated with 10 nM [1,2-3H]taurine at 37 degrees C and 5% CO2 and taurine uptake was examined over the range of 0.1-10 microM to determine kinetic parameters of the transporter. The culture medium was then supplemented with dexamethasone and/or lipopolysaccharide (LPS) and taurine uptake was calculated as picomoles per milligram protein per hour. Statistics were by unpaired Student's t test. Taurine uptake was hyperbolically related to taurine concentration and obeyed Michaelis-Menten kinetics with a K(m) of 5.27 +/- 0.95 microM and Vmax of 1125.43 +/- 130.9 pmole/mg protein/ hour. Dexamethasone (1-1000 microM) significantly reduced taurine uptake by up to 66.15%. LPS (1 microgram/ml) impaired transport of taurine by 15.7%, and in combination with dexamethasone (100 microM) by 42.4%. All results are mean of at least three experiments and P < 0.05. We have established that taurine uptake by enterocytes is downregulated by dexamethasone. This may relate to the decreased intestinal levels of taurine observed in trauma and surgery patients. Further study may elucidate mechanisms whereby homeostasis of enterocyte taurine might be maintained during sepsis.
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PMID:Dexamethasone and lipopolysaccharide regulation of taurine transport in Caco-2 cells. 922 2

A 38-year-old male was admitted to the intensive care unit with a full-thickness burn involving 30 per cent of his total body surface area (TBSA) and severe inhalation injury. Respiratory failure developed within 54 h and CO2 could not be eliminated, even by very invasive mechanical ventilation. Because of the patient's age and the minor extent of the burned TBSA, we started extracorporeal CO2 elimination (ECCO2-R) and continued ECCO2-R for 30 days, when the patient was weaned from ECC. The clinical course during ECCO2-R was complicated by major bleeding from a thoracotomy tube, from the site of tangential excision and by four septic episodes. Lung biopsy was performed twice on day 29 (during ECCO2-R) and day 58 (after ECCO2-R) after admission and revealed bronchiolitis obliterans without tendency to recovery. The patient died of sepsis with multiorgan failure on day 81 after trauma.
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PMID:Inhalation injury treated with extracorporeal CO2 elimination. 924 48

The hemodynamic effects of sepsis have been attributed in part to increased nitric oxide (NO) production and activation of guanylate cyclase, resulting in increased cGMP and relaxation of vascular smooth muscle. Heme oxygenase-1 (HO-1), a heat shock protein, has been shown to increase intracellular cGMP levels by formation of carbon monoxide (CO). We hypothesized that HO may be an important mediator of the hepatic response to infection. Male Swiss Webster mice underwent standard cecal ligation and puncture (CLP, 18 gauge 2X) or sham operation, and received either normal saline (NS) or Zn protoporphyrin IX (ZN PP IX), a competitive HO inhibitor (n = 6-8/group). Hepatic tissue samples were collected at 3, 6, 12, and 24 hr from separate mice. Serum was collected at 3 and 24 hr. A semiquantitative reverse transcriptase polymerase chain reaction method was used to measure HO-1 mRNA levels. Hepatic cGMP levels were measured by ELISA. Groups were repeated (n = 10/group) to assess mortality. Serum was collected at 3 and 24 hr to measure serum aspartate aminotransferase (AST) levels. HO-1 mRNA expression increased significantly by 3 hr after CLP and with HO inhibition alone (P < 0.05 vs sham + NS). HO-1 mRNA remained elevated through 24 hr. CLP animals with HO inhibition showed a significant reduction of hepatic cGMP following CLP compared with CLP + saline at 24 hr (P < 0.05). Mortality was significantly increased in the CLP + ZN PP group at 24 hr (P < 0.05 CLP NS vs CLP ZN PP). CLP caused a marked increase in AST activity, which was increased further with HO inhibition. HO-1 mRNA expression was induced by CLP. AST levels following CLP were markedly increased with HO inhibition. HO-1 function appeared to contribute to elevation of hepatic cGMP during peritonitis and may be an important hepatic adaptive response to infection.
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PMID:Heme oxygenase-dependent carbon monoxide production is a hepatic adaptive response to sepsis. 927 Dec 71

