6-ketoprostaglandin-f1-alpha and Respiratory-Distress-Syndrome

Lipid emulsions have been associated with changes in pulmonary function. Although these changes were related to the physical effects of the infusion-induced lipemia on gas exchange, several animal and human studies suggest that the impairment in pulmonary function observed with lipid infusions was mediated by prostaglandins. Prostaglandins are synthesized enzymatically from essential fatty acids. We studied the effects of two lipid emulsions, with different amounts of essential fatty acids (20% long-chain triacylglycerols [LCT] with 55% of linoleic acid and 7% of alpha linolenic acid in 100 g of emulsion, and a physical mixture of 20% medium-chain triacyglycerols [MCT] and LCT with 26% of linoleic acid and 4% of alpha linolenic acid in 100 g of emulsion), on plasma levels of eicosanoids in patients with acute respiratory distress syndrome (ARDS). Although in patients with ARDS, plasma levels of prostanoids were higher than the reference values, neither lipid emulsion, administered at the rate of 2 mg.kg-1.min-1 induced significant changes in the eicosanoids except for a decrease in systemic-pulmonary arterial 6-keto prostaglandin F1 alpha difference.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Double-Blind Method; Eicosanoids; Fat Emulsions, Intravenous; Humans; Leukotriene B4; Middle Aged; Parenteral Nutrition; Prospective Studies; Reference Values; Respiratory Distress Syndrome; Thromboxane B2

This study was undertaken to assess the effects of leukocyte and platelet depletion on postoperative lung injury in 42 patients who underwent heart operations. Blood was serially sampled before, during, and after cardiopulmonary bypass, and leukocyte count, platelet count, and thromboxane B2 6-keto-PGF1 alpha, leukocyte elastase, thrombin-antithrombin III complex, and D-dimer levels were determined. Postoperative respiratory function was assessed based on analyses of oxygenation and carbon dioxide elimination. Leukocyte and platelet depletion was performed in 21 patients (experimental group) but not in another (control group). In the experimental group, leukocytes and platelets were removed continuously by means of the blood cell separator CS-3000, beginning immediately after the start of the operation and ending 1 hour after the release of aortic occlusion. Leukocyte elastase, thromboxane B2, ratio of thromboxane B2 to 6-keto-PGF1 alpha, thrombin-antithrombin III complex, and D-dimer were significantly lower in the experimental group than in the control group. Of the various indexes of oxygenation, arterial oxygen tension was significantly higher in the experimental group and the alveolar-arterial oxygen pressure difference and respiratory index were significantly lower in the experimental group. The positive end-expiratory pressure needed to achieve an appropriate arterial oxygen tension was significantly lower in the experimental group. The elimination of carbon dioxide was lower in the experimental group. Depletion of leukocytes and platelets reduced respiratory dysfunction after heart operations with cardiopulmonary bypass. It was particularly effective in patients with a low preoperative oxygenation capacity and in those for whom an extended period of cardiopulmonary bypass was required.

Topics: 6-Ketoprostaglandin F1 alpha; Antithrombin III; Cardiac Surgical Procedures; Cardiopulmonary Bypass; Cell Separation; Female; Fibrin Fibrinogen Degradation Products; Humans; Intraoperative Care; Leukocyte Count; Leukocyte Elastase; Male; Middle Aged; Pancreatic Elastase; Peptide Hydrolases; Platelet Count; Postoperative Complications; Respiratory Distress Syndrome; Thromboxane B2

Intralipid (20 percent, 500 ml) was infused fast (5 h) or slow (10 h) randomly in patients with lung injury to relate changes in plasma prostaglandin (PG) concentrations to gas exchange and pulmonary hemodynamics. Data were collected at baseline, midpoint of infusion, and 2 h following infusion. Vasodilator and vasoconstrictor PG metabolites, 6-keto-PGF1 alpha, and thromboxane B2, respectively, were measured in radial arterial blood samples. Slow Intralipid infusion increased shunt fraction (QS/QT) without changing mean pulmonary artery pressure (MPAP), whereas fast Intralipid infusion increased MPAP without changing QS/QT. Prostaglandin levels did not change significantly during either infusion. However, in both groups when the PG substrate was removed, hemodynamic and metabolite values decreased in parallel. In conclusion, we were unable to demonstrate a cause and effect relationship between plasma levels of 6-keto-PGF1 alpha and thromboxane B2 and the observed pulmonary hemodynamic response to slow or fast Intralipid infusion.

