thromboxane-b2 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

Levels of thromboxane B2 (TxB2), the stable metabolite of thromboxane A2, are elevated in human and experimental septic shock. The thromboxane synthetase inhibitor dazoxiben has improved survival and decreased pulmonary hypertension in experimental endotoxemia. A randomized prospective study of 10 patients with the clinical diagnosis of sepsis and early adult respiratory distress syndrome (hypoxemia, radiologic evidence of the syndrome, and intrapulmonary shunt greater than 20%) was performed to test the efficacy of dazoxiben in ameliorating the effects of human sepsis. Five subjects received dazoxiben and five received placebo. Dazoxiben, 100 mg, or placebo was injected intravenously every 4 hours for a maximum of 72 hours. Plasma immunoreactive TxB2 (iTxB2) levels were determined by radioimmunoassay. Before dazoxiben, the plasma iTxB2 level was 752 +/- 261 pg/ml (n = 5) and was reduced within 1 hour to 333 +/- 137 pg/ml. The plasma levels of iTxB2 remained significantly decreased with subsequent doses of dazoxiben and it was 201 +/- 67 pg/ml (n = 4) 60 hours after dosing. In contrast, placebo had no significant effect on plasma iTxB2 levels (n = 5) throughout the entire period of observation. Dazoxiben did not induce any significant changes in pulmonary or systemic vascular resistance, intrapulmonary shunting, clotting studies, or extravascular lung water. One of the five subjects in the placebo group died and two of the five subjects in the dazoxiben group died. We conclude that dazoxiben was safe and effectively lowered plasma iTxB2 levels in patients with sepsis and incipient adult respiratory distress symptom, but did not significantly alter the hemodynamic and pulmonary sequelae of established sepsis.

Topics: Adult; Aged; Blood Pressure; Cardiac Output; Drug Evaluation; Female; Humans; Imidazoles; Infusions, Parenteral; Male; Middle Aged; Prospective Studies; Pulmonary Wedge Pressure; Radioimmunoassay; Random Allocation; Respiratory Distress Syndrome; Shock, Septic; Thromboxane B2; Vascular Resistance

Acute respiratory distress syndrome (ARDS) is an acute lung injury of high mortality rate, and sepsis syndrome is one of the most frequent causes of ARDS. Metabolites of arachidonic acid, including thromboxanes and leukotrienes, are proinflammatory mediators and potentially involved in the development of ARDS. A key enzyme for the production of these inflammatory mediators is cytosolic phospholipase A(2) (cPLA(2)). Recently, it has been reported that arachidonyl trifluoromethyl ketone (ATK) is a potent inhibitor of cPLA(2). In the present study, we hypothesized that pharmacological intervention of cPLA(2) could affect acute lung injury. To test this hypothesis, we examined the effects of ATK in a murine model of acute lung injury induced by septic syndrome. The treatment with ATK significantly attenuated lung injury, polymorphonuclear neutrophil sequestration, and deterioration of gas exchange caused by lipopolysaccharide and zymosan administration. The current observations suggest that pharmacological intervention of cPLA(2) could be a novel therapeutic approach to acute lung injury caused by sepsis syndrome.

Topics: Animals; Arachidonic Acids; Bronchoalveolar Lavage Fluid; Cytosol; Enzyme Inhibitors; Leukotriene C4; Leukotriene D4; Leukotriene E4; Lipopolysaccharides; Lung; Male; Mice; Mice, Inbred C57BL; Peroxidase; Phospholipases A; Phospholipases A2; Respiratory Distress Syndrome; Sepsis; Sodium Chloride; Thromboxane B2; Zymosan

High-dose intravenous immunoglobulin (IVIG) prevents immune damage by scavenging complement fragments C3b and C4b. We tested the hypothesis that exogenous immunoglobulin molecules also bind anaphylatoxins C3a and C5a, thereby neutralizing their pro-inflammatory effects. Single-cell calcium measurements in HMC-1 human mast cells showed that a rise in intracellular calcium caused by C3a and C5a was inhibited in a concentration-dependent manner by IVIG, F(ab)2-IVIG and irrelevant human monoclonal antibody. C3a- and C5a-induced thromboxane (TXB2) generation and histamine release from HMC-1 cells and whole-blood basophils were also suppressed by exogenous immunoglobulins. In a mouse model of asthma, immunoglobulin treatment reduced cellular migration to the lung. Lethal C5a-mediated circulatory collapse in pigs was prevented by pretreatment with F(ab)2-IVIG. Molecular modeling, surface plasmon resonance (SPR) and western blot analyses suggested a physical association between anaphylatoxins and the constant region of F(ab)2. This binding could interfere with the role of C3a and C5a in inflammation.

