thromboxane-b2 and Lung-Diseases

Topics: Animals; Humans; Lung; Lung Diseases; Prostaglandins; Thromboxane A2; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Aged; Alprostadil; Combined Modality Therapy; Cyclic AMP; Cyclic GMP; Dinoprost; Dinoprostone; Female; Humans; Laser Therapy; Lung Diseases; Male; Middle Aged; Pneumonectomy; Preoperative Care; Prostaglandin D2; Thoracoplasty; Thromboxane B2

To evaluate the efficacy of pentoxifylline (PTXF) in the attenuation of lung inflammation during volume-induced lung injury (VILI) in newborn piglets, 17 newborn piglets were mechanically ventilated with a large tidal volume (50 ml/kg) for a period of 8 h. They were randomly assigned to a placebo (PL, n = 9) or a treatment group (PTXF, n = 8) that received PTXF (20 mg/kg as a bolus, followed by a continuous infusion of 5 mg/kg/h). Hemodynamics, lung mechanics and arterial blood gases were measured during the 8 h of study. Serum and tracheoalveolar fluid (TAF) platelet-activating factor (PAF) and thromboxane (TXB(2)) levels were obtained at baseline and at 8 h, while lung tissue myeloperoxidase (MPO) and wet to dry weight were assessed after the completion of the study. In the PL group, a marked increase in TAF PAF and TXB(2) levels was observed only in TAF, suggesting that the inflammatory process was localized within the lungs. A significant decrease in lung tissue MPO activity (p < 0.005) and lung wet to dry weight ratio (p < 0.04) was observed in the PTXF group. There were no differences in hemodynamics, arterial blood gases or lung mechanics measurements between groups. A significant reduction in pulmonary inflammatory response was observed during VILI in the PTXF pretreated animals. These results suggest that PTXF may be effective in modulating lung inflammation associated with mechanical ventilation in neonates.

Topics: Animals; Animals, Newborn; Anti-Inflammatory Agents; Biomechanical Phenomena; Inflammation; Lung; Lung Diseases; Lung Injury; Pentoxifylline; Peroxidase; Placebos; Platelet Activating Factor; Respiration, Artificial; Swine; Thromboxane B2; Tidal Volume

An intravenous injection of oleic acid into animals can produce a lung injury with hypoxaemia and pulmonary vascular hyper-permeability. Although oleic acid lung injury is used as a model of acute respiratory distress syndrome (ARDS), the precise mechanisms of the lung injury are still unclear. We have investigated whether thromboxane A(2) (TXA(2)) participated in the lung injury and have evaluated the efficacy of ozagrel, a TXA(2) synthase inhibitor, on the lung injury in guinea-pigs. Oleic acid injection increased the plasma level of TXB(2), a stable metabolite of TXA(2), and the time-course of plasma TXB(2) was similar to that of the decreased partial oxygen pressure of arterial blood (Pao(2)) induced with oleic acid. Ozagrel administered intravenously 30 min before oleic acid injection prevented the decrease in Pao(2) and pulmonary vascular hyper-permeability. It also prevented increases in lactate dehydrogenase activity, a measure of lung cell injury, TXB(2 )and its weight ratio to 6-keto prostaglandin F(1alpha) in bronchoalveolar lavage fluid. Although ozagrel administered simultaneously with oleic acid ameliorated the decrease in Pao(2), post treatment showed little effect. We suggest that TXA(2) participated in the oleic acid lung injury, as an "early phase" mediator, and rapidly-acting TXA(2) synthase inhibitors were effective in the prevention of acute lung injury.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Bronchoalveolar Lavage Fluid; Enzyme Inhibitors; Guinea Pigs; L-Lactate Dehydrogenase; Lung Diseases; Methacrylates; Oleic Acid; Thromboxane A2; Thromboxane B2; Vascular Resistance

To explore the nature of pathology of sluggishness of lung-defensive qi and to offer objective experimental indexes for weifen syndrome (defensive phase syndrome).. According to the completely random design, the plasma levels of vasoactive intestinal peptide (VIP) and thromboxane B2 (TX2) of 19 patients with weifen syndrome and 13 patients with qifen syndrome (qi phase syndrome) were detected by radioimmunoassay. The plasma levels of VIP and TX2 at different stages of weifen syndrome and qifen syndrome were observed.. The plasma levels of VIP in weifen syndrome and in the late stage of weifen syndrome increased greatly at different stages as compared to qifen syndrome and the blank group (P < 0.01), while the plasma level of TX2 of weifen syndrome was higher only at the late stage than the blank group and qifen syndrome (P < 0.01). As for the levels of VIP and TX2 in weifen syndrome with different internal organs infected, there was no significant difference (P > 0.05).. VIP may be an index reflecting the pathology of weifen syndrome, and it is one of the material foundations of sluggishness of lung-defensive qi, but it has nothing to do with the infected internal organs. The level of TX2 increases only after the fever of patients with weifen syndrome subsided, so it can not be the basis for diagnosis of the early stage of weifen syndrome. It doesn't increase in qifen syndrome either, the mechanism remains to be further studied.

Topics: Female; Humans; Lung Diseases; Male; Radioimmunoassay; Syndrome; Thromboxane B2; Vasoactive Intestinal Peptide

To investigate the mechanism of perioperative lung injury in patients of ventricular septal defect (VSD) with severe pulmonary hypertension.. The thromboxane B(2) (TXB(2)), 6-keto-prostagladin F(1 alpha) (6-keto-PGF(1 alpha)), malonyldiadehyde (MDA), interleukin-6 (IL-6), and IL-8, and blood pressure, pulmonary arterial pressure (PAP) and total pulmonary pressure (TPR) in thirty-one patients of VSD, 16 cases without pulmonary hypertension and 15 cases with severe pulmonary hypertension, were examined after anesthesia (AA), over extracorporeal circulation (OEC), and 1 hour (PEC1), 6 hours (PEC6), 24 hours (PEC24), 48 hours (PEC48), and 72 hours (PEC72) post extracorporeal circulation. The respiratory index (RI) and ratio of 6-keto-PGF(1alpha) and TXB(2) (P/T) were calculated. Before and after extracorporeal circulation, pulmonary tissues were taken to be examined by light microscopy and electron microscopy.. In the cases with severe pulmonary hypertension the P/T was 0.81 +/- 0.26 after anesthesia, then decreased 0.65 +/- 0.28 over extracorporeal circulation, and reached its lowest value (0.51 +/- 0.32) 1 hour post extracorporeal circulation. MDA was 2.4 micromol/L +/- 0.6 micromol/L after anesthesia, then increased, was 7.0 micromol/L +/- 1.7 micromol/L OEC, and reached its peak value (7.3 micromol/L +/- 0.9 micromol/L) PEC1. IL-6 was 0.27 ng/L +/- 0.12 ng/L after anesthesia, then increased, and reached its peak value (0.50 ng/L +/- 0.19 ng/L) PEC1. IL-8 was 7.5 ng/L +/- 1.5 ng/L after anesthesia, then increased, was 152 ng/L +/- 50 ng/L PEC1, and reached its peak (183 ng/L +/- 63 ng/L) PEC6. TXB(2) was 251 ng/L +/- 44 ng/L after anesthesia, then increased, and reached its peak (967 ng/L +/- 145 ng/L) at PEC1. The PAP was 72.1 +/- 18.8 mm Hg after anesthesia, 55 mm Hg +/- 15.3 mm Hg OPC, and 7.4 +/- 2.1 at PEC1, then decreased, and was 53 mm Hg +/- 15 mm Hg at PEC72. The total pulmonary resistance (TPR) was 10.6 +/- 2.9 mm Hg x min(-1) x L(-1) after anesthesia, then increased, and reached its peak (15.0 +/- 3.9 mm Hg x min(-1) x L(-1) at PEC6. Respiratory index (RI) was 0.88 +/- 0.23, then increased, and reached its peak (2.35 +/- 0.72) at PEC6. TXB(2) and RI were positively correlated with pulmonary vascular resistance (gamma = 0.283, P < 0.05; gamma = 0.403, P < 0.05). RI was positively correlated with MDA (gamma = 0.403, P < 0.05). Morphologic studies revealed discontinuities in the endothelial cell lining of pulmonary capillaries, infiltration of inflammatory cells, plugging of pulmonary capillaries with neutrophils, and intraalveolar hemorrhage.. During the perioperative period, the pulmonary damage, which leads to pulmonary hypertensive crisis, is more severe among the cases of VSD with severe pulmonary hypertension than among the case without pulmonary hypertension.

Topics: Adolescent; Blood Pressure; Child; Extracorporeal Circulation; Female; Heart Septal Defects, Ventricular; Humans; Hypertension, Pulmonary; Interleukin-6; Interleukin-8; Lung Diseases; Lung Injury; Male; Malondialdehyde; Postoperative Complications; Pulmonary Artery; Thromboxane B2; Time Factors

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

We investigated the effects of low-dose Beraprost sodium (BPS), a stable prostaglandin I2 (PGI2) analogue, on microvascular permeability and the plasma concentrations of thromboxane and adenosine 3',5'-cyclic monophosphate (cAMP) in blood-perfused rabbit lungs subjected to ischemia-reperfusion (I/R). After an ischemic insult for 2 h, saline as a vehicle, 3 pmol/L of BPS (BPS-1), 150 to 300 pmol/L of BPS (BPS-2), 900 pmol/L of BPS (BPS-3), or 60 micromol/L of indomethacin (IND) was administered into the reservoir, then the lungs were reperfused and reventilated for 1 h. Vascular permeability was assessed by determining the microvascular filtration coefficient (Kf, ml/min/mm Hg/100 g wet lung). I/R resulted in increases in vascular resistance, Kf, and thromboxane. BPS-2, BPS-3, and IND inhibited the increase in vascular resistance, and BPS-3 and IND attenuated the increases in Kf and thromboxane. BPS-3 increased, but IND decreased, the concentrations of cAMP in the perfusate. Perfusate thromboxane released after reperfusion was significantly correlated with Kf. We conclude that cyclooxygenase products play a critical role in I/R-induced lung vascular injury and that 900 pmol/L of BPS inhibits the production of thromboxane and enhances the permeability barrier via a cAMP-elevating effect. However, vasodilatory action of BPS may exacerbate the reperfused lung injury by increasing the flow through injured capillaries via inhibition of thromboxane-induced vasoconstriction.