Topics: 6-Ketoprostaglandin F1 alpha; Blood Pressure; Fat Emulsions, Intravenous; Humans; Pulmonary Artery; Pulmonary Circulation; Pulmonary Gas Exchange; Pulmonary Wedge Pressure; Respiratory Distress Syndrome; Thromboxane B2

To investigate whether the release of lipid mediators is suppressed in rats with experimentally induced acute lung injury managed with partial liquid ventilation (PLV) using FC-77.. Prospective, randomized controlled study.. Research laboratory in a university.. Male Sprague-Dawley rats.. After tracheostomy was performed under general anesthesia, lung injury was induced by intratracheal instillation of HCl. The PLV group was then subjected to conventional gas ventilation for 30 mins, followed by PLV using FC-77. The control group was subjected to conventional gas ventilation throughout the study period.. In the PLV group the following results were obtained: a) impaired oxygenation was markedly improved; b) the increase in the serum levels of lipid mediators such as leukotriene B4, thromboxane A2, and 6-keto-prostaglandin F1alpha was suppressed; and c) the increase in the concentrations of leukotriene B4, thromboxane A2, and 6-keto-prostaglandin F1alpha in the total lung homogenate at 180 mins after lung injury was also suppressed.. This study indicates that PLV using FC-77 suppresses the release of lipid mediators in our rat model of acute lung injury. However, further investigation is needed to clarify the precise mechanism of this effect.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acids; Fluorocarbons; Hydrochloric Acid; Inflammation Mediators; Leukotriene B4; Liquid Ventilation; Male; Models, Animal; Rats; Rats, Sprague-Dawley; Respiratory Distress Syndrome; Thromboxane A2

This study evaluated whether prostacyclin is a necessary mediator of inflammation in graded bacteremia or is sufficient alone in pathophysiologic concentrations to cause the pulmonary derangement of bacteremic shock.. Experimental.. Laboratory.. Twenty-three anesthetized adult swine. INTERVENSIONS: Swine were studied in four groups for 4 hrs: a) an anesthesia control group (n = 6); b) a septic control group (n = 6), in which 1010/mL Aeromonas hydrophila was infused intravenously at 0.2 mL.kg-1.hr-1 and increased to 4.0 mL.kg-1.hr-1 over 3 hrs; c) a prostacyclin infusion group (n = 6), which received prostacyclin infusion to match septic control plasma concentrationsclm without bacteremia; and d) an antiprostacyclin antibody group (n = 5), which received continuous Aeromonas hydrophila infusion plus antiprostacyclin antibody infusion.. Pulmonary hemodynamics, arterial blood gases, and plasma concentrations of arachidonate metabolites were measured hourly over a 4-hr period. In the septic control group and antiprostacyclin antibody group, elevated pulmonary vascular resistance index and pulmonary artery pressure with decreased Pao2, as well as lower pH, were documented after 1 and 3 hrs of graded bacteremia compared with the anesthesia control group and prostacyclin infusion group (p <.05). Thromboxane B2 concentration increased significantly in all groups during septic shock. In the antiprostacyclin antibody group, leukotriene B4 increased immediately after starting antiprostacyclin antibody infusion and reached significance at 3 hrs compared with the septic control group (p <.05). The prostacyclin infusion group had consistently lower concentrations of leukotrienes C4, D4, and E4 than all other groups.. Prostacyclin does not mediate blood gas changes, alterations of pulmonary hemodynamics, or platelet abnormalities in porcine septic shock, because antiprostacyclin antibody infusion did not change the pulmonary hypertension and hypoxemia, and infusion of prostacyclin to pathophysiologic blood concentrations did not reproduce such changes. Antiprostacyclin blockade during bacteremia significantly increased concentrations of leukotrienes C4, D4, and E4 and leukotriene B4, whereas prostacyclin infusion suppressed concentrations of leukotrienes C4, D4, and E4, suggesting that endogenous prostacyclin may blunt leukotriene release.

Topics: 6-Ketoprostaglandin F1 alpha; Analysis of Variance; Animals; Antihypertensive Agents; Bacteremia; Epoprostenol; Gram-Negative Bacterial Infections; Hemodynamics; Hypertension, Pulmonary; Leukotriene B4; Lung Diseases; Matched-Pair Analysis; Pulmonary Gas Exchange; Respiratory Distress Syndrome; Shock, Septic; SRS-A; Swine; Thromboxane B2

