6-ketoprostaglandin-f1-alpha and Escherichia-coli-Infections

The goal of the study was to estimate the content of prostacyclin (PGI(2)), the levels of PGI synthase (PTGIS) and receptor (PTGIR) protein expression, and the cellular localization of these factors in the inflammatory-changed porcine uterus. The effect of PGI(2) on the contractility of the inflamed uteri was also determined. On Day 3 of the estrous cycle (Day 0 of the study), 50 mL of either saline or Escherichia coli suspension (10(9) colony-forming units/mL) were injected into each uterine horn. Acute endometritis developed in all bacteria-inoculated gilts, however on Day 8 of the study a severe form of acute endometritis was noted more often than on Day 16. Bacteria injections increased the contents of 6-keto-prostaglandin F(1α) in endometrium, myometrium, washings, and the level of PTGIS in endometrium on Days 8 and 16, and the content of PTGIR in endometrium on Day 16. In the inflamed uteri on both study days, stronger immunoreactivity for PTGIS was observed in part of the luminal and glandular epithelial cells and in a portion of the endometrial arteries, and for PTGIR in part of the luminal epithelium and endothelial cells in a portion of the endometrial arteries. On Day 8, PGI(2) decreased contraction intensity in endometrium/myometrium and myometrium of the saline-treated uteri and increased the contraction intensity in both types of strips from the inflamed organs. Our study reveals that inflammation of the porcine uterus upregulates PGI(2) synthesis and that PGI(2) increases contractility, which suggests that PGI(2) might be essential for the course of uterine inflammation.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cytochrome P-450 Enzyme System; Endometritis; Endometrium; Epoprostenol; Escherichia coli Infections; Female; Fluorescent Antibody Technique; Intramolecular Oxidoreductases; Myometrium; Receptors, Epoprostenol; Swine; Swine Diseases; Uterine Contraction; Uterus

Sepsis-related acute kidney injury (AKI) is the leading cause of AKI in intensive care units. Endotoxin is a primary initiator of inflammatory and hemodynamic consequences of sepsis and is associated with experimental AKI. The present study was undertaken to further examine the role of the endothelium, specifically prostacyclin (PGI(2)), in the pathogenesis of endotoxemia-related AKI. A low dose of endotoxin (LPS, 1 mg/kg) in wild-type (WT) mice was associated with stable glomerular filtration rate (GFR) (164.0 +/- 16.7 vs. 173.3 +/- 6.7 microl/min, P = not significant) as urinary excretion of 6-keto-PGF(1alpha), the major metabolite of PGI(2), increased. When cyclooxygenase inhibition with indomethacin abolished this rise in 6-keto-PGF(1alpha), the same low dose of LPS significantly decreased GFR (110.7 +/- 12.1 vs. 173.3 +/- 6.7 microl/min, P < 0.05). The same dose of indomethacin did not alter GFR in WT mice. To further study the role of PGI(2) in endotoxemia, renal-specific PGI synthase (PGIs) transgenic (Tg) mice were developed that had increased PGIs expression only in the kidney and increased urinary 6-keto-PGF(1alpha). These Tg mice, however, demonstrated endotoxemia-related AKI with low-dose LPS (1 mg/kg) (GFR: 12.6 +/- 3.9 vs. 196.5 +/- 21.0 microl/min P < 0.01), which did not alter GFR in WT mice (164.0 +/- 16.7 vs. 173.3 +/- 6.7 microl/min, P = not significant). An elevation in renal cAMP, however, suggested an activation of the PGI(2)-cAMP-renin system in these Tg mice. Moreover, angiotensin-converting enzyme inhibition afforded protection against endotoxin-related AKI in these Tg mice. Thus endothelial PGIs-mediated PGI(2), as previously shown with endothelial nitric oxide synthase-mediated nitric oxide, contributes to renal protection against endotoxemia-related AKI. This effect may be overridden by excessive activation of the renin-angiotensin system in renal-specific PGIs Tg mice.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Kidney Injury; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Cyclooxygenase Inhibitors; Cytochrome P-450 Enzyme System; Enalapril; Endothelium; Endotoxemia; Endotoxins; Epoprostenol; Escherichia coli Infections; Glomerular Filtration Rate; Indomethacin; Intramolecular Oxidoreductases; Kidney; Lipopolysaccharides; Male; Mice; Mice, Transgenic; Prostaglandin-Endoperoxide Synthases; Regional Blood Flow