Topics: Animals; Asthma; Blood Pressure; Calcium; Cell Line; Cell Migration Inhibition; Complement C3a; Complement C5a; Dose-Response Relationship, Drug; gamma-Globulins; Histamine Release; Humans; Immunoglobulins, Intravenous; Mast Cells; Mice; Respiratory Distress Syndrome; Swine; Thromboxane B2

To assess the effect of diisopropyl phenol (propofol), with and without Intralipid, on the cardiopulmonary system and on thromboxane production in endotoxic pigs.. Prospective, randomized animal study.. Animal research laboratory at a major teaching hospital.. Twenty-four pigs, divided into three groups (n = 8).. Pulmonary arterial catheters and arterial cannulas were inserted into all pigs. Each pig received a 30 ng/kg bolus of endotoxin at 1 hr, followed by a continuous infusion of endotoxin at 24 ng x kg-1 x hr-1. Diisopropyl phenol at 25, 75, and 200 microg x kg-1 x min-1 was administered to all pigs, beginning at 1, 2, and 3 hrs, respectively. The pigs were divided into three groups to receive 0.25 g x kg-1 x hr-1, 0.08 g x kg-1 x hr-1, or no Intralipid, starting at time t = 0. Heart rate and mean arterial, central venous, and pulmonary arterial pressures were recorded continuously. Core temperature, arterial blood gases, mixed venous oxygen saturation, pulmonary arterial occlusion pressure, and cardiac output were measured intermittently. Thromboxane B(2) concentrations were measured at baseline and at 60, 75, 120, 135, 180, 195, and 240 mins. Data are expressed as mean +/- sd. Groups were compared by using repeated analysis of variance, with p <.05 used for statistical significance.. All pigs completed the 4-hr study. Marked variabilities were noted for individual pigs. Following the infusion of endotoxin, compared with baseline, there was a significant increase in pulmonary vascular resistance and a decrease in Pao(2) (p <.001 and p <.008, respectively). This response was not affected by the increasing dose of diisopropyl phenol, nor were there differences between the Intralipid and control groups. Pao(2) remained significantly lower in all groups, compared with the baseline measurements (p <.001) over the 4 hrs of the experiment. Thromboxane B(2) concentrations remained elevated compared with baseline and were significantly higher (p <.05) in the high-dose Intralipid group, compared with the low-dose and the control groups, during the last hour of the experiment.. Small doses of endotoxin, when given to pigs, induce major perturbations of cardiopulmonary function. Neither Intralipid, high vs. low dose, nor diisopropyl phenol, at sedating vs. anesthetizing doses, worsened the physiologic derangement associated with the stress of low-dose endotoxemia.

Topics: Animals; Dose-Response Relationship, Drug; Fat Emulsions, Intravenous; Hemodynamics; Lung; Male; Propofol; Respiratory Distress Syndrome; Shock, Septic; Swine; Thromboxane B2; Vascular Resistance