This study was carried out to determine the efficacy of and dose-response relationships to inhaled aerosolized prostacyclin (IAP), when used as a selective pulmonary vasodilator (SPV) in patients with severe hypoxemia due to ARDS.. Unblinded, interventional, prospective clinical study.. A general ICU in a university-affiliated, tertiary referral center.. Nine adult patients with severe ARDS (lung injury score, > or = 2.5).. All patients received IAP over the dose range 0 to 50 ng/kg/min. The IAP was delivered via a jet nebulizer placed in the ventilator circuit. Dose increments were 10 ng/kg/min every 30 min.. Cardiovascular parameters (cardiac index and mean pulmonary and systemic pressures), indexes of oxygenation (PaO(2)/fraction of inspired oxygen [FIO(2)] ratio and alveolar-arterial oxygen partial pressure difference [P(A-a)O(2)]) and shunt fraction were measured or calculated at each dose interval, as were platelet aggregation and systemic levels of prostacyclin metabolite (6-keto prostaglandin F1(alpha)). A generalized linear regression model was used to determine a dose effect of IAP on these parameters. The Wilcoxon rank sum test for related measures was used to compare the effects of various doses of IAP. IAP acted as an SPV, with a statistically significant dose-related improvement in PaO(2)/FIO(2) ratio (p = 0.003) and P(A-a)O(2) (p = 0.01). Systemic prostacyclin metabolite levels increased significantly in response to delivered IAP (p = 0.001). There was no significant dose effect on systemic or pulmonary arterial pressures, or on platelet function, as determined by platelet aggregation in response to challenge with adenosine diphosphate.. IAP is an efficacious SPV, with marked dose-related improvement in oxygenation and with no demonstrable effect on systemic arterial pressures over the dose range 0 to 50 ng/kg/min. Despite significant systemic levels of prostacyclin metabolite, there was no demonstrable platelet function defect.

Topics: 6-Ketoprostaglandin F1 alpha; Administration, Inhalation; Adult; Aerosols; Aged; Dose-Response Relationship, Drug; Drug Administration Schedule; Epoprostenol; Female; Hemodynamics; Humans; Hypoxia; Male; Middle Aged; Oxygen; Platelet Aggregation; Prospective Studies; Respiratory Distress Syndrome; Treatment Outcome; Vasodilator Agents

Responses to inhaled nitric oxide (iNO) in acute lung injury (ALI), as evidenced by improvements in oxygenation, are variable. We hypothesized that the effect of iNO may be related to the pre-iNO distribution of pulmonary blood flow (PBF). In the present study we evaluated the effect of iNO on PBF in normal healthy dogs and in a canine model of ALI induced by oleic acid (OA). In Group "OA only" (n = 5), ALI was induced by central venous injection of 0.08 ml/kg OA. In Group "E+OA" (n = 5), hypoxic pulmonary vasoconstriction after ALI was blocked with low-dose endotoxin (15 microg/kg of Escherichia coli endotoxin) administered 30 min before giving the same dose of OA. Measurements of regional PBF and lung water concentration (LWC) using positron emission tomography (PET) and H215O were performed before and after OA or placebo, and then again at concentrations of 10, 40, and 0 ppm iNO. One hundred twenty minutes after OA injury, PaO2/FIO2 fell significantly in Group OA only, from 567 +/- 32 to 437 +/- 67 mm Hg. In these animals, PBF redistributed from the dorsal edematous regions of the lungs to the nondependent zones, thus partially preserving normal ventilation/ perfusion relationships. As in the normal animals, in Group OA only, iNO did not significantly change either PBF or oxygenation. In Group E+OA, the administration of low-dose endotoxin eliminated perfusion redistribution from the dorsal edematous lung regions. As a result, PaO2/FIO2 fell from 558 +/- 70 to 119 +/- 53 mm Hg, a decrease that was significantly greater than that in Group OA only. In Group E+OA, administration of iNO restored perfusion redistribution to a similar level as in Group OA only, which was associated with a significant improvement in PaO2/FIO2, from 119 +/- 53 to 251 +/- 159 (10 ppm iNO), and 259 +/- 165 mm Hg (40 ppm iNO). We conclude that the effect of iNO on oxygenation after ALI depends on the pre-iNO perfusion pattern, which may help explain the variable response to iNO often observed in patients with acute respiratory distress syndrome.