Topics: 6-Ketoprostaglandin F1 alpha; Analysis of Variance; Animals; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Blood Pressure; Capillaries; Capillary Permeability; Cyclic AMP; Epoprostenol; Indomethacin; Lung; Lung Diseases; Male; Microcirculation; Rabbits; Reperfusion Injury; Respiration, Artificial; Thromboxane B2; Tumor Necrosis Factor-alpha; Vascular Resistance; Vasodilation; Vasodilator Agents

To evaluate the in vivo production of prostacyclin and thromboxane A2 during the initial phase of experimental fat embolism as assessed, respectively, by determinations of urine 2,3-dinor-6-ketoprostaglandin F1alpha and 11-dehydrothromboxane B2 excretion.. Randomized, controlled trial.. Animal laboratory.. Twenty seven domestic pigs, weighing 24 to 31 kg.. All pigs were anesthetized and mechanically ventilated during the experiment. Eighteen pigs were subjected to an intracaval infusion of 10% allogeneic bone marrow suspension at a dose of 100 mg/kg over 5 mins. Nine pigs received only bone marrow suspension (fat embolism group). Nine pigs were given an intravenous bolus of aspirin (300 mg) 1 hr before the bone marrow suspension infusion. After the induction of fat embolism, intravenous aspirin was administered at a dose of 150 mg/hr for 2 hrs (aspirin-treated group). Nine pigs were infused with saline (control group).. In the fat embolism group, cardiac index decreased within 30 mins, while mean arterial pressure remained unchanged. Central venous pressure and pulmonary artery occlusion pressure remained relatively stable over time in the animals with fat embolism. Mean pulmonary arterial pressure and pulmonary vascular resistance increased immediately after the bone marrow suspension infusion from 23 +/- 0.8 (SEM) to 34 +/- 1.3 mm Hg and from 305 +/- 28 to 585 +/- 45 dyne x sec/cm5, respectively; these variables remained increased throughout the study period. Simultaneously, pulmonary shunt in the fat embolism group increased persistently from the baseline of 12.3 +/- 2.8%, and reached its maximum of 26.1 +/- 4.8% at the end of the experiment. Instant and gradual decreases in PaO2 (from 95 +/- 4 to 67 +/- 5 torr [12.6 +/- 0.5 to 8.9 +/- 0.7 kPa]), hemoglobin oxygen saturation (from 97.2 +/- 0.4 to 91.8 +/- 1.8%), and oxygen delivery (from 16.3 +/- 1.0 to 12.6 +/- 0.4 mL/min/kg) were observed in the fat embolism group. In the bone marrow suspension-infused animals, urine 2,3-dinor-6-ketoprostaglandin F1alpha excretion increased transiently from 451 +/- 63 up to 1466 +/- 499 pg/micromol creatinine, while urine 11-dehydrothromboxane B2 excretion increased transiently from 385 +/- 36 up to 2307 +/- 685 pg/micromol creatinine. In the aspirin-treated animals, urinary excretion of these prostanoid metabolites was reduced by 81% and 88%, respectively. The changes in mean pulmonary arterial pressure and PaO2 were ameliorated, and the alterations in pulmonary shunt and SaO2 were abolished in the animals with aspirin treatment.. Pulmonary hypertension, increased pulmonary vascular tone, and increased pulmonary shunt are hallmarks of the present fat embolism model. These hemodynamic responses may, at least partly, be related to the changed balance between prostacyclin and thromboxane A2 production.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aspirin; Cyclooxygenase Inhibitors; Embolism, Fat; Epoprostenol; Evaluation Studies as Topic; Hemodynamics; Hypertension, Pulmonary; Lung Diseases; Random Allocation; Swine; Thromboxane A2; Thromboxane B2

Total cardiopulmonary bypass, in an ovine model, is associated with increased pulmonary thromboxane A2 production, cellular sequestration of white cells and platelets, transient pulmonary hypertention, and increased lung lymph flow and lymph protein clearance when compared with respective findings with partial cardiopulmonary bypass. This study evaluates the effect of neutrophil adhesion blockade on lung injury after cardiopulmonary bypass.. Two groups of anesthetized sheep were placed on total cardiopulmonary bypass without assisted ventilation. One group of seven sheep was treated before and during total cardiopulmonary bypass with the neutrophil adhesion blocker NPC 15669. A second group of seven sheep did not receive NPC 15669 treatment before total cardiopulmonary bypass. A third group of seven sheep was treated with NPC 15669 before initiation of partial cardiopulmonary bypass with continued assisted ventilation. Aortic occlusion and hypothermia were not used. After 90 minutes all sheep were separated from cardiopulmonary bypass, with resumption of assisted ventilation and pulmonary arterial flow. After 30 minutes the left atrial pressure was elevated mechanically. Hemodynamics, thromboxane A2 levels, platelet levels, and white blood cell and plasma protein concentrations were measured before cardiopulmonary bypass and afterwards at four 15-minute intervals. Samples were taken from the right and left atria simultaneously. Lung lymph protein levels and flow were measured before and after cardiopulmonary bypass at two 30-minute intervals.. In the total cardiopulmonary bypass group not treated with NPC 15669 signs of lung injury developed after cardiopulmonary bypass. Animals treated with NPC 15669 did not manifest a similar degree of lung injury after either partial or total cardiopulmonary bypass. Increased pulmonary vascular resistance did not develop in treated sheep nor did sequestration of platelets or white blood cells occur. Despite the drug, increased pulmonary capillary permeability after total cardiopulmonary bypass persisted, but was reduced.. Compared with unmodified total cardiopulmonary bypass, blockade of neutrophil adhesion with NPC 15669 reduces, but does not entirely eliminate, lung derangement after total cardiopulmonary bypass.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cardiopulmonary Bypass; Cell Adhesion; Leucine; Lung; Lung Diseases; Neutrophils; Reperfusion Injury; Sheep; Thromboxane B2; Vascular Resistance

The role of leukotriene B4 (LTB4) in the pathogenesis of acute lung injury was examined in endotoxemic pigs. In a preliminary study, the activity and specificity of an LTB4-receptor antagonist, LY-306669, were evaluated. In vitro, LY-306669 completely blocked the functional upregulation of phagocyte opsonin receptors induced by LTB4 but had a much smaller effect on opsonin receptor upregulation induced by platelet-activating factor. In pigs treatment with LY-306669 prevented leukopenia induced by injection of authentic LTB4 but had no effect on the hematologic or hemodynamic effects of PAF or U-48816, a thromboxane-A2 mimetic. In a second study, pigs received an intravenous priming dose of lipopolysaccharide (LPS) at time (t) = -18 h and were randomized to receive 1) no further treatment (n = 5), 2) LPS (250 micrograms/kg over 1 h beginning at t = 0 h) and LY-306669 (10 mg/kg bolus and 3 mg.kg-1.h-1 infusion beginning at t = -15 min) (n = 7), or 3) LPS and vehicle (n = 6). Treatment with LY-306669 significantly ameliorated LPS-induced hypoxemia, pulmonary edema, and alveolitis. These data suggest that LTB4 is an important mediator of pulmonary dysfunction and transendothelial migration of neutrophils in LPS-induced acute lung injury.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Endotoxins; Hemodynamics; Leukotriene B4; Lipopolysaccharides; Lung; Lung Diseases; Neutrophils; Phenols; Receptors, Leukotriene B4; Swine; Tetrazoles; Thromboxane B2

We examined the effect of substituting linoleic acid (LA) with eicosapentaenoic acid (EPA) and gamma-linolenic acid (gamma-LA), precursors of trienoic and monoenoic eicosanoids, respectively, on acute lung injury (ALI). Three groups (n = 8/group) of pigs were fed enteral diets containing LA (diet A), EPA (diet B), or EPA+gamma-LA (diet C) for 8 days. ALI was then induced with a 0.1 mg/kg bolus of Escherichia coli endotoxin followed by a continuous infusion for 4 h (0.075 mg.kg-1.h-1). Pulmonary arterial and capillary wedge pressures, cardiac index (CI), arterial blood gases, arterial O2 content, and plasma thromboxane B2 (TxB2) were measured. Arterial PO2 decreased at 20 min in animals fed diet A. This change was attenuated with diets B and C. The EPA- and EPA + gamma-LA-enriched diets attenuated the fall in O2 delivery at 20 min, an improvement that was sustained throughout the 4-h study period with the EPA+gamma-LA-enriched diet only. This improvement in O2 delivery was due not only to the improved arterial PO2, but also to the maintenance of CI at 20 min in animals fed diets B and C and throughout the 4-h study period in animals fed diet C. At 4 h, TxB2 increased 10-fold over baseline in animals fed diet A, whereas in animals fed diets B and C the increase was only 3-fold. These decreased TxB2 levels in animals fed diets B and C correlate with an attenuation in the increase in pulmonary vascular resistance that was observed at 20 min after endotoxin infusion in animals fed diet A. These data suggest that specialized enteral diets enriched in EPA+gamma-LA improve gas exchange and O2 delivery, presumably in part through a modification of TxB2 production with a decrease in pulmonary vascular resistance and an increase in CI, during ALI.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Bleeding Time; Blood Platelets; Dietary Fats; Dietary Fats, Unsaturated; Endotoxins; Fatty Acids; Fish Oils; gamma-Linolenic Acid; Heart; Lung; Lung Diseases; Male; Phospholipids; Plant Oils; Platelet Aggregation; Swine; Thromboxane B2

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

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

We studied the effects of a 5-lipoxygenase inhibitor, SC-45662, on endotoxin-induced pulmonary dysfunction in chronically instrumented unanesthetized sheep. Each sheep was studied with endotoxin alone, SC-45662 alone, and endotoxin after SC-45662 pretreatment. Endotoxin did not cause consistent increases in plasma or lung lymph concentrations of leukotriene B4 (LTB4). Ex vivo stimulation of whole blood from sheep before and after treatment with SC-45662 demonstrated no inhibition of cyclooxygenase metabolism but an approximately 80% inhibition of LTB4 production. At drug concentrations obtained in vivo, SC-45662 did not significantly inhibit in vitro A23187-stimulated whole blood thromboxane B2 production but did inhibit LTB4 production from ionophore-stimulated sheep granulocytes. SC-45662 attenuated the early changes in lung mechanics and pulmonary hypertension but did not attenuate the later increase in lung fluid and solute exchange observed after endotoxemia. We conclude that 5-lipoxygenase products are not measurably involved in the later increase in lung fluid and solute exchange observed after endotoxemia in sheep.

