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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The use of prostaglandins is currently undergoing clinical trials in respiratory failure accompanying sepsis. The effect of prostaglandin E1 (PGE1) and prostacyclin (PGI2) infusion on endotoxin-induced lung injury, with attention to interstitial fluid flux (QL), pulmonary vascular pressure (Ppa), leukocytes, platelets, and release of the lysosomal enzyme beta-glucuronidase, was investigated. A chronic lung lymph fistula model in sheep was used. Seven sheep alternately received Escherichia coli endotoxin and endotoxin plus PGE at a dosage of 1 microgram/kg/min. Six sheep received PGI2 (0.2 microgram/kg/min) instead of PGE1. Both PGE1 and PGI2 decreased the pulmonary hypertension and the interstitial edema produced by endotoxin primarily through their vasodilatory properties. Prostacyclin seemed to have an additional membrane-stabilizing effect. A rebound increase in QL, Ppa, and platelets occurred when PGE1 or PGI2 infusion was discontinued.
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PMID:Prostaglandin infusion and endotoxin-induced lung injury. 703 77

In acute hypoxemic respiratory failure of term and near-term neonates, extra- and intrapulmonary right-to-left shunting contribute to refractory hypoxemia. Inhaled nitric oxide (NO) decreases pulmonary arterial pressure and improves ventilation-perfusion mismatch in a variety of animal models and selected human patients. We report on 10 consecutive term and near-term newborns with severe acute hypoxemic respiratory failure due to diaphragmatic hernia, meconium aspiration syndrome, group B streptococcus sepsis, pneumonia or acute respiratory distress syndrome, who received increasing doses of inhaled NO (up to 80 ppm) to improve the arterial partial pressure of oxygen (PaO2). The response to NO and the optimum NO concentration which improved PaO2 varied considerably between patients. Improvement of PaO2 was absent or poor (less than 10 mm Hg) in the 4 newborns with meconium aspiration syndrome and in 1 patient with congenital diaphragmatic hernia, while in the other 5 patients inhaled NO increased the mean (+/- SE) PaO2 from 41 +/- 6 to 57 +/- 9 mm Hg (P < 0.05). Optimum NO concentrations determined by dose-response measurements performed during the first 8 hr of NO inhalation were 8-16 ppm except for 2 newborns with congenital diaphragmatic hernia who required 32 ppm to effectively increase PaO2. Four of the 5 patients in whom the PaO2 rose by more than 10 mm Hg received inhaled NO for extended periods of time (5 to 23 days) with no signs of tachyphylaxis. The optimum NO concentration dropped to less than 3 ppm after prolonged mechanical ventilation or when intravenous prostacyclin was given concomitantly.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Dose-response to inhaled nitric oxide in acute hypoxemic respiratory failure of newborn infants: a preliminary report. 756 4

The development of techniques for manipulating nucleic acids and strategies for delivering DNA to humans has made gene therapy a reality. Although mostly focused on genetically based diseases so far, there is every reason to expand the concept to include acquired diseases. Critical illness may be a good target for gene therapy because of the high mortality and need for only transient treatment. Genes can be delivered in vivo using viral vectors (replication-deficient adenovirus and adeno-associated virus most often). Viral vectors have some negatives, mainly the triggering of an inflammatory and an immune response. Nonviral DNA delivery systems include liposomes (cationic or anionic), direct DNA injection, and polycation-DNA-glycoconjugates. Combining liposomes with viral components to deliver plasmids with a transgene may improve efficiency of delivery without causing toxicity. In a model of acute lung injury, in vivo delivery of a vector hyperexpressing the prostaglandin synthase gene using cationic liposomes resulted in increased production of prostaglandin E2 and prostacyclin in the lungs, and protected the lungs from the effects of endotoxin. This end-result demonstrates the feasibility of this approach. A similar rationale for the treatment of sepsis could be used. Other promising therapeutic genes would include those encoding antioxidant enzymes or antiproteases. The logistics for moving to initial studies of gene therapy in critically ill humans have been worked out for other diseases; such steps should expedite the exploration of this new category of therapies.
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PMID:Gene therapy in acute critical illness. 758 73

The study deals with an animal model for the problems of surgical intensive care patients. Following repeated applications of E. coli endotoxin WO 111:B4 under standard conditions, specific hemodynamic and biochemical (TNF, TXA2, PGI2, IL-6, PAF) and morphological (endothelium of the lung) alterations were detected. ARDS patterns induced by the sepsis were analyzed by high-frequency measurement of pressure and flow (385 measurements per breathing cycle). The role of the intestine in sepsis was investigated by ion-selective monitoring of surface potassium activity comparing mucosa and serosa. Every injection of endotoxin was followed by a selective increase of the potassium activity revealing relative ischemia induced by the endotoxin. The profile of the potassium levels on the surface correlates both with the cardiac output and with the prostacyclin levels. The continuous narrowing of the difference between mucosa and serosa, potassium during the period of investigation can be regarded as evidence for pathologic change in permeability fostering the septic course.
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PMID:[Septic shock and multiple organ failure in surgical intensive care. An animal experiment model on the analysis of pulmonary and intestinal dysfunction]. 769 Jan 6