Topics: 6-Ketoprostaglandin F1 alpha; Administration, Inhalation; Animals; Blood Gas Analysis; Bronchodilator Agents; Cardiac Output; Disease Models, Animal; Dogs; Lung; Nitric Oxide; Oleic Acid; Pulmonary Wedge Pressure; Regional Blood Flow; Respiratory Distress Syndrome; Thromboxane B2; Tomography, Emission-Computed

The purpose of the present study was to examine the efficacy of U-74006F, a 21-aminosteroid, on lung dysfunction induced by endotoxaemia in awake sheep with lung lymph fistula and haemodynamic monitoring. We measured pulmonary haemodynamics, lung lymph balance, circulating leucocyte count, arterial blood gas tensions, and levels of thromboxane (Tx) B2 and 6-keto-prostaglandin (PG) F1 alpha in plasma and lung lymph. We performed two experiments. In experiment 1 (n = 6), we intravenously infused Escherichia coli lipopolysaccharide endotoxin (1 microgram/kg) over 30 min and observed the parameters over 5 h. In experiment 2 (n = 6), we pretreated sheep with an intravenous bolus of U-74006F (2 mg/kg) 30 min before the infusion of endotoxin in the same manner of experiment 1, and continuously infused U-74006F (0.5 mg/kg per h) over 5 h after the bolus during the experiment. The U-74006F significantly suppressed the early pulmonary hypertension, the late increase in pulmonary permeability and the elevations of TxB2 and 6-keto-PGF1 alpha levels in plasma and lung lymph during the early period following endotoxaemia, although the compound did not change the time course of leucocytopenia and hypoxaemia. These findings suggest that the administration of U-74006F attenuates the lung dysfunction induced by endotoxaemia in awake sheep.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Antioxidants; Blood Gas Analysis; Disease Models, Animal; Drug Evaluation, Preclinical; Escherichia coli; Hemodynamics; Leukocyte Count; Lipopolysaccharides; Lymph; Pregnatrienes; Pulmonary Circulation; Respiratory Distress Syndrome; Sheep; Thromboxane B2; Wakefulness

Eicosanoid production appears to be important to both edemagenesis and the pattern of pulmonary perfusion in experimental acute lung injury (ALI). We hypothesized that these effects could be mediated by the inducible form of cyclooxygenase (COX-2). We used positron emission tomography to evaluate the pulmonary perfusion pattern in dogs given oleic acid (OA) only (n = 6), the novel COX-2 inhibitor SC-236 50 min before OA (n = 3), and SC-236 given 20 min before endotoxin (Etx), followed by OA given 30 min after Etx (n = 5). Thromboxane B(2) (TXB(2)) and prostacyclin (6-keto prostaglandin F(1alpha); 6-keto PGF(1alpha)) metabolite concentrations in plasma and lung tissue were measured in these groups and in another group given Etx + OA (n = 4). Inhibition of COX-2 before administration of OA alone or before administration of Etx and OA did not have any significant effect on plasma or lung tissue concentrations of TXB(2). However, inhibition of COX-2 prior to Etx and OA significantly reduced the plasma and lung tissue concentrations of 6-keto PGF(1alpha) as compared with those in the group given only Etx + OA. Moreover, SC-236 prevented the expected loss of perfusion redistribution associated with Etx + OA only. The effect of endotoxin on pulmonary perfusion in ALI is therefore the result of a COX-2-mediated increase in prostacyclin production in lung tissue.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dogs; Endotoxins; Escherichia coli; Immunoenzyme Techniques; Isoenzymes; Lung; Oleic Acid; Prostaglandin-Endoperoxide Synthases; Pulmonary Circulation; Pyrazoles; Radionuclide Imaging; Respiratory Distress Syndrome; Sulfonamides; Thromboxane B2

To investigate changes of cyclooxygenase-2 (COX-2) mRNA expression and intervention effect of selective cyclooxygenase-2 inhibitor Meloxicam on acute lung injury (ALI).. We measured COX-2 mRNA expression by reverse-transcription polymerase chain reaction in rat lung with ALI induced by lipopolysaccharide, and observed changes of prostaglandins (PGs), PaO2 and histopathology.. Resting rat lung expressed a little COX-2 mRNA; expression of cyclooxygenase-2 mRNA was up-regulated significantly in the lung after rats were injured by LPS. Selective COX-2 inhibitor Meloxicam alleviated histopathologic damage in the lung, inhibited production of PGs and attenuated PaO2 decline.. COX-2 is a main isoform responsible for enhancing PGs production during ALI. Meloxicam can inhibit activity of COX-2 and may be useful in the treatment of ALI.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Gas Analysis; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Isoenzymes; Lipopolysaccharides; Lung; Meloxicam; Oxygen; Prostaglandin-Endoperoxide Synthases; Rats; Respiratory Distress Syndrome; Thiazines; Thiazoles; Up-Regulation