Although various inflammatory mediators have been previously shown to be released into the peritoneal cavity during peritonitis in peritoneal dialysis patients, those that are involved in governing changes in peritoneal permeability to small solutes and protein remain incompletely defined.. We determined the importance of prostanoid production in the enhanced protein loss observed during acute peritonitis by inhibition experiments using indomethacin, an inhibitor of cyclooxygenase activity. The association between changes in peritoneal permeability and the generation of inflammatory mediators after adding Escherichia coli to peritoneal dialysate was first examined in series 1 experiments. Series 2 experiments then determined the effect of intraperitoneal administration of indomethacin (75 microg/mL) on changes in peritoneal permeability after adding E. coli to peritoneal dialysate. All experiments were performed in male New Zealand White rabbits (2.6 to 3.4 kg body weight) using an eight-hour dwell of dialysate containing 2.5% glucose. Peritoneal permeability to creatinine and protein was assessed by time-dependent changes in the dialysate to plasma concentration ratios of these solutes.. Series 1 experiments showed enhanced leukocyte migration into the peritoneal cavity and increased peritoneal permeability to protein during bacterial challenge that was accompanied by an increase in the dialysate concentrations of prostaglandin E2 (PGE2), 6-keto-PGF1alpha, and interleukin-8, but not nitrate + nitrite (a measure of local nitric oxide production). Inhibition of prostanoid production by intraperitoneal administration of indomethacin in series 2 experiments resulted in lower dialysate concentrations of PGE2 and 6-keto-PGF1alpha and in lower peritoneal permeability to protein, both to control levels. No effect of indomethacin on transperitoneal migration of leukocytes or the generation of interleukin-8 was observed.. Enhanced production of prostanoids likely plays an important role in governing the increase in peritoneal permeability to protein during acute, bacterial peritonitis in the rabbit.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cell Movement; Cyclooxygenase Inhibitors; Dialysis Solutions; Dinoprostone; Escherichia coli Infections; Indomethacin; Injections, Intraperitoneal; Interleukin-8; Leukocytes; Male; Peritoneum; Peritonitis; Prostaglandins; Proteins; Rabbits

The interaction between constitutive nitric oxide and oxygen may depend on the degree of tissue oxygenation and may play a critical role in the pathophysiological response to endotoxaemia. We investigated if hyperoxia (100% O2) attenuated the systemic and pulmonary vasoconstriction and increased biosynthesis of thromboxane B2 (TXB2) and 6-keto-prostaglandin (PG) F1alpha induced by inhibition of nitric oxide synthase with NG-nitro-L-arginine-methyl-ester (L-NAME) in a porcine model of endotoxaemia. Twenty-two domestic, random source pigs, weighing 15.4 +/- 2.7 kg (mean +/- standard deviation) were the subjects of this study. Pigs were anaesthetized with isoflurane in 100% O2, orotracheally intubated and ventilated to maintain normocapnia, and then instrumented for haemodynamic monitoring. Following instrumentation, pigs were maintained at an end-tidal isoflurane concentration of 2%. Pigs were randomly assigned to treatment groups: saline + 30% O2 (Control, n = 6); Escherichia coli lipopolysaccharide (5 microg/kg/h from 1 to 2 h followed by 2 microg/kg/h from 2 to 5 h) + 30% O2 (LPS, n = 4); L-NAME (0.5 mg/kg/h, from 0 to 5 h) + LPS + 100% O2 (n = 6); and L-NAME + LPS + 30% O2 (n = 6). L-NAME and endotoxin significantly (P < 0.05) increased mean arterial pressure, mean pulmonary arterial pressure, and systemic and pulmonary vascular resistance index beginning at 90 min. When results were pooled across all time periods, mean arterial pressure and mean pulmonary arterial pressure were significantly higher in the L-NAME + LPS + 30% O2 group than all other groups, reflecting pulmonary and systemic vasoconstriction. Hyperoxia attenuated the L-NAME + LPS-induced increases in TXB2 and 6-keto-PGF1alpha concentrations at 90 and 120 min and 120 min, respectively, although the differences were not statistically significant. These results support the observation that nitric oxide synthase inhibition with L-NAME has deleterious haemodynamic effects in this model of endotoxaemia. The temporal attenuation of L-NAME-induced pulmonary and systemic vasoconstriction by hyperoxia suggested that the haemodynamic effects of acute endotoxaemia were in part influenced by the relative amounts of nitric oxide and oxygen present.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Endotoxemia; Enzyme Inhibitors; Escherichia coli Infections; Hemodynamics; Hyperoxia; Lung; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Pulmonary Circulation; Swine; Swine Diseases; Thromboxane B2; Vasoconstriction