Neonatal group B streptococcal (GBS) sepsis and pneumonia cause lung endothelial cell injury. GBS invasion of the lung endothelium may be a mechanism for injury and the release of vasoactive eicosanoids. Pulmonary artery endothelial cells (PAEC) and lung microvascular endothelial cells (LMvEC) were isolated from neonatal piglets and were characterized as endothelial on the basis of morphology, uptake of acyl low-density lipoprotein, factor VIII staining, and formation of tube-like structures on Matrigel. PAEC and LMvEC monolayers were infected with COH-1 (parent GBS strain), isogenic mutants of COH-1 devoid of capsular sialic acid or all capsular polysaccharide, or a noninvasive Escherichia coli strain, DH5 alpha. Intracellular GBS were assayed by plate counting of colony-forming units resistant to incubation with extracellular antibiotics. All GBS strains invaded LMvEC significantly more than PAEC, showing that the site of lung endothelial cell origin influences invasion. DH5 alpha was not invasive in either cell type. Both isogenic mutants invaded PAEC and LMvEC more than COH-1 did, showing that GBS capsular polysaccharide attenuates invasion. Live GBS caused both LMvEC and PAEC injury as assessed by lactate dehydrogenase release; heat-killed GBS and DH5 alpha caused no significant injury. Supernatants from PAEC and LMvEC were assayed by radioimmunoassay for prostaglandin E2 (PGE2), the stable metabolite of prostacyclin (6-keto-PGF1 alpha), and the thromboxane metabolite thromoxane B2. At 4 h, live COH-1 caused no significant increases in eicosanoids from both PAEC and LMvEC. At 16 h, live COH-1, but not heat-killed COH-1, caused a significant increase in 6-keto-PGF1 alpha greater than PGE2 from LMvEC, but not PAEC. We conclude that live GBS injure and invade the lung microvascular endothelium and induce release of prostacyclin and PGE2. We postulate that GBS invasion and injury of the lung microvasculature contribute to the pathogenesis of GBS disease.
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PMID:Group B streptococci (GBS) injure lung endothelium in vitro: GBS invasion and GBS-induced eicosanoid production is greater with microvascular than with pulmonary artery cells. 780 66

The baboon model of E. coli sepsis illustrates three concepts with respect to the host response and vascular endothelium. First, the endothelium is the primary target. E. coli sepsis is an acute inflammatory disease of the vascular endothelium. Second, the endothelium is not a passive target. Initially it regulates both the inflammatory and coagulopathic aspects of E. coli sepsis through membrane associated regulatory receptor/plasma protein assemblies including protein C/thrombomodulin, activated protein C/protein S, C4bBP/protein S, tissue factor pathway inhibitor/Xa, antithrombin III/glycosaminoglycans. Third, when overridden by inflammatory events, the endothelium can change its anticoagulant phenotype and mount a massive procoagulant fibrinolytic counter-attack on its luminal side through the expression of tissue factor and release of tissue plasminogen activator. Fourth, again when overridden by inflammatory events, the endothelium can change its antioxidant phenotype and produce a "distal" tissue hypoxia on its abluminal side through induction of free radical generation and peroxidation of mitochondrial lipid membranes of those tissues with high metabolic rates. It has become increasingly clear that the so-called anticoagulant systems which act on the proximal factors of the clotting cascade (protein C, TFPI, AT-III, PGI2) also attenuate the amplification of the inflammatory response. Aspects of the mechanism by which this occurs are coming to light. This includes the attenuation of Il-6 response by TFPI and the attenuation of the complement effects by C4bBP/PS. The specifics of these observations in the E. coli sepsis model will be reviewed.
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PMID:Studies on the inflammatory-coagulant axis in the baboon response to E. coli: regulatory roles of proteins C, S, C4bBP and of inhibitors of tissue factor. 783 58