Topics: 6-Ketoprostaglandin F1 alpha; Acetates; Animals; Arachidonate 5-Lipoxygenase; Blood Pressure; Dinoprostone; Endotoxins; Female; Gas Chromatography-Mass Spectrometry; Granulocytes; Hemodynamics; Leukotriene B4; Lipoxygenase Inhibitors; Lung Diseases; Lymphatic System; Male; Phenols; Phenothiazines; Respiratory Mechanics; Sheep; Superoxides; Thromboxane B2

We evaluated the effect of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 alpha (IL-1 alpha) on pig cardiopulmonary function by intravenously infusing each cytokine individually or in combination (0.5 microgram/kg from 0 to 0.5 h + 5 ng.kg-1 x min-1 from 0.5 to 6 h for each cytokine). The role of eicosanoids in mediating the TNF-alpha + IL-1 alpha-induced cardiopulmonary dysfunction was also investigated by pretreating cytokine-infused pigs with CGS 8515 (5-lipoxygenase inhibitor) or indomethacin (cyclooxygenase inhibitor). Coinfusion of TNF-alpha with IL-1 alpha caused additive increases (P < 0.05) in total peripheral resistance and plasma concentrations of 6-keto-prostaglandin F1 alpha (PGF1 alpha). The increases in mean pulmonary arterial pressure (Ppa), pulmonary vascular resistance (PVR), alveolar-arterial O2 gradient (AaDO2), alveolar dead space-to-tidal volume ratio (VD/VT), and plasma concentrations of thromboxane B2 were either additive or synergistic. CGS 8515 blocked the TNF-alpha + IL-1 alpha-induced increases (P < 0.05) in mean aortic pressure, total peripheral resistance (4-6 h), VD/VT (5-6 h), and, at 6 h, attenuated the increases in Ppa, PVR, and AaDO2. Indomethacin blocked or attenuated the cytokine-induced increases (P < 0.05) in Ppa, PVR, AaDO2, VD/VT, and plasma concentrations of thromboxane B2 and 6-keto-PGF1 alpha. The 1-to 2-h systemic hypotension, caused by TNF-alpha + IL-1 alpha, was not abrogated by either indomethacin or CGS 8515. The cytokines did not alter plasma concentrations of leukotriene B4 or 5-hydroxyeicosatetraenoic acid. We conclude that coinfusion of TNF-alpha with IL-1 alpha induces physiological responses that are additive or synergistic and that cyclooxygenase and 5-lipoxygenase products (other than leukotriene B4 and 5-hydroxyeicosatetraenoic acid) importantly mediate cardiopulmonary dysfunction in pigs infused with TNF-alpha + IL-1 alpha.

Topics: 6-Ketoprostaglandin F1 alpha; Albumins; Animals; Arachidonic Acids; Bronchoalveolar Lavage Fluid; Chromatography, High Pressure Liquid; Cyclooxygenase Inhibitors; Cytokines; Dinoprost; Drug Synergism; Eicosanoids; Heart; Heart Diseases; Hydroxyeicosatetraenoic Acids; Indomethacin; Injections, Intravenous; Interleukin-1; Leukotriene B4; Lipoxygenase Inhibitors; Lung; Lung Diseases; Naphthoquinones; ortho-Aminobenzoates; Swine; Thromboxane B2; Tumor Necrosis Factor-alpha; Vascular Resistance

Effects of a single dose of 3-methylindole (3-MI) (250 mg/kg intraperitoneally) were studied at different times ranging from 12 hours to 2 weeks post-treatment (PT). Microscopic study revealed mild Clara cell injury 24 hours PT and mucus hyperplasia 24 hours to 2 weeks PT. Diffuse type I alveolar epithelial cell necrosis occurred at 48 hours, followed by type II cell hyperplasia. Septal edema and accumulation of interstitial and capillary polymorphonuclear leukocytes and perivascular mixed mononuclear inflammatory cells accompanied the injury and repair. A gradual resolution of lesions with persistent mononuclear inflammatory cellular clusters at septal junctions, focal septal fibrosis, and accumulation of alveolar macrophages was evident at 1 and 2 weeks PT. Collagen, measured as hydroxyproline, in 3-MI-treated rats was significantly increased to 130% and 139% of control (3.0 mg/lung) at 1 and 2 weeks PT, respectively. Biphasic peaks of plasma 6-keto-prostaglandin F1 alpha occurred at 12 to 24 hours and at 96 hours PT with 3-MI and thromboxane B2 was elevated 12, 48, and 96 hours PT. Right ventricular/left ventricular and septal weight was increased to 120% and 140% of the control 1 and 2 weeks PT. We concluded that 3-MI induces alveolar septal injury in the rat with relatively complete repair of the alveolar epithelium and residual mild focal septal fibrosis and pulmonary hypertension 2 weeks PT. Arachidonic acid-derived mediators and inflammation are associated with 3-MI-induced lung injury.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Collagen; Dose-Response Relationship, Drug; Drug Administration Schedule; Injections, Intraperitoneal; Lung Diseases; Pulmonary Alveoli; Rats; Rats, Sprague-Dawley; Skatole; Thromboxane A2; Thromboxane B2

There have been several studies that have already explored the potential beneficial role of cyclo-oxygenase (CO) inhibitors on oleic acid (OA)-induced lung injury in different species. These studies report no significant effect of CO inhibition, though thromboxane B2 (TxB2) was effectively blocked. However, recent studies indicate that pre-treatment with aspirin (ASA) preserve gas exchange in OA lung injury in dogs. Aim of our study has been to evaluate the potential beneficial effects of the pre-treatment with low doses of ASA on gas exchange, hemodynamics, respiratory mechanics, prostanoids and lung histology in OA-induced lung injury in sheep.. 0.09 ml/kg of OA was administered into the right atrium of 14 anaesthetized sheep. Six received a bolus of ASA (10 mg/kg i.v.) 30 min before OA, the others saline as placebo.. Pulmonary and tissue gas exchange, pulmonary and systematic hemodynamics, respiratory system mechanics, TxB2 and 6-keto-PGF1 alpha, leukocytes and platelets concentrations were measured throughout the subsequent 3 h and lung histology was effected at end-experiment. The principal findings of our study are: 1) ASA reduces OA-induced early pulmonary vasoconstriction and bronchoconstriction, parallelled by a suppression of TxB2 generation; 2) the late increase in pulmonary artery pressure and airway resistance due to OA is not inhibited by ASA; 3) the early disturbance in pulmonary gas exchange is reduced by ASA, whereas the late severe deterioration is exaggerated by ASA; 4) the stability of tissue exchange ratio (R) at approximately 1 in ASA-group compared to its fall to approximately 0.7 in controls.. Our findings suggest that ASA: 1) is only effective to treat the very transient TxB2-induced pulmonary vasoconstriction resulting in hydrostatic edema, and it is ineffective, even accentuates, the subsequent major pulmonary endothelial cell injury leading to alveolar flooding that is unrelated to TxB2; 2) has a transient protective effect on the TxB2-induced early bronchospasm; 3) has a biphasic behaviour on gas exchange, with a benefit which lasts only one hour and then results in a worse gas exchange; 4) has an immediate, stabilizing, persisting effect on R, contrasting with its transient effect on pulmonary hemodynamics and PaO2.

Topics: 6-Ketoprostaglandin F1 alpha; Analysis of Variance; Animals; Aspirin; Blood Gas Analysis; Hemodynamics; Least-Squares Analysis; Lung; Lung Diseases; Oleic Acid; Oleic Acids; Premedication; Pulmonary Gas Exchange; Respiration; Sheep; Thromboxane B2

The present studies evaluated the role cyclooxygenase products play in bacterial sepsis induced pulmonary injury in the rat. Lung injury was assessed by determining the pulmonary capillary filtration coefficient (Kf) and the lung lavage protein concentration four and 18 hours after cecal ligation and puncture. Four hours after cecal ligation, the Kf was unchanged from control, however, by 18 hours, the Kf was increased 171% (p < .05). Similarly, lung lavage protein levels were unchanged four hours after cecal ligation but were significantly (p < .05) elevated at 18 hours. On the other hand, pulmonary lavage immunoreactive thromboxane B2 (iTXB2) levels were increased both four and 18 hours after the initiation of sepsis. In order to determine if cyclooxygenase products played a role in the sepsis associated lung injury, ibuprofen was administered prior to cecal ligation. Ibuprofen pretreatment prevented the sepsis associated increase in both Kf and lung lavage protein concentration. These studies suggest that bacterial sepsis in the rat is associated with pulmonary injury and that early administration of ibuprofen ameliorates this damage.