To compare effects of a single dose of pentoxifylline (PTX), flunixin meglumine (FM), and their combination (FM/PTX) in a model of equine endotoxemia.. 24 healthy horses, aged 2 to 15 years.. 4 groups (n = 6/group) received 30 ng of Escherichia coli O55:B5 endotoxin/kg of body weight, i.v., over 30 minutes, and 1 of the following preparations 15 minutes before and 8 hours after endotoxin infusion: FM, 1.1 mg/kg; PTX, 8 mg/kg; FM/PTX, 1.1 mg of FM and 8 mg of PTX/kg; and saline solution bolus (ENDO). Clinical and hematologic variables were measured over 24 hours.. Compared with ENDO, FM given before endotoxin significantly reduced TxB2, and 6-keto-PGF1 concentrations, pulse, rectal temperature, and attitude score. Pentoxifylline given before endotoxin resulted in significantly higher 6-keto-PGF1 concentration at 1.5 hours and significantly lower PAI-1 activity at 12 hours. Tumor necrosis factor and IL-6 activities in horses given PTX alone were not significantly different from values in those given the saline bolus. FM/PTX induced effects similar to those of FM alone on endotoxin-induced changes in temperature and TxB2 concentration, and 6-keto-PGF1 concentration was significantly lower than that in horses of the ENDO group at 1 hour. In horses of the FM group, 6-keto-PGF1 concentration was significantly lower than that in horses of the ENDO group, from 0.5 hour to 2 hours. Horses of the FM and FM/PTX groups had significantly higher IL-6 activity at 1.5 and 2 hours than did horses of the PTX and ENDO groups; those of the FM and FM/PTX groups had significantly lower WBC count than did those of the PTX and ENDO groups.. FM/PTX may help offset deleterious hemodynamic effects of endotoxin more effectively than does either FM or PTX alone.

Topics: 6-Ketoprostaglandin F1 alpha; Analysis of Variance; Animals; Anti-Inflammatory Agents, Non-Steroidal; Body Temperature; Clonixin; Disease Models, Animal; Drug Combinations; Endotoxemia; Escherichia coli; Escherichia coli Infections; Hemodynamics; Horse Diseases; Horses; Interleukin-6; Leukocyte Count; Pentoxifylline; Plasminogen Activator Inhibitor 1; Thromboxane B2; Time Factors; Tissue Plasminogen Activator; Tumor Necrosis Factor-alpha; Vasodilator Agents

The purpose of the present study was to assess the role of polymorphonuclear leukocyte (neutrophil) elastase in endotoxin-induced acute lung injury in sheep with lung lymph fistula. We studied the effects of ONO-5046, a specific inhibitor of neutrophil elastase, on the lung dysfunction induced by the intravenous infusion of 1 microgram/kg of Escherichia coli endotoxin. Endotoxin alone produced a biphasic response as previously reported. Early (0.5-1 h) after endotoxin, pulmonary arterial pressure increased from 19.5 +/- 0.9 cmH2O at baseline to a peak of 46.8 +/- 2.4 cmH2O (P < 0.05). Pulmonary vascular resistance increased from 3.03 +/- 0.17 cmH2O.l-1.min at baseline to a peak of 9.77 +/- 0.70 cmH2O.l-1.min (P < 0.05). Circulating neutrophils decreased from 7,355 +/- 434/mm3 at baseline to a nadir of 1,762 +/- 32/mm3 (P < 0.05). Thromboxane B2 and 6-ketoprostaglandin F1 alpha concentrations in plasma and lung lymph were significantly increased. Late (3-5 h) after endotoxin, pulmonary arterial pressure and pulmonary vascular resistance returned to baseline levels, but lung lymph flow remained increased from 4.2 +/- 0.3 ml/0.5 h at baseline to 7.3 +/- 0.7 ml/0.5 h (P < 0.05), with a slight increase in lung lymph-to-plasma protein concentration ratio, suggesting increased pulmonary vascular permeability. The histopathological features of the lungs during the early period in sheep treated with endotoxin alone revealed a large increase in neutrophils per 100 alveoli and changes of pulmonary edema such as thickening of the interstitium of the lung and alveolar flooding.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Bacteremia; Blood Gas Analysis; Endotoxins; Escherichia coli Infections; Esterases; Glycine; Hypertension, Pulmonary; Leukocytes; Lung Diseases; Lymph; Neutrophils; Pulmonary Circulation; Sheep; Sulfonamides; Thromboxane B2