Sepsis is a major cause of adult respiratory distress syndrome. In this study, we evaluated the effect of FR167653, which is a potent suppressant of tumor necrosis factor (TNF)-alpha and interleukin (IL)-1 production, on lipopolysaccharide (LPS)-induced lung injury and lethality in rats, and we examined the involvement of p38 mitogen-activated protein (MAP) kinase in the action of FR167653.. Prospective, randomized study.. Animal research facility in a university.. Male Sprague-Dawley rats weighing 200-270 g.. All the animals were assigned to one of the following four groups: control group, FR-only group, LPS-only group, and LPS/FR group. Animals in the LPS-only and LPS/FR groups received 6 mg/kg of LPS intravenously. The animals in the FR-only and LPS/FR groups also received an infusion of FR167653 at 0.2 mg x kg(-1) x hr(-1), commencing 30 mins before the LPS (or vehicle) injection and continuing for 5.5 hrs.. LPS significantly induced the accumulation of pulmonary neutrophils and lung edema, both of which were significantly attenuated by treatment with FR167653. FR167653 also significantly decreased the LPS-induced lethality. Histologically, tissue damage was milder in the LPS/FR group than in the LPS-only group. Serum concentrations of TNF-alpha and IL-1beta and plasma concentrations of thromboxane B2 were all suppressed in the LPS/FR group compared with the LPS-only group. Western blot analysis revealed that FR167653 inhibited the phosphorylation of p38 MAP kinase in lung tissues.. FR167653 administration decreased serum TNF-alpha and IL-1beta concentrations, which was associated with decreased lung injury and lethality. The mechanism responsible for the decreased TNF-alpha and IL-1 may be related to the inhibitory effect of FR167653 on p38 MAP kinase activation.

Topics: Animals; Disease Models, Animal; Drug Evaluation, Preclinical; Escherichia coli; Escherichia coli Infections; Immunosuppressive Agents; Interleukin-1; Lipopolysaccharides; Lung; Male; Mitogen-Activated Protein Kinases; p38 Mitogen-Activated Protein Kinases; Prospective Studies; Pyrazoles; Pyridines; Random Allocation; Rats; Rats, Sprague-Dawley; Respiratory Distress Syndrome; Survival Analysis; Thromboxane B2; Time Factors; Tumor Necrosis Factor-alpha

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

Antithrombin (AT) III reduces lung damage in animal models of septic acute respiratory distress syndrome (ARDS), which is generally attributed to stimulation of endothelial prostacyclin synthesis. However, clinical studies have failed so far to demonstrate mortality reduction by application of AT III. We investigated whether AT III stimulates pulmonary prostacyclin release. In addition, we hypothesized that it may promote pulmonary endothelins, thereby mitigating its own protective effect in the course of ARDS.. Controlled experiment using isolated organs.. Experimental laboratory.. Male Wistar rats.. Isolated lungs were perfused over 120 mins in recirculatory mode in the presence of 50 microg/mL endotoxin (n = 11), 2U/mL AT III (n = 10), 5 U/mL AT III (n = 13), endotoxin plus 2 U/mL AT III (n = 5), or vehicle alone (controls, n = 13), respectively.. We determined the effects of AT III on vascular release of thromboxane B2, 6-keto-prostaglandin-F1alpha, big endothelin-1, and endothelin-1. Control lungs released 59+/-23 pg/mL thromboxane B2, 1,480+/-364 pg/mL 6-keto-prostaglandin-F1alpha, 15.2+/-4.5 pg/mL big endothelin-1, and 0.46+/-0.13 pg/mL endothelin-1. Exposure to endotoxin increased thromboxane B2 release 2.9-fold, 6-keto-prostaglandin-F1alpha release 1.6-fold, and endothelin-1 1.6-fold (p < .05 each); levels of big endothelin-1 were unchanged. AT III at 2 U/mL elevated production of big endothelin-1 (1.7-fold) and endothelin-1 (1.2-fold) (p < .05 for both). AT III at 5 U/mL enhanced levels of big endothelin-1 (1.6-fold) and endothelin-1 (1.3-fold) (p < .05 for both). Neither dose of AT III affected thromboxane B2 or 6-keto-prostaglandin-F1alpha concentrations. Application of 2 U/mL AT III plus endotoxin stimulated big endothelin-1 production (2.6-fold) compared with endotoxin or AT III alone (p < .05 for both), but did not further elevate endothelin-1 release.. AT III does not stimulate pulmonary prostacyclin, but promotes pulmonary release of big endothelin-1 and endothelin-1 under basal and, particularly, under septic conditions, which may blunt the AT III-induced lung protection during ARDS. Therefore, we suggest combined application of AT III and endothelin antagonists in animal models of septic ARDS.