Tumor necrosis factor (TNF) is involved in the pathogenesis of acute sepsis-induced organ injury and has been implicated as a mediator of metabolic alterations observed during sepsis. Pancreatic islet cell function may be significantly compromised during sepsis or endotoxemia, and sepsis also increases plasma levels of epinephrine, a modifier of islet insulin secretion. We proposed that islets exposed to bacterial lipopolysaccharide (LPS) produce TNF and that epinephrine attenuates islet secretory activity. We monitored the effects of LPS and epinephrine on TNF and insulin activity of isolated Wistar-Furth rat islets (pancreas digested with collagenase, islets isolated using Ficoll gradients; n = 4 islet populations, each with 632 +/- 11 islets/2.5 ml culture medium). Islets were incubated (37 degrees C, 5% CO2) 3 days. LPS (Escherichia coli, 1 microgram/ml) and epinephrine (14 micrograms/ml) were added to the islets, and incubations were continued for 1-4 h. Glucose (Beckman Glucose Analyzer), insulin (radioimmunoassay), and TNF (L929 cytotoxicity assay) were measured in the islet medium samples at 1- to 4-h time points. In the conditioned medium, glucose decreased (P < 0.05), insulin increased (P < 0.05), and exposure to LPS did not alter these levels [P = not significant (NS)] but did increase TNF activity by 400% (P < 0.05). Epinephrine reduced insulin by 38-43% (P < 0.05) and TNF by 20-25% (P < 0.05) but had no effect on glucose levels (P = NS). We conclude that insulin is secreted from isolated islets and that exposure to LPS acutely increases islet-derived TNF activity, whereas epinephrine modifies TNF and insulin secretion of rat pancreatic islets.
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PMID:Tumor necrosis factor activity of pancreatic islets. 927 98

This study was performed to quantify the impact of Haldane effect (HE) on the relationship between O2 extraction (O2Ex; mL O2/dL blood) and venous pH in 247 measurements performed in 91 septic patients (73 patients with intra-abdominal sepsis, 11 with retroperitoneal abscesses, 6 with severe cholangitis, and 1 with gangrenous fasclitis). The severity of sepsis varied from relatively compensated to extremely diseased conditions. This allowed a detailed assessment of the impact of HE over a wide range of cardiorespiratory and metabolic abnormalities. A recently developed model was used to quantify blood CO2 exchange and Haldane relationships and, in particular, the buffering of venous pH allowed by O2Ex (O2-linked H+ binding) on the basis of arterial and mixed venous blood gas measurements. Arterio-venous pH difference (a-vDpH) was .033 +/- .024 (mean +/- SD). It increased with venoarterial CO2 concentration difference (v-aDCO2; mL CO2/dL blood), but the increase was moderated by a simultaneous increase in O2Ex, as the likely consequence of HE: a-vDpH = .006 + .017 (v-aDCO2) - .009 (O2Ex) [r2 = .96, p < < .001]. To confirm this, the moderation of a-vDpH allowed by the HE (DpH) was calculated. A first component, due to O2-linked H+ binding, had a value of .016 +/- .012, and a second component, due to the Haldane-mediated reduction in venous CO2 tension and plasma carbonic acid concentration, had a value of .019 +/- .006. Their sum (total DpH) was .033 +/- .017 and was related directly and strongly to O2Ex: DpH = -.002 + .009 (O2Ex) [r2 = .85, p < < .001], thus confirming the quantitative impact of HE in moderating the decrease in venous pH relative to arterial pH. The loss of this effect was responsible for the larger decreases in venous pH observed in hypodynamic patients developing impaired O2Ex. These results allow an easy quantification of the Haldane component, separated from the other components affecting pH, and are also useful for assessing the protective role exerted by HE against excessive decreases in venous pH in circulatory failure.
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PMID:The relationship between oxygen extraction and venous pH in sepsis. 936 49

We describe a patient with combined meningococcal septicemia and meningitis, cerebral edema and acute respiratory distress syndrome, in whom we balanced the conflicting carbon dioxide strategies for optimal pulmonary and neurological management using jugular oxygen saturation (SjvO2) monitoring to identify the upper limit of "tolerable" hypercapnia. Our observations suggest that significant acidosis was not well tolerated; however, cautious induction of pH down to 7.32 and an arterial carbon dioxide tension (PaCO2) < 5.9 kPa was tolerated acutely without significant cerebral hyperemia. Moreover, with the development of metabolic compensation and normal pH, higher levels of PaCO2 could be permitted. In similar cerebro-pulmonary circumstances we suggest that these findings warrant consideration. Alternatively, invasive monitoring of SjvO2 could be undertaken so that patient-specific criteria for permissive hypercapnia can be determined.
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PMID:Combined lung injury, meningitis and cerebral edema: how permissive can hypercapnia be? 1005 Oct 94