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.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Critical Care; Epoprostenol; Escherichia coli Infections; Hemodynamics; Interleukin-6; Intestinal Mucosa; Intestines; Ion Channels; Ischemia; Lung; Microscopy, Electron; Multiple Organ Failure; Platelet Activating Factor; Postoperative Complications; Potassium; Pulmonary Gas Exchange; Respiratory Distress Syndrome; Shock, Septic; Swine; Thromboxane A2; Tumor Necrosis Factor-alpha

To evaluate the hypothesis that treatment with LY255283, a novel leukotriene B4-receptor antagonist, is beneficial in an animal model of the adult respiratory distress syndrome induced by endotoxin.. Prospective, randomized, controlled trial.. Laboratory at a large university medical center.. Twenty-five, immature, random-bred swine.. Four groups of pigs were studied: the LPS group of animals (n = 6) were infused with Escherichia coli lipopolysaccharide (strain 0111:B4, 250 micrograms/kg) from 0 to 60 mins; the LPS + 255283 group of animals (n = 6) were infused with lipopolysaccharide as above, but were also treated with LY255283 (30 mg/kg, then 10 mg/kg/hr), beginning at -15 mins; the 255283 group of animals (n = 6) were infused with the same dose of LY255283, but were not challenged with lipopolysaccharide; and the RL control group of subjects (n = 7) received only the lactated Ringer's solution vehicle. Beginning at 30 mins, all groups were infused with dextran-70 solution as needed to maintain cardiac output at 90% to 110% of baseline value.. Treatment with LY255283 significantly (p < .05) ameliorated lipopolysaccharide-induced systemic arterial hypotension, pulmonary arterial hypertension, and arterial hypoxemia. Treatment with this drug also abrogated lipopolysaccharide-induced increases in pulmonary extravascular water content and bronchoalveolar lavage fluid protein concentration.. These data suggest that leukotriene B4 may be an important mediator of acute lung injury in this porcine model of septic shock and acute lung injury. Further studies to assess the specificity of LY255283 as a leukotriene B4 antagonist are necessary in order to exclude the possibility that the beneficial effects of this compound are due to pharmacologic actions other than the blockade of LTB4 receptors.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Drug Evaluation, Preclinical; Escherichia coli Infections; Extravascular Lung Water; Hemodynamics; Leukotriene B4; Male; Peroxidase; Proteins; Random Allocation; Respiratory Distress Syndrome; Shock, Septic; Swine; Tetrazoles; Thromboxane B2

To evaluate the effects of ibuprofen on gram-negative septic shock, immature piglets were subjected to fecal-Escherichia coli peritonitis. Group I (n = 5) received a 12.5 mg/kg bolus of ibuprofen in 0.9% benzyl alcohol, followed by a continuous infusion of 6.25 mg/kg/h. Group II (n = 5) received the vehicle, benzyl alcohol, and Group III (n = 5) received lactated Ringer's solution. Mean survival times among the three groups were not significantly different. Ibuprofen-treated animals had a mean survival time (+/- S.E.M.) of 17.1 +/- 2 h vs. 19.2 +/- 2.4 h in the benzyl alcohol group and 15.7 +/- 2.7 h in the animals receiving lactated Ringer's solution. Thromboxane B2 levels were not significantly different in the treatment vs. non-treatment groups while 6-keto-PGF1a levels were significantly lower in the ibuprofen-treated animals. Neutropenia and thrombocytopenia were not prevented by treatment with ibuprofen.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Escherichia coli Infections; Ibuprofen; Leukocyte Count; Peritonitis; Platelet Count; Pulmonary Circulation; Shock, Septic; Swine; Thromboxane B2; Vascular Resistance