Topics: Analysis of Variance; Animals; Antithrombin III; Endothelin-1; Endotoxins; Epoprostenol; Humans; Infant, Newborn; Male; Rats; Rats, Wistar; Respiratory Distress Syndrome; Sepsis; Serine Proteinase Inhibitors; Thromboxane B2

Recently, eicosapentaenoic acid (EPA) was found to have an anti-inflammatory effect attributable to diminished synthesis of arachidonic acid metabolites that initiate acute lung injury. We evaluated the ability of dietary EPA supplementation to prevent endotoxin-induced acute lung injury in rats.. Rats fed a standard diet were divided randomly into two groups: for 2 weeks one group additionally was fed 1000 mg/kg/day of EPA ethyl ester emulsion (EPA rats), while in the other group the diet was supplemented with vehicle alone (control rats). Fatty acid components of alveolar macrophages (AM) were measured, as well as leukotriene (LT) B(4) and LTB(5) production by AM exposed in vitro to calcium ionophore A23187. Plasma concentrations of thromboxane (Tx) B(2), a stable metabolite of TxA(2), were examined 1 h after inducing lung injury with endotoxin (2 mg/kg iv). At 6 h, wet/dry (W/D) weight ratios were calculated for the lungs to assess pulmonary edema, and neutrophils were counted in pulmonary parenchyma and peripheral blood.. Arachidonic acid content and LTB(4) generation in AM were significantly lower in EPA rats than in controls; conversely, EPA content and LTB(5) generation in AM were significantly higher in the EPA group. Neutrophil counts in lung parenchyma and peripheral blood did not differ between groups, but W/D and plasma TxB(2) concentrations were significantly lower in EPA rats.. EPA supplementation depressed arachidonic acid content and LTB(4) generation in AM and plasma TxB(2) in our model, leading to decreased pulmonary edema.

Topics: Animals; Arachidonic Acid; Eicosapentaenoic Acid; Endotoxemia; Fatty Acids; Leukotriene B4; Male; Neutrophils; Pulmonary Edema; Rats; Rats, Wistar; Respiratory Distress Syndrome; Thromboxane B2

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

We have studied prospectively the clinical course and serum concentrations of thromboxane B2 (TxB2) and leukotriene B4 (LTB4) in patients developing adult respiratory distress syndrome (ARDS) after oesophagectomy. The clinical course was assessed according to a validated ARDS score, and intra- and postoperative measurements of TxB2 and LTB4 in pre- and post-pulmonary blood were performed in 18 patients undergoing oesophagectomy for oesophageal carcinoma and 11 control patients undergoing thoracotomy and pulmonary resection. Six of 18 patients undergoing oesophagectomy, but no control patient, developed ARDS. The ARDS score was highest on day 8 after operation. Only patients with ARDS had a significant postoperative increase in post-pulmonary, but not pre-pulmonary, TxB2 concentrations (P < 0.05 vs patients without ARDS). This study provides evidence that TxA2, originating from the lungs, was associated with the development of ARDS after oesophageal resection. In view of the high incidence of ARDS after oesophagectomy (10-30%), prophylactic treatment of patients undergoing oesophageal resection with clinically applicable thromboxane synthetase inhibitors may be warranted.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Esophageal Neoplasms; Esophagectomy; Female; Humans; Leukotriene B4; Male; Middle Aged; Postoperative Period; Prospective Studies; Respiratory Distress Syndrome; Risk Factors; Thromboxane B2