Topics: Animals; Bronchoalveolar Lavage Fluid; Capillaries; Capillary Permeability; Cecum; Ibuprofen; Ligation; Lung; Lung Diseases; Male; Prostaglandin-Endoperoxide Synthases; Punctures; Rats; Rats, Sprague-Dawley; Sepsis; Thromboxane B2

Interleukin-2 was recently shown to cause acute lung injury characterized by microvascular permeability defect, interstitial edema, and leukosequestration. Similar responses can also be produced by platelet activating factor (PAF). Thus, the present study aimed to examine whether PAF plays a key role in the development of IL-2-induced lung injury in the anesthetized rat. Intravenous infusion (60 min) of recombinant human IL-2 at 10(5)-10(6) U/rat (n = 7-9) dose-dependently elevated lung water content (27 +/- 1%, P less than 0.01), myeloperoxidase activity (+84 +/- 23%, P less than 0.05), and serum thromboxane B2 (990 +/- 70%, P less than 0.01), but failed to alter blood pressure, hematocrit, serum tumor necrosis factor-alpha, and circulating leukocytes and platelets. Pretreatment (-30 min) with a potent and specific PAF antagonist, BN 50739 (10 mg/kg, intraperitoneally, n = 6) prevented the pulmonary edema (P less than 0.05) and thromboxane B2 production (P less than 0.01), and attenuated the elevation of lung myeloperoxidase activity (+18 +/- 16%, P less than 0.05) induced by IL-2. These data suggest that PAF is involved in the pathophysiological processes leading to IL-2-induced lung injury, and point to the potential therapeutic capacity of PAF antagonists in preventing pulmonary edema during IL-2 therapy.

Topics: Animals; Azepines; Blood Pressure; Interleukin-2; Leukocyte Count; Lung Diseases; Male; Peroxidase; Platelet Activating Factor; Platelet Count; Rats; Rats, Inbred Strains; Thromboxane B2; Triazoles; Tumor Necrosis Factor-alpha

To examine the role of thromboxane (Tx) A2 in the pathogenesis of acute lung injury caused by tumor necrosis factor alpha (TNF), we tested the effects of OKY-046, a selective thromboxane synthase inhibitor, on pulmonary hemodynamics, lung lymph balance, circulating leukocytes, arterial blood gas analysis, and TxA2 (as TxB2) and prostacyclin (as 6-keto-prostaglandin F1 alpha) levels in plasma and lung lymph after TNF infusion in awake sheep. Infusion of human recombinant TNF (3.5 micrograms/kg) into a chronically instrumented awake sheep caused a transient increase in pulmonary arterial pressure (Ppa). The Ppa peaked within 15 min of the start of TNF infusion from 23.3 +/- 1.1 (SE) cmH2O of baseline to 42.3 +/- 2.3 cmH2O and then decreased toward baseline. The pulmonary hypertension was accompanied by transient hypoxemia, peripheral leukopenia, and the increases in TxB2 in plasma and lung lymph. These changes were followed by an increase in flow of protein-rich lung lymph, consistent with an increase in pulmonary microvascular permeability. OKY-046 significantly prevented the rises of Ppa and TxB2 concentrations in plasma and lung lymph during early phase after TNF infusion. OKY-046, however, did not attenuate the increase of lung lymph flow, transient hypoxemia, and leukopenia. From these data, and by comparison with our previous studies of OKY-046-pretreated sheep during endotoxemia, we conclude that TxA2 has an important role of the increase in the early pulmonary hypertension, but it is not related to the early hypoxemia, leukopenia, and lung lymph balances in TNF-induced lung injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Gas Analysis; Hemodynamics; Leukocyte Count; Lung; Lung Diseases; Lymphatic System; Methacrylates; Sheep; Thromboxane B2; Thromboxane-A Synthase; Tumor Necrosis Factor-alpha

Products of cyclooxygenase activity have been proposed to mediate the pulmonary hypertension and increased microvascular permeability associated with phorbol myristate acetate- (PMA) induced acute lung injury. Previously, we reported that thromboxane (Tx) does not mediate PMA-induced pulmonary hypertension in intact anesthetized dogs. In the present study, PMA was administered to isolated canine lungs perfused with autologous blood at constant flow to investigate a possible role for Tx in the PMA-induced increase in microvascular permeability. Changes in permeability were assessed by determining changes in the capillary filtration coefficient (Kfc). In lobes pretreated with papaverine to prevent PMA-induced increases in pulmonary vascular resistance, Kfc increased from a baseline value of 0.2 +/- 0.03 to 1.5 +/- 0.29 ml.min-1.cmH2O-1.100 g wet lobe wt-1 (P < 0.01) 30 min after PMA (5.8 x 10(-8) M, n = 10). Concomitantly, TxB2, the stable metabolite of TxA2, increased from 138 +/- 44 to 1,498 +/- 505 pg/ml (P < 0.05) in the blood. Both the selective Tx synthase inhibitor, OKY-046 (7 x 10(-4) M, n = 6), and the cyclooxygenase inhibitor, indomethacin (10(-4) M, n = 7), prevented the PMA-induced increase in TxB2, but neither compound attenuated the PMA-induced increase in Kfc. ONO-3708 (10(-6) M), a selective prostaglandin (PG) H2/TxA2 receptor antagonist, prevented the vasoconstriction resulting from administration of U-46619, a stable PGH2/TxA2 receptor agonist, but it did not prevent the PMA-induced increases in Kfc (n = 6).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Capillary Permeability; Dogs; In Vitro Techniques; Indomethacin; Leukocyte Count; Lung Diseases; Male; Methacrylates; Papaverine; Prostaglandin-Endoperoxide Synthases; Tetradecanoylphorbol Acetate; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

Platelet-activating factor (PAF) is a glycerophospholipid known for its unusual potent vasoactive and proinflammatory activities. The present study examined whether PAF might serve as a priming factor in endotoxin-induced tumor necrosis factor-alpha (TNF alpha) synthesis, cardiovascular shock, and lung injury in anesthetized rats. Intravenous infusion of PAF (1 pmol/kg/min for 60 minutes, n = 5) alone or endotoxin (0.1 micrograms/kg i.v. bolus, n = 5) failed to alter blood pressure, serum TNF alpha and thromboxane B2, platelet and leukocyte count, and hematocrit, nor was lung histology, myeloperoxidase activity, and water content changed. In contrast, the combined administration of PAF and endotoxin markedly elevated serum TNF alpha (1,359 +/- 362 pg/ml, n = 5, p less than 0.01) and thromboxane B2 (43 +/- 5 pg/100 microliters, n = 8, p less than 0.01) along with hypotension, hemoconcentration, leukopenia, and thrombocytopenia. Most notably, the combined regimen caused neutrophil aggregation, adhesion, and accumulation into the lung parenchyma along with platelet-fibrin deposits in postcapillary venules, pulmonary edema, and increased lung myeloperoxidase activity. The role of PAF in this process was confirmed by 1) the prevention of the priming effect by pretreatment with the PAF antagonist BN 50739 (n = 5), and 2) the failure of lyso-PAF, the cardinal nonactive PAF-metabolite, to prime for endotoxin-induced production of TNF alpha (n = 4). These data suggest that PAF could serve as a key mediator in priming for endotoxin-induced tissue injury, especially the typical pulmonary pathophysiology of adult respiratory distress syndrome, a severe pathological outcome of septic shock, burns, and multiple organ injury.

Topics: Animals; Body Water; Cardiovascular Diseases; Drug Synergism; Endotoxins; Escherichia coli; Hemodynamics; Lipopolysaccharides; Lung; Lung Diseases; Male; Microscopy, Electron, Scanning; Organ Size; Peroxidase; Platelet Activating Factor; Rats; Rats, Inbred Strains; Thromboxane B2; Tumor Necrosis Factor-alpha

Guinea pigs were intravenously injected with icterhemorrhagiae serogroup Lai serovar strain 017 leptospirosis to model the pulmonary diffuse hemorrhage (PDH) in leptospirosis. Thirty-eight hours after the injection, the jugular arteries were catheterized to collect blood sample. The plasma was prepared for radioimmunoassay of TXB2 and 6-keto-PGF1a, the stable metabolites of TXA2 and PGI2 respectively. The plasma level of TXB2 in the experimental group, 107.15 +/- 41.65 pg/ml (n = 7), almost doubled that of the control, 54.05 +/- 12.93 pg/ml (n = 7), with significant difference (P less than 0.01); meanwhile, no significant difference was observed of 6-keto-PGF1a, 67.97 +/- 16.89 pg/ml (n = 6) vs. 98.06 +/- 40.63 pg/ml (n = 9) with P greater than 0.1. The fact that TXA2 causes vasoconstriction and increases vessel permeability suggests that TXA2 elevation should play a role in the mechanism of PDH in leptospirosis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Disease Models, Animal; Epoprostenol; Guinea Pigs; Hemorrhage; Lung Diseases; Thromboxane B2; Weil Disease

Ischemia of the lower extremity has been shown to cause pulmonary leukostasis and increased pulmonary artery pressure. Thromboxane (TX) has been implicated as a mediator in this process. The effect of OKY-046, a TX synthetase inhibitor, on polymorphonuclear leukocyte (PMN) production of superoxide anion (O2-) as determined by ferricytochrome reduction was examined. Fourteen dogs were subjected to 6 hours of bilateral gracilis muscle ischemia followed by 1 hour of reperfusion. O2- production from resting PMNs and PMNs stimulated with opsonized zymosan (OZ, 0.1 mg/ml) was measured prior to ischemia or drug treatment (baseline), and following reperfusion in both treated (n = 7) and control groups (n = 7). Serum TX levels were measured using a radioimmunoassay. Following reperfusion, TX levels in the treated group were decreased as compared with the control group (18 +/- 2 pg/ml vs. 72 +/- 26 pg/ml, P less than 0.05). Superoxide production by both resting and stimulated PMNs was also decreased in the treated group; from 0.98 +/- 0.16 nmol to 0.43 +/- 0.12 nmol O2- in the resting state (P less than 0.05) and from 13.3 +/- 1.5 nmol to 9.0 +/- 1.1 nmol O2- after stimulation (P less than 0.005). O2- production was increased in the control group following reperfusion as compared with baseline samples, and this increase was attenuated by treatment with OKY-046. TX synthetase inhibition decreases activation of PMNs following hindlimb ischemia.