The effect of selenium deficiency on the product profile of arachidonic acid oxidation by enzymatic pathways in Holstein cows with experimentally-induced coliform mastitis was investigated. The animals were fed dairy rations containing 0.05 mg Se/kg dry matter, with the supplemented group receiving additional Se to increase the dietary concentration to approximately 0.35 mg Se/kg dry matter. Cows were inoculated intracisternally with 30 colony-forming-units of Escherichia coli at 14-16 weeks of lactation. Eicosanoids and bacteria numbers were recorded at various intervals of time for 60 h postinoculation. Milk from cows fed the Se-depleted diet had significantly higher (p less than 0.05) concentrations of TXB2 between 24 and 48 h and 6-keto-PGF1 alpha between 24 and 60 h postinoculation. Milk PGE2 concentration was significantly higher in the Se-deficient group at 24 h, whereas LTB4 was higher between 36 and 60 h postinoculation in the Se-deficient cows (p less than 0.05). Milk bacteria numbers were significantly higher between 16 and 24 h postinoculation in the Se-deficient group and three of the four cows in this group required euthanasia, whereas all four cows in the Se-supplemented group recovered without therapeutic intervention. These data indicate marked effects of dietary Se on milk eicosanoid concentrations in response to an E. coli infection. The changes in eicosanoid concentrations may be associated with the altered pathogenesis and outcome of mastitis in a Se-deficient state.

Topics: 6-Ketoprostaglandin F1 alpha; Administration, Oral; Animals; Cattle; Deficiency Diseases; Dinoprostone; Eicosanoids; Escherichia coli Infections; Leukotriene B4; Mastitis, Bovine; Milk; Selenium; Thromboxane B2; Time Factors; Treatment Outcome

Thirty two rabbits were equally divided at random into 4 groups: A. control; B. E.coli; C. E.coli + ibuprofen; D. E.coli + tetramethylpyrazine. The plasma concentration of 6-keto-PGF1 alpha and TXB2, arterial blood gas as well as platelet aggregability were measured and the pathological changes of lung tissue were observed. The results suggest that TXA2 and PGI2 do take part in the pathogenesis of acute lung injury; that PGI2 may serve as an indicator in the evaluation of the degree of injury in the pulmonary endothelial cells and may also contribute to septic shock; and that both tetramethylpyrazine and ibuprofen possess therapeutic effects on the amelioration of acute lung injury, and the former is rather stronger than the latter in the inhibitory effect on granulocytic sequestration within the lung.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Escherichia coli Infections; Lung; Lung Diseases; Male; Platelet Aggregation; Platelet Aggregation Inhibitors; Pyrazines; Rabbits; Thromboxane B2

The effect of the leukotriene D4 (LTD4) receptor antagonist, LY-171883, on the respiratory and cardiovascular changes in endotoxemia was studied in 20 unanesthetized sheep. In group 1 (n = 2), 4 mg/kg LY-171883 was injected iv. In group 2 (n = 12), Escherichia coli endotoxin (1 micrograms/kg) was infused iv, and in group 3 (n = 6), 4 mg/kg LY-171883 was administered 15 min before and 30 min after the same dose of endotoxin. Infusion of LY-171883 in group 1 did not alter baseline ventilatory and cardiovascular measurements. A two-phase pulmonary response was observed in group 2: an early pulmonary hypertension phase in which pulmonary artery pressure (PAP) increased from 18.7 to 51.2 mm Hg (p less than .001), with a fall in cardiac index (CI) from 171 to 114 ml/min.kg (p less than .01). The ratio of peak inspiratory/expiratory flow rate (PIF/PEF) increased from 1.08 to 1.35 (p less than .01) and the respiratory rate from 50 to 70 breath/min (p less than .005) 30 min postendotoxin. The flow rate measured at midexpiration time (V50) decreased from 81% to 25% of its peak expiration (p less than .001) and the airway resistance increased from 3.8 to 32.7 cm H2O/L.sec (p less than .001). The second permeability phase was characterized by an increase in pulmonary lymph flow (QL) from 8.5 to 35.2 ml/h (p less than .01), a decrease in PaO2 from 76 to 61 torr (p less than .01), and an increase in pulmonary shunt ratio (Qsp/Qt) from 16% to 31% (p less than .005).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Acetophenones; Animals; Autacoids; Azoles; Escherichia coli Infections; Hemodynamics; Respiration; Sheep; Tetrazoles; Thromboxane B2