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

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

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

We recently reported that the combined administration of lipopolysaccharide (LPS) and platelet-activating factor (PAF) in rats, at doses that are completely devoid of any effect when given alone, caused lung injury characterized by neutrophil adhesion to lung capillaries and postcapillary venules, neutrophil accumulation in the lung parenchyma, platelet-fibrin deposits in postcapillary venules, and pulmonary edema. A marked increase in lung myeloperoxidase activity and an elevation of serum tumor necrosis factor-alpha and thromboxane B2, along with leukopenia and thrombocytopenia, were also noticed. The present study aimed to examine whether repeated LPS-PAF stimulus can cause progressive lung injury reminiscent of adult respiratory distress syndrome (ARDS). A second LPS-PAF challenge, 4 h (n = 11) after the original challenge, induced mortality (69% at 24 h, P < 0.01) and some of the pathological changes seen in clinical ARDS, including severe pulmonary edema, alveolar proteinaceous exudates, monocytic infiltration, and a further increase in lung myeloperoxidase activity (700%, P < 0.01). Repeated LPS-PAF dosing also resulted in sustained increased serum tumor necrosis factor-alpha levels (1,610 +/- 470 pg/ml, P < 0.01) and further exacerbation of the leukopenia (-68 +/- 6%, P < 0.01) and thrombocytopenia (-65 +/- 8%, P < 0.01). These data suggest that repeated LPS-PAF actions are sufficient to elicit pathophysiology of ARDS-like lung injury.

Topics: Animals; Disease Models, Animal; Endotoxins; Hemodynamics; Lipopolysaccharides; Lung; Lung Injury; Male; Microscopy, Electron; Platelet Activating Factor; Rats; Rats, Sprague-Dawley; Respiratory Distress Syndrome; Thromboxane B2; Tumor Necrosis Factor-alpha

We studied the effects of two structurally unrelated sulfidopeptide leukotriene receptor antagonists on endotoxin-induced pulmonary dysfunction in chronically instrumented unanesthetized sheep. The agents employed were L-660,711 (MK-571) (Merck-Frosst, Canada) and SK&F 104,353 (Smith Kline and French, King of Prussia, PA). The efficacy and specificity of the agents were verified in sheep by administering boluses of exogenous leukotrienes (LTB4, LTC4, LTD4, and LTE4) in doses as great as 100 micrograms while monitoring lung mechanics and vascular pressures. The antagonists blocked the changes in lung mechanics and pulmonary hemodynamics induced by the sulfidopeptide leukotrienes (LTC4, LTD4, and LTE4) while having no effect on the animals' responses to LTB4. The endotoxin studies were performed by administering endotoxin alone (Escherichia coli endotoxin 0.75 microgram/kg) or endotoxin after pretreatment with one of the sulfidopeptide leukotriene receptor antagonists. In control studies, each animal received a continuous infusion of one of the receptor antagonists for a duration identical to that of the endotoxin studies. Neither L-660,711 nor SK&F 104,353 significantly altered the endotoxin-induced changes in pulmonary hemodynamics, lung mechanics, lung fluid and solute exchange, oxygenation, or leukopenia. Peak lung lymph thromboxane B2 levels were significantly lower in sheep pretreated with L-660,711. When the antagonists were given alone, no effects were seen. We conclude that (1) sulfidopeptide leukotrienes do not measurably contribute to endotoxin-induced pulmonary dysfunction in chronically instrumented sheep; (2) sulfidopeptide leukotrienes may contribute to thromboxane release after endotoxin.

Topics: Animals; Consciousness; Dicarboxylic Acids; Endotoxins; Escherichia coli; Female; Lymph; Male; Propionates; Pulmonary Circulation; Quinolines; Respiratory Distress Syndrome; Respiratory Mechanics; Sheep; SRS-A; Thromboxane B2

Artifactual formation of thromboxane (TX) B2 during blood collection falsifies real value of TXB2 in plasma. A part (29.3%) of TXB2 is metabolized to 11-dehydro (DH)-TXB2 in several organs. 11-DH-TXB2 was not generated during blood collection or during serum formation. The peak amount of 11-DH-TXB2 after intravenous injection of TXB2 to rabbits was lower than that of TXB2, but the level of 11-DH-TXB2 was kept 2-3 times higher than that of TXB2 even after more than 5 min. A half life of 11-DH-TXB2 is 45-60 min in the human. Large species differences were found. In human urine, 11-DH-TXB2 was excreted 1.5-5.8 times more than 2,3-dinor-TXB2. Patients with ARDS and DIC, who received platelet transfusion, excreted increased amounts of 2,3-dinor-TXB2 and 11-DH-TXB2 in urine. 11-DH-TXB2 may be a useful parameter of TXA2 formation in pathological states.