Topics: Animals; Dogs; Female; Injections, Intravenous; Ischemia; Leg; Lung Diseases; Lymphocyte Activation; Male; Methacrylates; Neutrophils; Superoxides; Thromboxane B2; Thromboxane-A Synthase

This study was designed to investigate the effects of ketoconazole, a thromboxane synthetase inhibitor, on pulmonary and systemic hemodynamics and pulmonary function in experimental respiratory distress syndrome. Pulmonary artery infusion of oleic acid (PAIOA), 0.1 ml/kg, was used to cause lung injury. Ten dogs were randomized into two groups (Gps): Gp I (n = 5) acted as control, whereas Gp II (n = 5) were treated with IV ketoconazole (2.5 mg/kg bolus then 10 mg/kg/hour for 2.5 hours). Hemodynamics, extravascular lung water (EVLW), serum levels of PGE2, and TxB2 were obtained at baseline (BL) and at 30-minute intervals for 2.5 hours (T30-T150). After 30 minutes of PAIOA the mean arterial pressure (MAP) decreased significantly in both Gps (131 +/- 17 vs. 88 +/- 9 mmHg Gp 1, 119 +/- 9 vs. 79 +/- 8 mmHg Gp II, P less than 0.05); however, while MAP returned to BL values in Gp II, it remained significantly lower throughout the experimental interval in Gp I. Mean pulmonary artery pressure (MAP) was not significantly affected by PAIOA in either Gp, while pulmonary vascular resistance increased significantly from BL at T120 in Gp II. Pulmonary function measured by partial pressure of arterial O2 (PaO2) and extravascular lung water (EVLW) were significantly affected by PAIOA. There was a significant decrease in PaO2 (66 +/- 6 vs. 96 +/- 8 mmHg, Gp I and 60 +/- 7 vs. 100 +/- 6 mmHg, Gp II) as well as an increase in EVLW (604 +/- 61 vs. 135 +/- 9 ml, Gp I and 641 +/- 110 vs. 117 +/- 18 ml, Gp II) in both Gps.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Dogs; Hemodynamics; Ketoconazole; Lung; Lung Diseases; Oleic Acid; Oleic Acids; Thromboxane B2

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

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

The effects of adenosine (ADO) on pulmonary vascular resistance (PVR) distribution, vascular compliance (C), and permeability were determined in normal and PMA-injured isolated rabbit lungs perfused with a 1:1 mixture of 6% albumin in Krebs-Henseleit buffer and autologous blood. ADO or vehicle was continuously infused into the reservoir at 1,4, or 5 mumol/min after a 1-mumol bolus of ADO or vehicle. The capillary filtration coefficient (Kf) and arterial, venous, and double occlusion pressures were measured at baseline and 30 min after phorbol myristate acetate (PMA; 4 x 10(-8) M) or vehicle. Perfusate differential and total leukocyte counts as well as adenine nucleotides, 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha), and thromboxane B2 (TxB2) concentrations were determined at each measurement period. ADO was recovered as hypoxanthine and inosine in the perfusate. ADO alone did not alter PVR, C, Kf, or TxB2 but reduced 6-keto-PGF1 alpha levels. PMA induced an increase in Kf (0.024 +/- 0.002 to 0.040 +/- 0.006 g.cmH2O-1.min-1, P less than 0.05) that was completely blocked by 4 or 5 mumol/min ADO. PVR increased by 63 +/- 11% after PMA, primarily in the arteries and arterial and venous microvessels. The postcapillary resistance increase was blunted by 4 mumol/min ADO; 5 mumol/min ADO prevented the PVR increase in all segments. ADO did not affect the initial adherence of neutrophils in the lung or the PMA-induced 87 +/- 2% decrease in circulating leukocytes (greater than 98% lymphocytes) or threefold increase in TxB2 levels. These results suggest that protection by ADO is not mediated by the altering of cyclooxygenase products or by leukocyte adherence.

Topics: 6-Ketoprostaglandin F1 alpha; Adenine Nucleotides; Adenosine; Animals; Capillary Permeability; Filtration; Hypertension, Pulmonary; In Vitro Techniques; Leukocyte Adherence Inhibition Test; Leukocyte Count; Lung Compliance; Lung Diseases; Male; Perfusion; Prostaglandin-Endoperoxide Synthases; Pulmonary Circulation; Rabbits; Tetradecanoylphorbol Acetate; Thromboxane B2; Vascular Resistance

We evaluated the role of sulfidopeptide leukotrienes as mediators of endotoxin-induced respiratory failure in pigs. Escherichia coli endotoxin (055-B5) was infused intravenously into anesthetized 10- to 14-wk-old pigs at 5 micrograms/kg the 1st h followed by 2 micrograms.kg-1.h-1 for 3 h in the presence and absence of LY171883, a specific leukotriene D4 (LTD4)/LTE4 receptor antagonist. Endotoxin caused hemoconcentration, granulocytopenia, decreased cardiac index, systemic hypotension, pulmonary hypertension, increased pulmonary vascular resistance, bronchoconstriction, hypoxemia, increased permeability of the alveolar-capillary membrane, pulmonary edema, and increased plasma concentrations of thromboxane B2 (TxB2), prostaglandin F2 alpha (PGF2 alpha), and 6-keto-PGF1 alpha. LY171883 did not modify endotoxin-induced cardiopulmonary and hematologic abnormalities, except for a modest attenuation of pulmonary hypertension (at 1 h) and increased pulmonary vascular resistance (at 1-2 h). Ex vivo stimulation of whole blood with calcium ionophore caused large increases in plasma concentrations of TxB2, PGF2 alpha, and LTB4. These increases were not significantly modified in blood derived from pigs treated with LY171883, indicating no inhibition of cyclooxygenase or 5-lipoxygenase. We conclude that LTD4 and LTE4 are not important mediators of endotoxin-induced lung injury in anesthetized pigs, although they may contribute modestly to pulmonary vasoconstriction.

Topics: Acetophenones; Animals; Autacoids; Blood Gas Analysis; Calcimycin; Capillary Permeability; Cyclooxygenase Inhibitors; Dinoprost; Endotoxins; Hemodynamics; Infusions, Intravenous; Leukotriene B4; Lung Diseases; Organ Size; Radioimmunoassay; Respiration; Swine; Tetrazoles; Thromboxane B2

Pulmonary hypertension and foreign body granulomas are recognized sequelae of chronic intravenous drug abuse. We have recently described the development of transient pulmonary hypertension and increased permeability pulmonary edema after the intravenous injection of crushed, suspended pentazocine tablets in both humans and dogs. To determine the role of vasoactive substances in the development of this transient pulmonary hypertension, we measured pulmonary hemodynamics and accumulation of arachidonic acid metabolites in dogs during the infusion of indomethacin, a cyclooxygenase inhibitor, diethylcarbamazine (DEC), a lipoxygenase inhibitor, and FPL 55712, a receptor antagonist for leukotriene C4/D4 (LTC4/D4). Following the intravenous administration of crushed, suspended pentazocine tablets (3-4 mg/kg of body weight), mean pulmonary artery pressure increased from 14 +/- 2 mmHg to 30 +/- 6 mmHg (p less than 0.05) at 60 secs with a concomitant increase in plasma concentrations of 6-keto-PGF1 alpha from 187 +/- 92 pg/ml to 732 +/- 104 pg/ml and thromboxane B2 from 206 +/- 83 pg/ml to 1362 +/- 117 pg/ml (both p less than 0.05). Indomethacin prevented the increase in both cyclooxygenase metabolites, but had no effect on the pulmonary hypertension. In contrast, DEC had no effect on the increase in cyclooxygenase products, but blocked the pulmonary hypertension. FPL 55712 did not effect either the increase in cyclooxygenase metabolites or the pulmonary hypertension. We conclude that the transient pulmonary hypertension, induced by the intravenous injection of crushed, suspended pentazocine tablets, is not mediated by cyclooxygenase products but may be mediated by lipoxygenase product(s) other than LTC4/D4.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Arachidonic Acids; Blood Pressure; Chromones; Cyclooxygenase Inhibitors; Diethylcarbamazine; Dogs; Foreign-Body Reaction; Granuloma, Foreign-Body; Hemodynamics; Hypertension, Pulmonary; Indomethacin; Lipoxygenase; Lipoxygenase Inhibitors; Lung; Lung Diseases; Pentazocine; Prostaglandin-Endoperoxide Synthases; Thromboxane B2; Vascular Resistance

Release of arachidonic acid metabolites (eicosanoids) by alveolar macrophages may be important in regulating pulmonary inflammatory reactions. The purpose of this study was to characterize eicosanoids released by rat alveolar macrophages during the evolution of experimentally induced pulmonary inflammation. Immunization with subcutaneous bacillus Calmette-Guerin (BCG) followed 2 wk later by intravenous BCG challenge resulted in mild granulomatous pulmonary inflammation for up to 30 days. At serial intervals, alveolar macrophages were lavaged from the BCG-treated rats as well as from control normal rats. Lavaged macrophages were cultured in vitro, and culture supernatants were assayed by radioimmunoassay for release of prostaglandin E2 (PGE2), Leukotriene B4 (LTB4), and thromboxane B2 (TXB2). Cells were cultured alone, or with added LPS or calcium ionophore A23187 to stimulate eicosanoid release. During BCG-induced inflammation, spontaneous release of PGE2 and LTB4 was unchanged, while spontaneous release of TXB2 was depressed acutely and then returned to control levels. The capacity of alveolar macrophages to release specific eicosanoids in response to an in vitro stimulus was dramatically altered during the course of BCG-induced inflammation. Stimulated release of PGE2 was transiently increased during acute lung injury, but stimulated release of LTB4 was significantly decreased at all stages of inflammation. Stimulated release of TXB2 was unchanged. These results indicate that during the course of granulomatous pulmonary inflammation there are dynamic changes in the profile of eicosanoids released by alveolar macrophages, both spontaneously and in response to in vitro stimulation. This alteration in the release of eicosanoids by alveolar macrophages may be an important factor in the resolution of pulmonary inflammation.