In a common bile duct contamination model, we studied the effect of Streptococcus faecalis compared with Escherichia coli in sheep with chronic lymph fistulas to investigate the role of enterococcus in acute lung injury and acute sepsis. Early pulmonary hypertension in the E coli group was not expressed in the S faecalis group, probably due to a failure of S faecalis to illicit a thromboxane A2 response. In the late period, E coli was associated with significantly greater lung microvascular damage compared with S faecalis. The lack of difference between groups with respect to complement activation suggests the action of chemotactic factors, in addition to complement, mediating granulocyte aggregation, and neutropenia. In this model, S faecalis demonstrated limited pathogenicity as expressed in lung microvascular injury compared with E coli.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Cardiac Output; Enterococcus faecalis; Escherichia coli Infections; Hematocrit; Leukocyte Count; Lung; Lymphatic System; Pulmonary Artery; Pulmonary Circulation; Pulmonary Wedge Pressure; Sheep; Streptococcal Infections; Thromboxane B2

Time-related changes in eicosanoid release and hemodynamic parameters were characterized in baboons during the early development of sepsis induced by intravenous (i.v.) infusion of live Escherichia coli (4 x 10(10) organisms/kg) in baboons. Plasma levels of thromboxane B2 (TxB2), a stable metabolite of thromboxane A2 (TxA2), rose rapidly in arterial, venous, and pulmonary arterial blood after infusion of live E. coli, attaining maximal increases at 30 min and returning to control values by 60 min. In contrast, plasma concentrations of 6-keto-PGF1 alpha rose slowly after infusion, reaching peak concentrations at 120 min, then slowly returned to control values between 4 and 5 hr after infusion of live E. coli. Hemodynamic values remained stable during the first 2 hr after infusion, although early changes in cellular energy metabolism and incipient hemodynamic failure were inferred from pyrexia, tachycardia, and metabolic acidosis. At 3 hr, signs of further hemodynamic compromise developed, including increased venous PCO2, reduced pulmonary capillary wedge pressure, and reduced stroke volume, followed by gradual increases in systemic and pulmonary vascular resistance. These factors coincided with progressive reductions in cardiac output and deteriorating circulatory efficiency. The time course of events following infusion of live E. coli indicates that alterations in cellular energy provision occurred early (within 1 hr), whereas central hemodynamic parameters decayed much more slowly. Additionally, TxA2 and PGI2 appear related to the early events in the development of sepsis as their release preceded cardiocirculatory failure.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Eicosanoic Acids; Escherichia coli Infections; Male; Papio; Sepsis; Thromboxane B2

Goats were divided into three groups and given infusions of live Escherichia coli bacteria. Group I received no treatment, group II was treated with indomethacin (a cyclooxygenase inhibitor), and group III with dazoxiben (a thromboxane synthase inhibitor). Double indicator-dilution extravascular lung water (EVLW) in group I was significantly different from the treated groups. There was an early increase in EVLW in group I and group III but not in group II animals. At 6 h EVLW's in group I, group II, and group III were 100, 45, and 30% above base line, respectively. Lymph flow (QL) and lymph-to-plasma protein ratio (L/P) was not statistically different between groups. Estimated total fluid filtration [QL + d(EVLW)/dt] in group I and III was markedly elevated between 0 and 1.5-2 h after E. coli infusion. Cardiac output (QT) decreased to 40% of base line in group I, and it decreased slightly in group II because of the indomethacin but did not decrease after E. coli. QT decreased in group III but recovered more rapidly than group I. Mean pulmonary arterial pressure increased more rapidly in group I and reached a higher peak than either treated group. At 6 h these groups had similar pulmonary arterial and pulmonary arterial wedge pressures. We conclude that 1) indomethacin but not dazoxiben blocks the early increase in total fluid filtration after bacterial infusion, 2) dazoxiben does not prevent the increased endothelial permeability resulting from infusion of live bacteria, and 3) indomethacin may somewhat ameliorate the endothelial permeability change.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Body Water; Cardiac Output; Escherichia coli Infections; Imidazoles; Indomethacin; Lung; Lymph; Pulmonary Circulation; Reference Values; Thromboxane B2; Thromboxane-A Synthase