We evaluated the effects of low-dose endotoxin (15 microg/kg) on the pulmonary and systemic responses to oleic acid (OA)-induced acute lung injury in dogs. Animals given endotoxin alone (n = 5) showed a modest decrease in arterial blood pressure, but no effects on pulmonary hemodynamics, blood gases, cardiac output, or lung water accumulation. Animals (n = 6) given only OA (0.08 ml/kg) showed the expected development of mild-moderate pulmonary hypertension, a comparable reduction in arterial blood pressure, hypoxemia, increased lung water concentration, and an altered intrapulmonary perfusion pattern, as assessed by positron emission tomography. Animals (n = 7) given the same dose of endotoxin, followed 30 min later by the same dose of OA, developed a similar increase in lung water concentration as the group given OA alone, but failed to develop pulmonary hypertension or to redistribute pulmonary blood flow away from the edematous lung regions. In addition, arterial blood pressure fell significantly more than in the other groups. These responses were associated with a 30-fold increase in circulating prostacyclin (assayed as 6-keto prostaglandin F1 alpha [PGF1alpha]). The effects on systemic blood pressure, intrapulmonary blood flow redistribution, and eicosanoid production were eliminated by pretreating (n = 5) animals with meclofenamate (2 mg/kg). The results are consistent with a "priming" effect of low-dose endotoxin on the pulmonary endothelium, with exaggerated prostacyclin production in response to a subsequent lung injury. This interaction leads to altered intrapulmonary hemodynamics that exacerbate the development of hypoxemia, and to significant decreases in systemic blood pressure. To the extent that the lung is the most likely source of the increased prostacyclin production, the synergistic effects of low-dose endotoxin and lung injury may produce a kind of "lung shock."

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Cardiac Output; Cyclooxygenase Inhibitors; Dogs; Endotoxins; Extravascular Lung Water; Hemodynamics; Lung; Meclofenamic Acid; Oleic Acid; Pulmonary Circulation; Respiratory Distress Syndrome; Thromboxane B2; Tomography, Emission-Computed

We previously demonstrated that antithrombin III reduced the injury to endothelial cells caused by activated leukocytes in rats administered endotoxin. This occurred via the increase of the endothelial release of prostaglandin I2, which is a potent inhibitor of leukocyte activation. We evaluated the dose of antithrombin III required to prevent such endothelial cell injury in rats administered endotoxin, by comparing the effects of various antithrombin II doses on the pulmonary vascular injury. The intravenous administration of endotoxin, 5 mg/kg, produced a transient accumulation of leukocytes in the lung, followed by pulmonary vascular injury, as indicated by an increase in the pulmonary vascular permeability, and coagulation abnormalities. The dose of 250 U/kg significantly inhibited all such effects of endotoxin. While lower doses of antithrombin III (50 and 100 U/kg) significantly inhibited such coagulation abnormalities, they failed to prevent either the pulmonary accumulation of leukocytes or the subsequent pulmonary vascular injury. Rats administered endotoxin exhibited an accumulation of neutrophils and edematous changes in the pulmonary interstitial space. Although such changes were reduced after 250 U/kg of antithrombin III, they were unaffected by lower doses of 50 and 100 U/kg. Plasma levels of 6-keto-PGF1alpha were markedly increased in rats 90 min after the administration of endotoxin, and were significantly decreased in the endotoxin-treated rats administered the lower doses of antithrombin III (50 and 100 U/kg), but not altered in those endotoxin-treated rats receiving 250 U/kg of antithrombin III. These findings suggest that a higher antithrombin III dose is necessary to prevent endothelial cell injury than is required to inhibit coagulation abnormalities in an animal model of sepsis. These observations support the notion that antithrombin III may prevent endotoxin-induced endothelial cell injury by promoting endothelial release of prostaglandin I2 and thus inhibiting leukocyte activation.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Antithrombin III; Blood Coagulation Disorders; Dose-Response Relationship, Drug; Endothelium, Vascular; Endotoxins; Lymphocyte Activation; Male; Pulmonary Circulation; Rats; Rats, Wistar; Respiratory Distress Syndrome; Sepsis