Topics: Animals; Bronchoalveolar Lavage Fluid; Cells, Cultured; Culture Media; Dinoprostone; Eicosanoids; Granuloma; Inflammation; Leukotriene B4; Lung Diseases; Macrophages; Male; Mycobacterium bovis; Pulmonary Alveoli; Radioimmunoassay; Rats; Rats, Inbred F344; Thromboxane B2

1. The role of prostanoids in 3-methylindole (3MI)-induced lung disease was investigated. Goats were infused with 3MI in propylene glycol at a dose of 35 mg 3MI/kg body weight. Control goats were infused with propylene glycol alone. 2. Blood was collected at regular intervals starting 24 hr before and ending 72 hr following 3MI infusion. In a second experiment, 3MI-treated goats were killed at 2, 6, 12, 24, 48 and 72 hr post-infusion. The concentrations of PGF2 alpha, PGE, 6-keto PGF1 alpha and TXB2 in plasma and lung of 3MI-infused and control goats were determined by radioimmunoassay. 3. Comparison of individual prostanoid concentrations showed that 3MI-infused and control goats exhibited similar plasma profiles for all four prostanoids measured. 4. In addition, prostanoid concentrations in lungs did not seem to be affected by 3MI infusion. 5. Thus, plasma and lung prostaglandin and TXB2 concentrations do not appear to be altered in 3MI-induced lung disease.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dinoprost; Goats; Indoles; Lung; Lung Diseases; Male; Prostaglandins; Prostaglandins E; Radioimmunoassay; Skatole; Thromboxane B2

Arachidonic acid (AA) metabolites may be important mediators in the hyperoxic lung injury process. We have previously demonstrated, in an adult model of hyperoxic lung injury, that bronchoalveolar lavage (BAL) fluid levels of AA metabolites of the cyclooxygenase pathway increase before evidence of overt injury. Nonselective inhibition with indomethacin or dexamethasone failed to ameliorate the injury process, possibly because production of prostaglandin I2 (PGI2) was suppressed. In this study, we attempted to ameliorate hyperoxic lung injury using an infusion of prostaglandin E1 (PGE1), since PGE1 has some of the potentially protective effects of PGI2. Thirty-two adult rabbits were exposed to greater than 95% oxygen; eight served as controls and 24 received PGE1 infusion (five, nine, and ten received 0.1, 0.06, and 0.03 micrograms/kg.min, respectively). At the end of the 65-h exposure period, BAL of the left lung was performed; the right was saved for light microscopy. PGE1 infusion at the 0.06 and 0.03-micrograms/kg.min doses resulted in significantly fewer polymorphonuclear leukocytes (PMN) in BAL fluid (p less than .05). However, PGE1 infusion did not significantly ameliorate the lung injury process. In summary, although PGE1 infusion inhibited the influx of PMN into the lung, treatment did not result in any significant amelioration of the hyperoxic lung injury process.

Topics: Alprostadil; Animals; Bronchoalveolar Lavage Fluid; Dinoprostone; Female; Humans; Infant, Newborn; Infusions, Intravenous; Lung Diseases; Neutrophils; Oxygen; Prostaglandins F; Rabbits; Thromboxane B2

Interleukin (IL)-2 administration leads to respiratory dysfunction due to increased vascular permeability. This study examines the role of thromboxane (Tx)A2 in IL-2 induced lung injury in sheep with chronic lung lymph fistulae. This preparation enables evaluation of permeability prior to the development of gross edema. IL-2, 10(5) units/kg (n = 6), or its excipient control (n = 5) was given as an i.v. bolus over 2 min. After 2 h of IL-2 administration, plasma TxB2 increased from 168 to 388 pg/ml (P less than 0.05) and lung lymph TxB2 from 235 to 694 pg/ml (P less than 0.05). Mean pulmonary artery pressure (MPAP) rose from 13 to 29 mm of Hg (P less than 0.05) at 30 min and remained elevated for 4 h while the pulmonary artery wedge pressure was unchanged at 4 mm of Hg. Arterial oxygen tension (PaO2) fell from 88 to 77 mm of Hg (P less than 0.05). Lung lymph flow (QL) rose from 2.2 to 3.8 ml/30 min (P less than 0.05) at 1 h and to 6.4 ml/30 min at 3 h. This rise coincided with an increase in the lymph/plasma (L/P) protein ratio from 0.67 to 0.77 (P less than 0.05). In contrast, the non-IL-2-infused sheep (n = 3) recruitment of the lung vasculature by left atrial balloon inflation led to a rise in QL from 2.4 to 8.2 ml/30 min, whereas the L/P ratio declined from 0.62 to 0.25, suggesting that the protein-rich lymph flow after IL-2 administration reflected increased microvascular permeability. In further proof of an increase in permeability, IL-2 administration into sheep (n = 2) with an inflated left atrial balloon led, after a pressure-independent L/P protein ratio had been achieved, to an increase in L/P protein ratio and decrease in protein reflection coefficient. At 2 h after IL-2, the blood leukocyte count fell from 8156 to 4375/mm3 (P less than 0.05) primarily due to a 73% drop in lymphocytes. The platelet count declined from 292 to 184 x 10(3)/mm3 (P less than 0.05). Body temperature rose from 38.9-40.3 degrees C (P less than 0.05), and shaking chills were common. Pretreatment with the Tx synthetase inhibitor OKY 046 (n = 7) lowered baseline plasma and lymph TxB2 levels to 22 and 52 pg/ml (P less than 0.05) and prevented the IL-2-induced increase in plasma and lung lymph TxB2 (P less than 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Animals; Blood Cell Count; Blood Platelets; Blood Pressure; Capillary Permeability; Female; Interleukin-2; Lung Diseases; Methacrylates; Neutrophils; Pulmonary Circulation; Sheep; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase; Time Factors

Activation of several cascade systems, e.g. coagulation, fibrinolysis, kallikreinkinin, complement and eicosanoid systems, has been implicated in the etiology of septic-lung microvascular injury. A chronic lung lymph fistula preparation in sheep (n = 9) was used to study coagulation, kallikrein-kinin and eicosanoids during Escherichia coli septicemia. Lung lymph flow and lymph composition indicated an increased lung microvascular permeability approximately 2 h after infusion of bacteria. Stable prothrombin and antithrombin III levels in lymph contradicted local activation of the coagulation cascade in the lung and systemic activation was not evident until 4 h after bacteria infusion. Lymph thromboxane B2 and 6-keto PGF1 alpha peaked early (1 h). Reduced lymph prekallikrein and kallikrein inhibitors indicated local activation of this system in the lung. Systemic activation of kallikrein could not be demonstrated. Thus, (1) changes in systemic blood may not adequately reflect local events and (2) studies of proteolytic enzymes and other inflammatory mediators in lung may contribute to clarifying the etiology of microvascular injury.

Topics: Animals; Blood Cells; Enzyme Activation; Escherichia coli Infections; Hemodynamics; Kallikreins; Kinins; Lung; Lung Diseases; Lymph; Peptide Hydrolases; Respiration; Sheep; Thromboxane B2

Infusion of the oxidant lipid peroxide tert-butyl hydroperoxide (t-bu-OOH) causes pulmonary vasoconstriction and increases vascular permeability in isolated perfused rabbit lungs. We have previously shown that t-bu-OOH stimulates arachidonic acid metabolism, increasing the synthesis of the cyclooxygenase products. The current experiments were designed to determine the role that cyclooxygenase- and lipoxygenase-derived mediators play in the lung injury caused by t-bu-OOH. In the present experiments, we found that t-bu-OOH not only increased the synthesis of the cyclooxygenase-derived products thromboxane and prostacyclin but also increased the synthesis of the lipoxygenase-derived products leukotrienes B4, C4, D4, and E4. To determine the role that these arachidonic acid metabolites play in the increase in pressure and vascular permeability caused by t-bu-OOH, we studied the effect that inhibitors of arachidonic acid metabolism or a leukotriene receptor blocker had on the pulmonary edema. We compared an uninjured control group with 4 groups of lungs given t-bu-OOH: a t-bu-OOH control group; a group pretreated with the cyclooxygenase inhibitor indomethacin (14 microM); a group pretreated with an analogue of arachidonic acid, 5-, 8-, 11-, 14-eicosatetraynoic acid (ETYA) (100 microM), that inhibits both the cyclooxygenase and lipoxygenase pathways; and a group pretreated with the leukotriene receptor antagonist FPL 55712 (38 microM). To produce lung injury, t-bu-OOH (300 microM) was infused throughout the first minute of 4 successive 10-min periods.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 5,8,11,14-Eicosatetraynoic Acid; 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Chromones; Free Radicals; Indomethacin; Leukotrienes; Lipoxygenase; Lung; Lung Diseases; Male; Organ Size; Oxygen; Peroxides; Prostaglandin-Endoperoxide Synthases; Pulmonary Artery; Rabbits; tert-Butylhydroperoxide; Thromboxane B2

We sought to determine the effect of corticosteroid therapy in a new acute model of oxidant lung injury, thoracic irradiation in awake sheep. Sheep were irradiated with 1,500 rads to the whole chest except for blocking the heart and adjacent ventral lung. Seven experimental sheep were given methylprednisolone (1 g intravenously every 6 h for four doses) and thoracic irradiation; control sheep received only irradiation. In irradiated control sheep, lung lymph flow increased from baseline (7.6 ml/h) to peak at 3 h (13.2), and lung lymph protein clearance increased from 5.1 to 9.7 ml/h. Mean pulmonary artery pressure increased in the irradiated control sheep from 19 to 32.4 cm H2O, whereas the lung lymph thromboxane concentration increased from 0.09 to 6.51 ng/ml at 3 h. Arterial oxygen tension in irradiated control sheep fell gradually from 86 mm Hg at baseline to 65 mm Hg at 8 h. Methylprednisolone administration significantly prevented the increase in lung lymph protein clearance, mean pulmonary artery pressure, and lung lymph thromboxane concentration. Methylprednisolone also prevented the fall in arterial oxygen tension after thoracic irradiation, but did not prevent a further decrease in lymphocytes in blood or lung lymph after radiation. We conclude that corticosteroid therapy prevents most of the acute physiologic changes caused by thoracic irradiation in awake sheep.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Disease; Animals; Blood Cell Count; Blood Gas Analysis; Hemodynamics; Leukocyte Count; Lung; Lung Diseases; Lymph; Methylprednisolone; Proteins; Pulmonary Artery; Radiation Injuries, Experimental; Sheep; Thorax; Thromboxane B2