Topics: Animals; Disseminated Intravascular Coagulation; Female; Humans; Infant, Newborn; Male; Platelet Aggregation; Respiratory Distress Syndrome; Thromboxane A2; Thromboxane B2

Using a goat endotoxin model with chronic lung lymph fistula, we continuously measured lung lymph flow (QL), lymph to plasma protein ratio (L/P), pulmonary arterial pressure (Ppa) and the level of thromboxane B2 in plasma and lymph. We also observed the changes of ultrastructure in leukocyte and pulmonary parenchyma. It showed that the alteration can be divided into two intervals: phase I is characterized by the abrupt onset of pulmonary hypertension and in phase II, the capillary permeability increased predominantly. It was suggested that this model is a good research tool for studying adult respiratory distress syndrome (ARDS).

Topics: Animals; Endotoxins; Escherichia coli; Female; Goats; Lung; Lymph; Respiratory Distress Syndrome; 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

Thirty multiply injured blunt-trauma patients at high risk for development of ARDS (multisystem trauma including more than one organ or extremity, Injury Severity Score of 26 or more, hypotension and need for 1500 mL or more blood within the first hour after admission, and PaO2 less than or equal to 70 torr) were studied sequentially with blood and physiologic evaluations beginning immediately after injury and every eight hours for eight days, or until death, to study the evolution of the ARDS process. Mixed venous blood samples were obtained for eicosanoids PGE2, PGF2 alpha, thromboxane B2, PGI2 (6-KetoPGF1 alpha) and leukotriene B4 (LTB4). Platelet (PLAT), and neutrophil (WBC) counts were also done and plasma elastase was measured. At 7:00 AM each day patient neutrophils were obtained for a study of zymosan-activated superoxide production using a chemiluminescence assay. These data were correlated with physiologic measurements of the Respiratory Index (RI), per cent pulmonary shunt (QS/QT), and respiratory compliance measures. Seven patients developed a fulminant post-traumatic ARDS syndrome within 96 hours after injury. Twelve patients without ARDS developed sepsis (TS) four or more days after injury, and 11 had uncomplicated postinjury courses (TR). Compared to both TR and TS, ARDS had a significant (p less than 0.01) rise in neutrophil superoxide production beginning on day 2 through day 4 after injury. This was preceded by rises in PGE2 and LTB4, which were significantly correlated with subsequent falls in PLAT and WBC and rises in TXB2, PGF1, and superoxide production and followed by increases in RI, QS/QT, and a fall in compliance. The significant difference in the pattern and sequence of events in ARDS compared to TR and TS patients suggests that in ARDS the earliest event may be related to peripheral release of PGE2 and LTB4 due to platelet activation and lung sequestration with release of PGF2 alpha, and by aggregation and leukocyte adherence with release of elastase. However, fulminant ARDS mortality appears to be related to the subsequent amplification of the LTB4 leukocyte activation with superoxide production that does not achieve significance before the second day after injury and rises to a maximum by day 4 after injury. These data suggest that post-trauma ARDS follows a different evolutionary pattern than that reported in animal models and is also different from that seen in human TS or TR patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Biomechanical Phenomena; Blood Platelets; Cell Communication; Humans; Infections; Leukotriene B4; Neutrophils; Prostaglandins; Respiratory Distress Syndrome; Statistics as Topic; Superoxides; Thromboxane B2; Time Factors; Wounds and Injuries

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

Topics: Animals; Digestive System; Endothelium; Humans; Interleukin-1; Lung; Macrophages; Multiple Organ Failure; Neutrophils; Prostaglandins; Rabbits; Respiratory Distress Syndrome; Shock, Septic; Syndrome; 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