To examine the pathophysiologic role of vasoactive eicosanoids and endothelin-1 in granulocyte-mediated effects in the pulmonary vasculature.. Prospective experimental study in rabbits.. Experimental laboratory in a university teaching hospital.. Thirty adult rabbits.. The experiments were performed on 30 isolated and ventilated rabbit lungs that were perfused with a cell- and plasma-free buffer solution.. The pulmonary arterial pressure and the lung weight gain were continuously registered. Intermittently perfused samples were taken to determine endothelin-1 and thromboxane A2 concentrations. Six experiments without intervention served as the sham group. The granulocytes in the pulmonary circulation were stimulated with N-formyl-L-leucin-methionyl-L-phenylalanine (FMLP; 10(-6) M; control, n = 6). To investigate whether activated granulocytes influence the pulmonary vasculature via endothelin-1, the endothelin-A receptor antagonist LU135252 (10(-6) M) was added to the perfusate before FMLP injection (n = 6). The potential involvement of thromboxane A2 in granulocyte-endothelial interaction was investigated by pretreatment with the cyclooxygenase inhibitor diclofenac (10 microg/mL; n = 6). Activation of granulocytes resulted in an acute increase in pulmonary arterial pressure (>9 mm Hg), which was followed by a second delayed pressure increase after 60 mins (>14 mm Hg) and was paralleled by a massive generation of thromboxane A2 (>250 pg/ mL). Fifteen minutes after FMLP-injection, endothelin-1 was detectable in the perfusate. Pretreatment with the selective endothelin-A antagonist LU135252 significantly (p< .01) reduced the initial pressure response after FMLP stimulation, while diclofenac significantly reduced (p < .05) the delayed pressure increase. Using diclofenac (10 microg/mL) in conjunction with LU135252 (10(-6) M; n = 6) before FMLP injection significantly reduced the early and the delayed pressure increase.. Activated granulocytes seem to enhance pulmonary vascular resistance via endothelin-1 and thromboxane A2. The endothelin-1 effects are probably mediated via endothelin-A receptors since the endothelin-A receptor antagonist LU135252 was able to suppress the early pressure reaction after FMLP injection, whereas the cyclooxygenase inhibitor diclofenac was able to reduce the second pressure increase.

Topics: 6-Ketoprostaglandin F1 alpha; Analysis of Variance; Animals; Cyclooxygenase Inhibitors; Diclofenac; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Female; Granulocytes; In Vitro Techniques; Male; N-Formylmethionine Leucyl-Phenylalanine; Perfusion; Phenylpropionates; Prospective Studies; Pulmonary Artery; Pyrimidines; Rabbits; Random Allocation; Respiratory Distress Syndrome; Thromboxane A2; Thromboxane B2; Vascular Resistance

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

Hypotension, respiratory failure and ARDS-like pulmonary morphological changes were induced by given continuous intravenous infusion of E. coli endotoxin (1-1.5 micrograms.kg/h) in goats. During endotoxin infusion, plasma TXB2 level rose markedly with peak at 0.5 h and then lowered, while 6-keto-PGF1 alpha elevated progressively with its highest level before death, and correlated with blood pressure and survival times negatively. So we suggested that prostacyclin may be one of the factors responsible for hypotension and death in late period of endotoxin induced shock and lung injury.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Endotoxins; Escherichia coli; Goats; Lung; Respiratory Distress Syndrome; Shock, Septic; Thromboxane B2

Acute lung injury was produced by intravenous injection of oleic acid. After oleic acid injection, PaO2 was decreased, dogs were involved in respiratory distress. Histological examination indicated aggregation of leukocytes in microvasculature, interstitial and intraalveolar pulmonary edema and congestion in the lung. Using radioimmunoassay technique, changes in arterial and venous plasma levels of stable metabolite of thromboxane A2 (TXA2), thromboxane B2 (TXB2) have been observed. After oleic acid administration, plasma 6-keto-PGF1alpha level was markedly elevated with two peaks. 6-keto-PGF1alpha level in arteries was higher in concentration than in veins. It was suggested that the lung might synthesis a great quantity of prostacyclin entering the systemic circulation. TXB2 was markedly elevated in plasma, which was more in veins than in arteries. A significant arteriovenous difference suggests that there might be extrapulmonary sources contributing to the elevation of plasma TXB2 in oleic acid induced lung injury in dogs. After treatment with large dose of anisodamine (654-2), platelets and leukocytes aggregation could be inhibited as well as the synthesis of TXA2 and prostacyclin. 654-2 might play a role of cyclo-oxygenase inhibitor. It was suggested that 654-2 reduce synthesis of the precursors of TXA2 and prostacyclin, reduce pulmonary edema and might be a therapeutical effect to lung injury.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dogs; Female; Male; Oleic Acids; Respiratory Distress Syndrome; Thromboxane A2

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Endotoxins; Escherichia coli; Lung; Rabbits; Respiratory Distress Syndrome; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Epoprostenol; Ibuprofen; Male; Oleic Acids; Rabbits; Respiratory Distress Syndrome; Thromboxane B2