We studied lung clearance of aerosolized technetium-labeled diethylenetriamine pentaacetic acid (99mTcDTPA), plasma concentrations of 6-keto-PGF1 alpha and thromboxane B2, and pulmonary edema as indices of lung injury in rabbits exposed to cigarette smoke (CSE). Forty-six rabbits were randomly assigned to 4 groups: control sham smoke exposure (SS, N = 9), sham smoke exposure ibuprofen-pretreated (SS-I, N = 10), CSE (N = 9), sham smoke exposure ibuprofen-pretreated (SS-I, N = 10), CSE (N = 9), and CSE ibuprofen-pretreated (CSE-I, N = 19). Ibuprofen (cyclooxygenase eicosanoid inhibitor) was administered as a single daily intramuscular injection (25 mg/kg) for 7 days before the experiment. Cigarette or sham smoke was delivered by syringe in a series of 5, 10, 20, and 30 tidal volume breaths with a 15-min counting period between each subset of breaths to determine 99mTcDTPA biological half-life (T1/2). In the ibuprofen pretreated group, CSE caused significant decreases in 99mTcDTPA T1/2 and dynamic lung compliance. Furthermore, these changes in lung function were accompanied by severe injury to type I alveolar cell epithelium, pulmonary edema, and frequently death of the rabbits. These findings suggest that inhibition of the cyclooxygenase pathway before CSE exacerbates lung injury in rabbits.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Female; Ibuprofen; Lung; Lung Diseases; Male; Nicotiana; Organometallic Compounds; Pentetic Acid; Plants, Toxic; Pulmonary Alveoli; Pulmonary Edema; Rabbits; Smoke; Technetium; Technetium Tc 99m Pentetate; Thromboxane B2; Time Factors

To investigate the acute physiological and structural changes after lung irradiation, the effects of whole-lung irradiation were investigated in fourteen sheep. Ten sheep were prepared with vascular and chronic lung lymph catheters, then a week later were given 1,500 rad whole-lung radiation and monitored for 2 days. Four sheep were given the same dose of radiation and were killed 4 h later for structural studies. Lung lymph flow increased at 3 h after radiation (14.6 +/- 2.1 ml/h) to twice the base-line flow rate (7.5 +/- 1.3), with a high lymph-to-plasma protein concentration. Pulmonary arterial pressure increased twofold from base line (18 +/- 1.6 cmH2O) at 2 h after radiation (33 +/- 3.8). Cardiac output and systemic pressure in the aorta did not change after lung radiation. Arterial O2 tension decreased from 85 +/- 3 to 59 +/- 4 Torr at 1 day after radiation. Lymphocyte counts in both blood and lung lymph decreased to a nadir by 4 h and remained low. Thromboxane B2 concentration in lung lymph increased from base line (0.07 +/- 0.03 ng/ml) to peak at 3 h after radiation (8.2 +/- 3.7 ng/ml). The structural studies showed numerous damaged lymphocytes in the peripheral lung and bronchial associated lymphoid tissue. Quantitative analysis of the number of granulocytes in peripheral lung showed no significant change (base line 6.2 +/- 0.8 granulocytes/100 alveoli, 4 h = 10.3 +/- 2.3). The most striking change involved lung airways. The epithelial lining of the majority of airways from intrapulmonary bronchus to respiratory bronchiolus revealed damage with the appearance of intracellular and intercellular cell fragments and granules. This new large animal model of acute radiation lung injury can be used to monitor physiological, biochemical, and morphological changes after lung radiation. It is relevant to the investigation of diffuse oxidant lung injury as well as to radiobiology per se.

Topics: Animals; Blood Pressure; Cardiac Output; Epithelium; Leukocyte Count; Leukocytes; Lung; Lung Diseases; Lymph; Lymphatic System; Microscopy, Electron; Oxygen; Pulmonary Artery; Radiation Injuries, Experimental; Sheep; Thromboxane B2

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

Arachidonic acid metabolites have biologic properties that can mimic the pulmonary changes produced by hyperoxic exposure, but little information is available regarding their importance in this setting. The role of prostacyclin (PGI2) and thromboxane (Tx) A2 in oxygen-induced lung injury was evaluated by exposing mice to 100% oxygen for up to 4 days and measuring plasma and bronchoalveolar lavage (BAL) fluid concentrations of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), a metabolite of PGI2, and TxB2, a metabolite of TxA2. To determine whether a relationship exists between changes in these arachidonic acid metabolites and the severity of the lung injury, we also measured mortality, BAL protein concentration, BAL angiotensin-converting enzyme (ACE) activity, and plasma lactate dehydrogenase activity, and we examined lung sections by light and electron microscopy. After 3 days of exposure to 100% oxygen, microscopic and biochemical changes consistent with mild lung damage were found, but there was no increase in either plasma or BAL 6-keto-PGF1 alpha concentration. On day 4, severe lung damage was present. and BAL 6-keto-PGF 1 alpha level increased threefold (P less than 0.001). The level of TxB2 in BAL fluid did not change on any day. Twice-daily administration of either a high (5 mg/kg) or a low (1 mg/kg) dose of indomethacin reduced BAL concentrations of 6-keto-PGF1 alpha, and it resulted in increased mortality and higher BAL protein concentration and BAL ACE activity. These data suggest that TxA2 has little if any role in the pathogenesis of oxygen-induced lung injury, whereas prostacyclin may play a protective role.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Arachidonic Acids; Epoprostenol; Indomethacin; Lung; Lung Diseases; Male; Mice; Mice, Inbred BALB C; Oxygen; Proteins; Therapeutic Irrigation; Thromboxane B2

To further study the role of arachidonic acid metabolites in the development of hyperoxic lung injury and the function of PMNs and/or alveolar macrophages in facilitating this role, we exposed adult rabbits to greater than 95% O2 or air for 24, 40, 48, or 65 hours. At the end of each study, bronchoalveolar lavage [BAL] of the left lung was performed, and the right lung was inflated and fixed for light and electron microscopy. PGE2, 6-keto-PGF1 alpha and thromboxane B2 were measured by RIA in arterial and venous plasma at the beginning and end of each study and in BAL fluid obtained at sacrifice. Production of these three PGs by BAL cells placed in cell culture was also measured. Significant hyperoxic lung injury did not develop until 65 hours, as evidenced by significant increase in BAL total protein and percent PMNs, and by morphologic findings. At 40 hours, however, BAL fluid PGE2 and 6-keto-PGF1 alpha increased and BAL cell production of all 3 PGs was significantly increased (p less than .05). In summary, the early PG increases observed in these studies may directly contribute to the development of hyperoxic lung injury or, rather, may be representative of a generalized increase in all arachidonic acid metabolites, including the lipoxygenase pathway. The increase in BAL cell PG production and increased PG concentrations in BAL fluid prior to any increase in BAL PMNs suggest that the AM may be the source of the early arachidonic acid metabolite increase in response to hyperoxia.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Arachidonic Acids; Dinoprostone; Lung; Lung Diseases; Macrophages; Microscopy, Electron; Neutrophils; Oxygen; Prostaglandins; Prostaglandins E; Pulmonary Alveoli; Rabbits; Therapeutic Irrigation; Thromboxane B2

During infusion of thrombin in rats pulmonary arterial pressure rose from 15 +/- 2 to 35 +/- 3 mmHg and mean arterial pressure fell from 120 +/- 6 to 49 +/- 27 mmHg. Plasma thromboxane B2 (TxB2) increased from 0.3 +/- 0.04 to 3.6 +/- 0.5 ng/ml. Ninety minutes later the lung weight and albumin concentration in the lung were increased (2.21 +/- 0.13 g and 22.7 +/- 4.7 mg/g) compared with controls (1.12 +/- 0.14 g and 8.5 +/- 0.9 mg/g). An inhibitor of thromboxane synthetase, Dazoxiben R, reduced the elevated pulmonary arterial pressure and the elevated plasma TxB2 concentration following infusion of thrombin. Ninety minutes after infusion of thrombin, the in vitro synthesis of TxB2 in lung tissue was increased. Dazoxiben and antineutrophil serum reduced this synthesis of TxB2 in vitro. The lung weight (2.18 +/- 0.20 g) and lung albumin concentration (21.4 +/- 3.4 mg/g) was not affected by Dazoxiben. The results indicate that TxA2 is an important mediator of the pressure changes in the early phase after infusion of thrombin and that neutrophils are associated with thromboxane formation in the lung tissue.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Cattle; Fibrinogen; Fibrinolysis; Imidazoles; Indomethacin; Lung; Lung Diseases; Male; Organ Size; Platelet Count; Rats; Rats, Inbred Strains; Serum Albumin; Thrombin; Thromboxane B2; Thromboxane-A Synthase