To examine the roles of leukotriene B4 (LTB4) and prostaglandin I2 (PGI2), the metabolites of arachidonic acid found in patients with sepsis, we measured the serum levels of LTB4 and a stable metabolite of PGI2, 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), in 22 patients with sepsis. Results were analyzed in relation to patients' survival. The serum levels of both LTB4 and 6-keto-PGF1 alpha were significantly higher in patients who died than in those who survived, thus serving as indicators of illness severity. There was a significant correlation between LTB4 and 6-keto-PGF1 alpha levels. The present study suggests that LTB4, a potent leukocyte activator, induces damage to vascular endothelial cells in patients with sepsis, resulting in the excessive production of PGI2 and, consequently, serious illness.
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PMID:Relationship between leukotriene B4 and prostaglandin I2 in patients with sepsis. 785 Feb 55

Studies indicate that hepatocellular dysfunction occurs at 2 h after cecal ligation and puncture (CLP, i.e., sepsis model) despite the increased cardiac output (CO) and hepatic perfusion. It, however, remains unknown whether hepatocellular function is depressed earlier than the onset of hyperdynamic circulation in sepsis. To determine this, rats were subjected to sepsis by CLP. At .5, 1, 1.5, or 2 h after CLP, CO was measured by dye dilution. Hepatocellular function (i.e., maximum velocity of indocyanine green clearance and the efficiency of the active transport) was determined using an in vivo indocyanine green clearance technique. Microvascular blood flow was measured by laser Doppler flowmetry. To determine whether there is any association between hemodynamics and prostaglandins (PGs), plasma levels of PGE2 and PGI2 were measured by radioimmunoassay. The results indicate that hepatocellular function decreased significantly as early as 1.5 h after CLP. Cardiac output and microvascular blood flow in the liver and small intestine, however, increased and vascular resistance decreased at 2 h after CLP. Thus, hepatocellular dysfunction occurs earlier than the occurrence of hyperdynamic circulation during sepsis. Although circulating PGE2 levels were not altered, plasma PGI2 increased significantly at 2 h after CLP. The elevated circulating PGI2 levels, therefore, may be partially responsible for the decreased vascular resistance and increased tissue perfusion at 2 h after CLP. Our findings also suggest that cellular dysfunction, observed in the very early stage of sepsis, is not due to any hyperdynamic circulation/hypermetabolism-related events, but may be associated with the release of proinflammatory cytokines.
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PMID:Hepatocellular dysfunction occurs earlier than the onset of hyperdynamic circulation during sepsis. 785 May 75

To examine the roles of thromboxane A2 and prostaglandin I2, which are arachidonic acid metabolites found in patients with sepsis, we measured the serum levels of their respective stable metabolites, thromboxane B2 (TXB2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) in 22 patients with sepsis. Results were analyzed in relation to patients' survival. The levels of both TXB2 and 6-keto-PGF1 alpha were significantly higher in patients who died than in those who survived, thus reflecting the severity of the patients' illness. There was a significant correlation between the levels of TXB2 and 6-keto-PGF1 alpha. These findings suggest that TXA2 and PGI2 are chemical mediators involved in the severity of clinical sepsis.
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PMID:Relationship between thromboxane B2 and 6-keto-prostaglandin F1 alpha in sepsis. 800 79

Nitric oxide (NO) and prostaglandins (PG) both possess the ability to induce vasodilatation and prevent the aggregation of platelets. The synthesis of these substances is increased following in vivo lipopolysaccharide (LPS) infusion, but their function during sepsis is incompletely understood. We studied the role of NO and PG in a murine model of chronic hepatic inflammation (Corynebacterium parvum injection), which is known to progress to sudden hepatic necrosis after LPS injection. NO synthesis, which is induced in hepatocytes by C. parvum treatment and in nonparenchymal cells by LPS treatment, was inhibited using NG-monomethyl-L-arginine (L-NMMA). High-dose aspirin (ASA) was used to block PG synthesis. Treatment with L-NMMA or ASA alone, in the absence of LPS, resulted in no increase in hepatic injury. C. parvum-treated mice that received both L-NMMA and ASA without LPS developed marked hepatic damage as reflected by increased hepatocellular enzyme release (aspartate aminotransferase and L-ornithine carbamoyl-transferase). Marked hepatic damage was seen after LPS administration, and ASA pretreatment alone had no effect on the LPS-induced hepatic injury, whereas L-NMMA markedly increased the hepatic damage. The combination of L-NMMA and ASA after LPS resulted in the greatest hepatocellular enzyme release, characterized histologically by intravascular thrombosis with diffuse infarction and necrosis. Simultaneous treatment with either PGI2 or L-arginine partially prevented this injury. These data demonstrate that NO and PG function synergistically to maintain hepatocellular integrity; thus increased synthesis of these mediators protects the liver from the pathophysiological effects of LPS in this model.
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PMID:Nitric oxide and prostaglandins interact to prevent hepatic damage during murine endotoxemia. 802 33


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