The effects of ibuprofen (I) and methylprednisolone (M) were studied in the Pseudomonas porcine model of adult respiratory distress syndrome (ARDS). Four groups of animals were anesthetized and ventilated with 0.5 FIO2, 5 cm PEEP, and 20 cc/kg tidal volume: a control group given saline alone; Pseudomonas infusion alone (P); Pseudomonas with ibuprofen (I), 12.5 mg/kg given at 20 and 120 min; and P with methylprednisolone (M), 30 mg/kg given at 20 and 120 min. We compared the alteration in pulmonary hemodynamics with the alteration in the plasma concentration of thromboxane (TxB2) and 6-keto PGF1 alpha in the treated and untreated groups. Hemodynamic parameters measured included the pulmonary (PAP) and systemic (SAP) arterial pressures, cardiac index (C1), thermal-cardiogreen extravascular lung water (EVLW), and PaO2. Albumin Flux was measured by a gamma scintigraphic method (slope index; SI). P produced a dramatic increase in PAP (P less than 0.05) with a progressive increase in EVLW and SI (P less than 0.05) and fall (P less than 0.05) in PaO2, CI, and SAP. The acute pulmonary hypertension was associated with a significant rise in TxB2 and 6-keto PGF1 alpha in the Pseudomonas group. I effectively blocked the elevation of TxB2 and caused a significant but transient improvement in PAP and rise in PaO2. Albumin flux and water leak as measured by SI and EVLW were not affected by ibuprofen. M reduced the elevation of TxB2 and 6-keto PGF1 alpha but failed to block these prostaglandins significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Capillary Permeability; Disease Models, Animal; Hemodynamics; Ibuprofen; Methylprednisolone; Pseudomonas Infections; Respiratory Distress Syndrome; Swine; Thromboxane B2

Plasma thromboxane B2 (TXB2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) were measured in 84 patients at risk of developing adult respiratory distress syndrome (ARDS) (44 patients following multiple trauma, 29 patients following abdominal surgery and 11 patients with acute pancreatitis). Forty-nine of these 84 patients developed an ARDS. High (greater than 140 pg/ml plasma) TXB2 values were found in 52/84 patients. The median values of TXB2 were: 360 pg/ml in multiple injured, 250 pg/ml in abdominal surgery and 410 pg/ml in acute pancreatitis patients. The median TXB2 value was 575 pg/ml in patients developing ARDS and 140 pg/ml in those without this complication: this difference was statistically significant (p less than 0.05). The median values of 6-keto-PGF1 alpha were 55 pg/ml in multiple injured, 25 pg/ml in abdominal surgery and 120 pg/ml in acute pancreatitis patients. The median 6-keto-PGF1 alpha value was 122 pg/ml in ARDS patients and 25 pg/ml in non-ARDS patients (statistically significant: p less than 0.05). High TXB2 and 6-keto-PGF1 alpha values were particularly related to sepsis in abdominal surgery patients (p less than 0.05) and in multiple injured patients (p less than 0.01). No relation could be established between abnormal TXB2 or 6-keto-PGF1 alpha values and death. High TXB2 values often persisted for several days and were observed particularly at the time ARDS diagnostic criteria were fulfilled.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Abdomen; Adult; Critical Care; Female; Humans; Male; Middle Aged; Postoperative Complications; Prognosis; Respiratory Distress Syndrome; Sepsis; Shock; Thromboxane B2; Wounds and Injuries

To test the hypothesis that the broad spectrum protease inhibitor, aprotinin, can prevent early pathophysiology of sepsis, we administered endotoxin (0.1-0.75 microgram/kg) by a 30-min infusion to awake goats. Animals were used as their own controls receiving endotoxin with no treatment on one day and treatment with a bolus injection (10 trypsin inhibitory units, TIU, per kg) followed by a 6-hr infusion (5 TIU/kg/hr) of aprotinin on another. The effect on systemic and pulmonary hemodynamics, lung lung lymph flow (QL), lymph plasma protein ratio (L/P), and systemic eicosanoid levels were assessed. QL quickly reached 28 ml/hr (four times baseline) in both groups then slowly returned toward baseline. L/P ratio of both groups decreased by about 10% then returned to baseline. QL and L/P were not different between groups. Likewise, vascular parameters were not different between groups. Mean pulmonary artery pressure increased approximately 150% to a peak of 58 cm H2O in both groups while pulmonary artery wedge pressure doubled from a baseline of 8 cm H2O then both groups returned to baseline. Systemic arterial pressure decreased over the 6 hr experimental period by 15 Torr to 70 Torr in both groups. Cardiac output declined from 4.3 to 3 liter/min after the endotoxin, remaining at the level for 2 hr then progressively increased to about 5 liter/min in both groups. We conclude that aprotinin, in doses similar to those reported to give protection from acute lung injury of various origins, fails to modify the early cardiopulmonary pathophysiology of endotoxin.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aprotinin; Blood Pressure; Cell Membrane Permeability; Endotoxins; Escherichia coli; Goats; Hemodynamics; Lung Diseases; Lymph; Pulmonary Circulation; Respiratory Distress Syndrome; Thromboxane B2