We tested the effects of OKY-046, a thromboxane synthase inhibitor, on lung injury induced by 2 h of pulmonary air infusion (1.23 ml/min) in the pulmonary artery of unanesthetized sheep with chronic lung lymph fistula so as to assess the role of thromboxane A2 (TxA2) in the lung injury. We measured pulmonary hemodynamic parameters and the lung fluid balance. The concentrations of thromboxane B2 (TxB2) and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) in plasma and lung lymph were determined by radioimmunoassay. Air infusion caused sustained pulmonary hypertension and an increase in pulmonary vascular permeability. The levels of TxB2 and 6-keto-PGF1 alpha in both plasma and lung lymph were significantly elevated during the air infusion. TxB2 concentration in plasma obtained from the left atrium was higher than that from the pulmonary artery at 15 min of air infusion. When sheep were pretreated with OKY-046 (10 mg/kg iv) prior to the air infusion, increases in TxB2 were prevented. The pulmonary arterial pressure, however, increased similarly to that of untreated sheep (1.8 X base line). The increase in lung lymph flow was significantly suppressed during the air infusion. Our data suggest that the pulmonary hypertension observed during air embolism is not caused by TxA2.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arteries; Blood Gas Analysis; Body Fluids; Embolism, Air; Hemodynamics; Hydrogen-Ion Concentration; Leukocyte Count; Lung; Lung Diseases; Methacrylates; Platelet Count; Pulmonary Circulation; Sheep; Thromboxane B2; Thromboxane-A Synthase

Paraquat, a widely used herbicide, causes severe lung damage in humans and laboratory animals. Pulmonary edema is a common initial feature of paraquat toxicity, but its pathophysiology is not well understood. The purpose of this investigation was to determine the acute toxic effect of paraquat (30 mg/kg) on pulmonary transvascular protein and fluid fluxes, histologic features, and prostanoid production, using awake sheep with chronic lung lymph fistulas (n = 6). Lung lymph flow increased significantly 3.5 h after intravenous infusion of paraquat and rose to 2.6 times baseline within 8 h (from 4.4 +/- 0.4 to 11.4 +/- 1.5 ml/h, p less than 0.05). Lymph-plasma protein concentration ratio increased during the same time period (from 0.64 +/- 0.05 to 0.75 +/- 0.04, p less than 0.05). Lung lymph protein clearance also increased at 3.5 h and remained elevated throughout the duration of the experiment. Pulmonary arterial and left atrial pressure were only slightly altered. Plasma and lung lymph thromboxane A2 (as TXB2) concentrations were significantly increased at 30 min and continued so thereafter. Plasma and lung lymph prostacyclin (6-keto-PGF1 alpha) concentrations increased significantly at 3 h and were more than 5 times baseline by 7 h. The time course of the increase in 6-keto-PGF1 alpha concentrations seemed similar to that of lung lymph flow. The high flow of protein-rich lymph strongly suggested an increase in pulmonary vascular permeability, which may indicate pulmonary endothelial damage. Histologic studies of the lungs revealed only minor changes in perivascular cuffing, minimal alveolar hemorrhage, and slight neutrophilic alveolar wall infiltration.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Cell Count; Body Fluids; Fistula; Hemodynamics; Lung; Lung Diseases; Lymph; Lymphatic Diseases; Paraquat; Prostaglandins; Sheep; Thromboxane B2; Time Factors; Wakefulness

Hyperoxia and infused granulocytes act synergistically in producing a nonhydrostatic high-permeability lung edema in the isolated perfused rabbit lung within 4 h, which is substantially greater than that seen with hyperoxia alone. We hypothesized that the interaction between hyperoxia and granulocytes was principally due to a direct effect of hyperoxia on the lung itself. Isolated perfused rabbit lungs that were preexposed to 2 h of hyperoxia (95% O2-5% CO2) prior to the infusion of unstimulated granulocytes (under normoxic conditions) developed significant nonhydrostatic lung edema (P = 0.008) within 2 h when compared with lungs that were preexposed to normoxia (15% O2-5% CO2) prior to granulocyte perfusion. The edema in the hyperoxic-preexposed lungs was accompanied by significant increases in bronchoalveolar lavage (BAL) protein, BAL granulocytes, BAL thromboxane and prostacyclin levels, perfusate chemotactic activity, and lung lipid peroxidation. These findings suggest that the synergistic interaction between hyperoxia and granulocytes in producing acute lung injury involves a primary effect of hyperoxia on the lung itself.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Biomechanical Phenomena; Bronchi; Cell Count; Chemotaxis; Granulocytes; In Vitro Techniques; Lipid Peroxides; Lung; Lung Diseases; Oxygen; Pulmonary Alveoli; Pulmonary Edema; Rabbits; Therapeutic Irrigation; Thromboxane B2

Pretreatment with estradiol (20 mg IM) attenuated vasoreactivity to decreases in inspired PIO2, lowered baseline resistance measured under conditions of maximal vasodilation (PIO2 = 0 mm Hg), and appeared to increase prostaglandin release in isolated, blood-perfused lungs of juvenile female sheep. Indomethacin (40 micrograms/ml) inhibited prostaglandin release and restored hypoxic vasoreactivity in estrogen-treated lungs, but did not alter the estrogen-induced decrease in baseline resistance. These results suggest that estradiol enhanced the production of prostaglandins which secondarily attenuated hypoxic vasoreactivity. The estradiol-induced decrease in baseline resistance, however, must have been mediated by some other mechanism.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Estradiol; Female; Hypoxia; Lung Diseases; Muscle, Smooth, Vascular; Oxygen; Respiration; Sheep; Thromboxane B2; Vasoconstriction

Our purpose was to determine whether peripheral soft tissues produce and release prostanoids in response to local sepsis, and whether this mediator release can produce pulmonary dysfunction. Escherichia coli endotoxin (2 micrograms/kg in 100 mL of saline) was injected below the hide of the flank in seven unanesthetized sheep. In three additional sheep, ibuprofen (12.5 mg/kg of body weight) was injected with the endotoxin. Thromboxane B2 and 6-keto-PGF1 alpha (prostacyclin) levels were measured in tissue lymph draining the flank, lung lymph, pulmonary artery (Ppa), and aortic plasma. One hour after endotoxin administration, mean PaO2 decreased from 90 to 74 mm Hg and Ppa increased from 22 to 35 mm Hg. Lung lymph flow (QL) increased only 50% with QL being protein poor. No increase in lung or peripheral soft-tissue vascular permeability was noted. Tissue lymph (TxB2) increased from 220 +/- 114 to greater than 10,000 pg/mL with levels in Ppa plasma increasing from 300 +/- 128 to 595 +/- 124 pg/mL and aortic plasma from 270 +/- 141 to 410 +/- 104 pg/mL. Lung lymph TxB2 paralleled aortic values. Peak levels of 6-keto-PGF1 alpha in systemic lymph exceeded 2,000 pg/mL while levels in lung lymph remained relatively constant. The pulmonary injury and the increase in TxB2 was prevented by ibuprofen. We conclude that the response of soft tissue to local endotoxin is to release thromboxane in quantities sufficient to raise plasma levels and to produce hypoxia and pulmonary hypertension. The lung dysfunction is not produced by an increase in lung water or vascular permeability.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Endotoxins; Escherichia coli; Hypertension, Pulmonary; Hypoxia; Ibuprofen; Lung; Lung Diseases; Lymph; Lymphatic System; Muscles; Sheep; Thromboxane B2

Prostaglandins are known to be secreted into body fluids. Arachidonic acid cyclooxygenase metabolites (AACM), including prostaglandin E (PGE), prostacyclin, and thromboxane, were measured in the bronchoalveolar lavage (BAL) fluid in 11 patients with active pulmonary sarcoidosis and 7 healthy volunteers. Using a quantitative technique, we found no difference in the amount of PGE per milliliter lung fluid between the sarcoid group (1,950 +/- 1,507.4 pg/ml lung fluid, mean +/- SD) and the control group (2,112 +/- 932.3 pg/ml lung fluid). In patients with sarcoidosis, there was a positive correlation between the number of lymphocytes in the BAL fluid and the amount of PGE and prostacyclin per milliliters of lung fluid (r = 0.71 and r = 0.81, p less than 0.01), but not thromboxane.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Body Fluids; Epoprostenol; Female; Humans; Lung Diseases; Male; Middle Aged; Prostaglandins E; Sarcoidosis; Therapeutic Irrigation; Thromboxane B2; Thromboxanes

We studied the effects of a burn injury on the response of the lung to endotoxin. Seventeen unanesthetized sheep with lung lymph fistulas were studied. Eight were given Escherichia coli endotoxin (1.5 micrograms/kg) alone and nine were given the same dose 72 hours after a 25% total body surface burn injury. At this time after burn, all physiologic parameters were at baseline levels. A characteristic two-phase lung injury was seen after administration of endotoxin with an initial hypertension phase, characterized by pulmonary artery hypertension, and a second or permeability phase, characterized by an increase in protein-rich lymph flow. all eight animals that underwent only endotoxin administration survived, whereas four of the nine burned animals died during the permeability phase in pulmonary edema. Major physiologic differences between the groups were noted during the permeability phase, including a more severe hypoxia, pulmonary hypertension, and increased postburn lymph flow. Major biochemical changes included significant increases in lymph thromboxane, thromboxane B2, and beta-glucuronidase activity in the burn group. We conclude that the lung is more sensitive to endotoxin after burn, probably as a result of an increased release of products of arachidonic acid metabolism and products of leukocyte activation caused by the body burn.

Topics: Animals; Burns; Endotoxins; Escherichia coli Infections; Fistula; Glucuronidase; Hypertension, Pulmonary; Hypoxia; Lung Diseases; Lymph; Sheep; Thromboxane B2; Thromboxanes

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Burns; Fistula; Hemodynamics; Lung Diseases; Lymphatic Diseases; Lymphatic System; Prostaglandins; Sheep; Thromboxane A2; Thromboxane B2; Thromboxanes

Topics: Animals; Arachidonic Acids; Biological Transport; Epoprostenol; Humans; Hydroxyprostaglandin Dehydrogenases; Hypoxia; Linolenic Acids; Lung; Lung Diseases; Prostaglandin Endoperoxides; Prostaglandin Endoperoxides, Synthetic; Prostaglandins; Prostaglandins E; Prostaglandins F; Thromboxane A2; Thromboxane B2; Vasomotor System