Tissue hypoxia, especially in the splanchnic area, is still considered to be an important cofactor in the pathogenesis of multiple organ failure. Thus, in the treatment of septic shock the specific effects of ino-tropic drugs on the splanchnic perfusion are of particular interest. To give strict recommendations for monitoring and for therapeutic strategies in the treatment of gastrointestinal failure in patients with sepsis is difficult not only due to the lack of data on clinical outcome and organ dysfunction, but also due to some limitations in the methods applied to assess splanchnic perfusion and oxygenation. A reasonable approach in the management of splanchnic underperfusion in septic patients includes: Measurement of gastric mucosal pH or CO2-gap because it is the only method for the assessment of splanchnic perfusion which can be useful in the clinical routine. Adequate volume loading likely is the most important step in the supportive treatment of patients with septic shock. Unfortunately, what kind of fluids, endpoints, and monitoring techniques should be used is still controversial. Nevertheless, techniques allowing us to achieve and tightly control volume loading and regional perfusion, e.g. the measurement of pHi or CO2-gap, may be helpful. Patients with high DO2 have had better outcome. However, measurement of parameters assessing global and regional oxygenation may be superior than to guide therapy by DO2. To maximize DO2 by the use of very high dosages of catecholamines can be harmful. The recommendation to use dobutamine as catecholamine of first choice seems to be justified. In critically ill patients, no negative effects of norepinephrine on regional perfusion have been demonstrated provided the patient is adequately volume resuscitated and the DO2 is normal or slightly elevated. Therefore, after volume resuscitation and treatment with dobutamine, norepinephrine should be used for achieving an adequate perfusion pressure. Epinephrine and dopamine should be avoided because they seem to restribute blood flow away from the splanchnic region. There are no convincing data yet to support the routine use of low dose dopamine or dopexamine in patients with sepsis. These recommendations are limited by the lack of outcome studies and optimal methods for the assessment of splanchnic perfusion/oxygenation.
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PMID:[Aspects in monitoring and treatment of gastrointestinal underperfusion in sepsis. Diagnosis and therapy of gastrointestinal underperfusion in sepsis]. 968 8

Early detection of pathophysiological factors associated with permanent brain damage is a major issue in neonatal medicine. The aim of our study was to evaluate the significance of the CO2 reactivity of cerebral blood flow (CBF) in neonates with perinatal risk factors. Fourteen ventilated neonates with perinatal risk factors (pathological cardiotocogramm, low cord pH, postpartal encephalopathy) were enrolled into this prospective study. The study was performed 18-123 h after birth. CBF was measured using the noninvasive intravenous 133Xe method. Two measurements were taken with a minimal PaCO2-difference of 5 mm Hg. From the two CBF values the CO2 reactivity was calculated. Outcome was evaluated 1 year after birth. The CBF values at a lower PaCO2 ranged from 6.6 to 115. 2 ml/100 g brain issue/min (median = 18.2) and at a higher PaCO2 level from 7.1 to 125.7 ml/100 g brain tissue/min (median = 18.75). The calculated CO2 reactivity ranged from -9.6 to 6.6% (median 1.1%) change in CBF/mm Hg change in PaCO2. CO2 reactivity correlated with lowest pH (r2 = 0.35, p = 0.02). Two infants died, one of neonatal sepsis, the other of heart failure. Neurological outcome at the age of 1 year was normal in 11 patients, 1 had severe cerebral palsy. From the 12 surviving patients the patient with severe neurological deficit showed the highest CBF values (125.7 ml/100 g/min). Impaired chemical coupling of cerebral blood flow is compatible with intact neurological outcome in neonates with perinatal risk factors. CO2 reactivity in these newborns correlates with the lowest pH and may reflect the severity of perinatal asphyxia.
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PMID:Impaired chemical coupling of cerebral blood flow is compatible with intact neurological outcome in neonates with perinatal risk factors. 983 79

Cu,Zn-superoxide dismutase (SOD1) acts as a peroxidase in the presence of H2O2 at high pH (pH > 9). The high pH species of H2O2, HO2-, was previously implicated as the reactive species. However, recent EPR studies of the enzyme performed in the physiological pH range 7.4-7.6 with the spin trap 5,5'-dimethyl-1-pyrolline-N-oxide attributed the intense EPR signal of 5, 5'-dimethyl-1-pyrolline-N-oxide-OH obtained from SOD1 and H2O2 to the peroxidase activity of the enzyme. The present study establishes that this intense signal is obtained only in the presence of bicarbonate. To explore the critical role of HCO3-, a comprehensive EPR investigation of the radical production and redox state of the active site copper was performed. The results indicate that HCO3- competes with other anions for the anion-binding site of SOD1 (Arg141) but does not bind directly to the copper. Structurally different anions that bind to Arg141 did not stimulate, but rather blocked, peroxidase function, ruling out an effect due to mere anion binding. However, the structurally similar anions HSeO3- and HSO3- mimic HCO3- in stimulating peroxidase function. These data suggest that HCO3- bound to Arg141 anchors the neutral H2O2 molecule at the active site copper, enabling its redox cleavage. Thus, SOD1 acquires peroxidase activity at physiological pH only in the presence of HCO3- or structurally similar anions. Alterations in pH that shift the HCO3-/CO2 equilibrium as occur in disease processes such as ischemia, sepsis, or shock would modulate the peroxidase function of SOD1.
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PMID:Bicarbonate is required for the peroxidase function of Cu, Zn-superoxide dismutase at physiological pH. 988 Apr 90


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