Septicemia by gram-negative organisms is a common cause of the adult respiratory distress syndrome (ARDS). The role of neutrophils in causing parenchymal lung damage in ARDS has recently been emphasized. A single intraperitoneal injection of Escherichia coli endotoxin in rats causes acute neutrophil alveolitis similar to that of ARDS. We studied the ability of pretreatment with either ibuprofen (IBU) or methylprednisolone (MP) to ablate directly the alveolar inflammatory response to endotoxin in the rat model. To compare the severity of inflammation, we quantified inflammatory cell recovery by whole lung lavage 24 hours after injection of endotoxin, the time point at which neutrophil alveolitis due to endotoxin is most intense. Pretreatment with a single dose of IBU 3.75 mg/kg prior to endotoxin injections was associated with a significant increase in the total number of inflammatory cells, and in both the percentage and the absolute number of neutrophils recovered from the lung, despite significantly decreasing the plasma level of thromboxane B2, which increased 10-fold after endotoxin. Paradoxically, IBU 30 mg/kg significantly decreased the intensity of neutrophil alveolitis. MP 30 mg/kg had no effect on recovery of inflammatory cells from the lung by bronchoalveolar lavage following endotoxin. Cyclooxygenase inhibitors such as ibuprofen may cause a dose-dependent biphasic effect on lung inflammation following endotoxin: enhancement of inflammation at a low dose and suppression of inflammation at a high dose.

Topics: Animals; Bronchitis; Gram-Negative Bacteria; Ibuprofen; Leukocyte Count; Methylprednisolone; Neutrophils; Rats; Rats, Inbred Strains; Respiratory Distress Syndrome; Shock, Septic; Thromboxane B2; Time Factors

Topics: Acrylates; Adult; Aged; Complement C3; Complement C4; Female; Humans; Methacrylates; Respiratory Distress Syndrome; Thromboxane B2; Thromboxane-A Synthase

Total hip replacement was carried out on 22 patients under general anaesthesia. Of these, 10 were pretreated with methylprednisolone (30 mg/kg); 1 of these developed the adult respiratory distress syndrome (ARDS) and had high levels of thromboxane B2 (TXB2) 5 minutes after fixation of the femoral prosthesis and at the end of the operation. The other 12 patients served as controls; 5 of them developed ARDS and had statistically significant higher TXB2 levels than the other 7 control patients who remained well. All patients who did not develop ARDS had low TXB2 levels. TXB2 and beta-thromboglobulin levels followed the same trend and there was good correlation (r=0,6806; P less than 0,01) at the end of the operation in the control group patients who developed ARDS. There was no statistical difference in 6-keto-PGF1 alpha levels between the patients who developed ARDS and those in the control group who remained well. Steroids reduce arachidonic acid metabolism by inhibiting the release of substrate for cyclo-oxygenase and lipoxygenase activity. Patients prone to ARDS thus benefit from methylprednisolone administration.

Topics: Aged; Arachidonic Acid; Arachidonic Acids; beta-Thromboglobulin; Epoprostenol; Hip Joint; Hip Prosthesis; Humans; Methylprednisolone; Middle Aged; Postoperative Complications; Respiratory Distress Syndrome; Thromboxane A2; Thromboxane B2; Time Factors

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

The effect of platelet depletion on the unanesthetized sheep's pulmonary response to endotoxemia was studied in eight unanesthetized sheep. Platelets were depleted with rabbit anti-sheep platelet antibodies (APA). Bolus injections of APA alone caused marked pulmonary hypertension (PPA increased from 21 +/- 2 to 62 +/- 5 cm H2O +/- SE) and alterations in lung mechanics (dynamic compliance of the lung [Cdyn] decreased to 38.5 +/- 4.6% and resistance to air flow across the lung [RL] increased to 705 +/- 162% +/- SE of control), which were attenuated by pretreatment with meclofenamate. It was possible to deplete platelets before endotoxemia through a slow continuous infusion of APA without altering base-line values of the measured variables. Platelet depletion did not significantly attenuate the alterations in pulmonary hemodynamics, lung mechanics, lung fluid and solute exchange, or the normal increase in lung lymph concentrations of thromboxane B2 or 6-keto-PGF1 alpha observed following endotoxemia in the sheep. We conclude that normal circulating platelet counts are not required for the full expression of the sheep's response to endotoxemia.

Topics: Animals; Blood Cell Count; Blood Platelets; Disease Models, Animal; Endotoxins; Hemodynamics; Lung; Prostaglandins F; Respiration; Respiratory Distress Syndrome; Sheep; Thromboxane B2

Topics: Adult; Anti-Inflammatory Agents; Humans; Respiratory Distress Syndrome; Thromboxane B2; Thromboxanes