Twelve male neonatal calves (39 to 50 kg) were allotted to 3 groups of 4 calves each. All calves were anesthetized with halothane, and then Escherichia coli endotoxin was given intravenously (3 times) and intraperitoneally (3 times) during a 6-hour period. Group-1 calves were untreated, group-2 calves were pretreated with a low dose of flunixin meglumine (1.1 mg/kg of body weight), and group-3 calves were pretreated with a high dose of flunixin meglumine (4.4 mg/kg). In calves of group 1, the mean systemic arterial blood pressure (MABP) and cardiac output (CO) decreased, but pulmonary arterial pressure increased after the initial intravenous and intraperitoneal injections of endotoxin. In calves of this group, these changes were accompanied by increased plasma thromboxane B2 (TxB2) concentration. During this period, increased plasma TxB2 concentration or hemodynamic changes were not detected in calves of groups 2 and 3. Only calves of group 1 had altered hemodynamics early in the experiment; however, after 6 hours, calves of all 3 groups had similarly decreased CO and MABP. In calves of the untreated group, plasma 6-keto-prostaglandin (PG)F1 alpha concentration increased steadily from the beginning of the experiment until 3 hours later. The CO and MABP were low at the time when serum 6-keto-PGF1 alpha concentration was high; however, these 2 measurements also were low in treated calves who did not have correspondingly high plasma 6-keto-PGF1 alpha concentration. Regional blood flow analysis did not reveal correlations between prostanoid concentrations and altered blood flow to selected tissues.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Cardiac Output; Cattle; Cattle Diseases; Endotoxins; Escherichia coli; Escherichia coli Infections; Hemodynamics; Lactates; Male; Thromboxane B2

The pulmonary and systemic response to a full-thickness burn (15% of total body surface area) was determined in 15 adult sheep. Also compared was the effect of wound bacterial content and prostanoid release on this response. Burn wound thromboxane A2, measured as TxB2, and prostacyclin, measured as 6-keto-PGF1 alpha, were measured in burn wound lymph. Animals were monitored for 7 days. On the final day, a full-thickness biopsy specimen of burn tissue was obtained for quantitative bacteriology. Wounds with 10(4) or less organisms per gram of burn tissue were considered colonized, whereas those with 10(5) or more organisms per gram of burn tissue indicated wound infection. Seven sheep had 10(4) or less bacteria and the remaining eight sheep had 10(6) or greater bacteria. We noted a significant mean increase in cardiac index from a baseline of 5 to 6.2 L/min/m2, a decrease in systemic vascular resistance from 16 to 12 mm Hg/L/min, and a mean increase in oxygen consumption from a baseline of 135 to 165 ml/min/m2 during the 7-day study period. There were no differences in these responses between the colonized and the infected wounds. Pulmonary artery pressure increased from a mean baseline of 19 to 24 mm Hg and arterial oxygen tension (PaO2) decreased from a baseline of 90 to 80 mm Hg in the infected wound group, with values remaining at baseline in the colonized wound group. These changes corresponded with an increase in lymph and plasma TxB2 from a baseline of 200 to 210 pg/ml to 1000 +/- 250 and 600 +/- 190 pg/ml, respectively. Values in the animals with colonized wounds were not significantly increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Burns; Escherichia coli Infections; Extracellular Space; Hemodynamics; Lung; Lymph; Pseudomonas Infections; Sheep; Thromboxane B2; Time Factors; Wound Infection

The pulmonary and systemic hemodynamic effects of recurrent endotoxemia were studied in the adult sheep with lung lymph fistulas. Six sheep were given 1 mu/kg Escherichia coli endotoxin every 12 hours for 5 days, after which animals were monitored for another 3 days. The pulmonary response to the first three injections was characterized by an initial severe pulmonary hypertension, hypoxia, and a two- to threefold increase in lymph flow, QL. Lymph and plasma thromboxane A2 (TxB2) and prostacyclin (6-keto-PGF1 alpha) levels increased from baseline values of nearly 200 pg/ml to values exceeding 2000 pg/ml. The systemic response to initial doses was characterized by an increase in systemic vascular resistance, a decrease in cardiac index, and a transient 20% increase in oxygen consumption. With later endotoxin doses, the pulmonary response was markedly attenuated, with only modest changes in pulmonary artery pressure, lymph flow, and arterial oxygen tension noted. TxB2 increases were less than 800 pg/ml, and 6-keto-PGF1 alpha levels remained unchanged. However, we noted the progressive onset of a hyperdynamic state characterized by a sustained increase in cardiac index and body temperature, and a 50% increase in oxygen consumption, whereas systemic vascular resistance decreased by 45%. Three days after endotoxin injections were discontinued, the hyperdynamic state (including leukocytosis) was still present, whereas pulmonary variables returned to baseline levels. We conclude that a hyperdynamic state can be produced by repeated doses of endotoxin that will present even after the endotoxin insult is discontinued, which is a characteristic of the multisystem organ failure syndrome.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Endotoxins; Escherichia coli Infections; Hemodynamics; Lung; Pulmonary Circulation; Recurrence; Respiratory Distress Syndrome; Sheep; Thromboxane B2