The effects of ibuprofen (I) were studied in the Pseudomonas (P) porcine ARDS model. Pigs, 14-26 kg (5 in each group), were anesthetized and ventilated with 0.5 FiO2 and 5 cm H2O PEEP. A control (C) group received saline only, a second group was given P, 1 X 10(8) org/ml at 0.3 cc/20 kg/min, and a third group was given P followed by 12.5 mg I at 20 and 120 min. Pulmonary arterial (PAP), wedge (PWP) and systemic arterial pressures, cardiac output (CO), and thermal-cardiogreen extravascular lung water (EVLW), thromboxane (TxB2), 6-keto-PGF1 alpha, PaO2, PaCO2 were determined every 30 min. Albumin flux was measured with scintigraphic determination of lung:heart radioactivity ratios versus time, called slope index (SI). At 3 hr, P produced marked (P less than 0.05) increases in PAP (18 +/- 7 to 37 +/- 2 mm Hg), TxB2 (471 +/- 513 to 9216 +/- 3615 pg/ml), 6-keto-PGF1 alpha, EVLW (6.4 +/- 1.4 to 14.6 +/- 5.7 mg/kg), and SI (0.4 +/- 0.2 to 1.7 +/- 0.5 X 10(-3) U/min) with decreases in PaO2 (214 +/- 47 to 101 +/- 41 torr), CO and SAP. Ibuprofen caused a rapid clearing of TxB2 and 6-keto-PGF1 alpha associated with a transient decrease in PAP; PaO2 was considerably improved compared to P; however, CO, SAP, EVLW, and SI were unaffected. Prostaglandin blockage temporarily ameliorated the pulmonary hypertension and markedly improved oxygenation in this porcine septic ARDS model, but failed to alter increased permeability, confirming other studies that the increased pulmonary shunt in ARDS is not only dependent upon capillary leak.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Carbon Dioxide; Cardiac Output; Disease Models, Animal; Ibuprofen; Oxygen; Pseudomonas Infections; Pulmonary Artery; Pulmonary Wedge Pressure; Radioimmunoassay; Respiratory Distress Syndrome; Swine; Thromboxane B2

The effects of Pseudomonas aeruginosa cytotoxin on the pulmonary microvasculature were studied in blood-free, perfused, isolated rabbit lungs. Cytotoxin was administered to the recirculating Krebs Henseleit albumin (1%) buffer during two consecutive 30-min-perfusion phases (phases 1 and 2) at a concentration of 13 micrograms/ml, followed by a third perfusion phase (phase 3) without toxin. After perfusion phases 2 and 3, the capillary filtration coefficient (Kf,c) and vascular compliance were determined gravimetrically from two-step microvascular pressure increments under zero-flow conditions. Cytotoxin caused a continuous release of K+ and lactate dehydrogenase, which started within the first 5 min and amounted to about 50% of the total lung cellular K+ and 5 to 7% of the total lactate dehydrogenase by the end of the experiment. The toxin caused the continuous generation of prostaglandin I2, which was detectable in the perfusates of all perfusion phases at maximum values five times above the control values and which was measured in the bronchoalveolar lavage fluid at the end of the experiment. Thromboxane generation in toxin-treated lungs did not significantly exceed that of control lungs or of lungs with mechanically induced edema. Cytotoxin caused a gradual increase in pulmonary vascular resistance, to maximum values 2.5 times above the control, starting within 1 min; the increase was partially reversible after washout of the toxin. After a lag period of 20 to 30 min, the lungs gained weight, amounting to a mean gain of 9.1 g at the end of the experiments. After perfusion phases 2 and 3, an almost fourfold increase in Kf,c, which was not reversible after washout of the toxin, was measured, whereas the values of vascular compliance were not altered. We conclude that pseudomonal cytotoxin may be an important factor in the pathogenesis of prolonged microvascular injury, encountered in states of P. aeruginosa sepsis or acute lung failure with secondarily acquired P. aeruginosa pneumonia.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Capillary Permeability; Cell Membrane Permeability; Epoprostenol; Female; L-Lactate Dehydrogenase; Leukocidins; Male; Potassium; Pulmonary Circulation; Rabbits; Respiratory Distress Syndrome; Thromboxane B2; Vascular Resistance

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