Acute respiratory failure in humans often follows extrathoracic sepsis. The purpose of this study was to determine the effect of repeated episodes of intra-abdominal sepsis over several weeks on the structure and function of rat lung. Intermittent peritonitis and a bacteremia of Escherichia coli and Bacteroides fragilis were produced by weekly intra-abdominal implants of gelatin capsules containing these organisms (3.0 +/- 1.0 X 10(7) and 5.0 +/- 1.0 X 10(7) colony-forming units/ml, respectively; mean +/- SEM). After 4 weeks alveolar walls were thickened and cellular with focal areas of alveolar space consolidation: circulating polymorphonuclear leukocytes were increased (12.2 +/- 1.2 to 19.9 +/- 2.0 X 10(3)/mm3; p less than 0.05), as were plasma levels of 6-keto-PGF1 alpha (0.56 +/- 0.08 to 1.02 +/- 0.18 ng/ml; p less than 0.01). After 8 weeks the capillary bed was dilated and the alveolar walls and ducts appeared less cellular but showed fibrosis: The WBC count had increased to 25.5 +/- 1.0 X 10(3) (p less than 0.01). After 4 or 8 weeks of intermittent sepsis there was no increase in the pulmonary artery pressure or vascular resistance or any change in arterial oxygen tension, plasma thromboxane beta 2 level, or platelet count. We conclude that repeated bouts of sepsis and bacteremia in the rat cause progressive injury to lung alveoli without evidence of altered blood gas tensions or pulmonary hemodynamics.

Topics: 6-Ketoprostaglandin F1 alpha; Abdomen; Abscess; Animals; Bacterial Infections; Bacteroides fragilis; Bacteroides Infections; Blood Cell Count; Capsules; Disease Models, Animal; Escherichia coli Infections; Hematocrit; Hemodynamics; Lung; Male; Rats; Rats, Inbred Strains; Respiratory Distress Syndrome; Thromboxane B2

This study investigates the role of prostaglandins (PG) in hyperdynamic sepsis. Thirteen chronically instrumented dogs were rendered septic by implanting in the peritoneal cavity a fibrin clot containing viable Escherichia coli. One day later, cardiac output (CO) increased from 2.80 +/- 0.22 to 3.72 +/- 0.32 l/min (p = 0.011); heart rate (HR) increased from 122 +/- 8 to 147 +/- 6 beats/min (p = 0.005); mean pulmonary artery pressure (PAP) increased from 15 +/- 1 to 19 +/- 1 mmHg (p = 0.003); mean systemic arterial pressure (MAP) decreased from 120 +/- 5 to 107 +/- 7 mmHg; and systemic vascular resistance (SVR) decreased from 44.1 +/- 2.6 to 29.3 +/- 1.9 mmHg/l/min (p less than 0.001). Sixty minutes after intravenous injection of indomethacin (2 mg/kg) or ibuprofen (25 mg/kg), CO decreased to 2.60 +/- 0.21 l/min (p less than 0.001); HR decreased to 118 +/- 5 beats/min (p less than 0.001); PAP decreased to 17 +/- 1 mmHg (p = 0.021); and SVR increased to 43.7 mmHg/l/min (p less than 0.001). In seven control dogs, laparotomy alone did not significantly affect any of these parameters. Infusion of indomethacin caused a slight increase in MAP (106 +/- 4 to 116 +/- 4 mmHg, p = 0.035) but otherwise did not alter hemodynamics. It is concluded that administration of indomethacin or ibuprofen restores normal hemodynamics in a canine model of high-output sepsis, probably by inhibiting PG synthesis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Disease Models, Animal; Dogs; Escherichia coli Infections; Female; Hemodynamics; Ibuprofen; Indomethacin; Male; Oxygen Consumption; Peritonitis; Prostaglandin Antagonists; Prostaglandins; Sepsis; Shock, Septic; Thromboxane A2