thromboxane-a2 and Respiratory-Insufficiency

Severe respiratory failure was made on twenty dogs with intratracheal administration of the linoleic acid to study the effectiveness of ECMO. The dogs were divided into four groups: First group (GI); respiratory failure, second group (G II); respiratory failure with pumpless A-V bypass, third group (G III); respiratory failure with V-A bypass, fourth group (G IV); respiratory failure with V-A bypass and administration of OP-41483 (PGI2 derivative). The effectiveness of ECMO was studied with different concentration of Prostaglandin I2 (PGI2) and Thromboxane A2 (TxA2). This experiment showed significant prolongation of mean survival time in dogs of respiratory failure treated with the use of ECMO. In GI and G II, TxB2, metabolic product of TxA2, increased and the ratio of 6-ketoPGF1 alpha, metabolic product of PGI2, versus TxB2, decreased progressively. In G III and G IV, the TxB2 was increased during the first two or three hours after intratracheal administration of linoleic acid and then reached a steady level. In G3, the ratio of 6-ketoPGF1 alpha versus TxB2 was approximately 0.5 after the linoleic acid administration. However, in the case of G IV with combined application of PGI2 derivative, the ratio decreased to 0.59 +/- 0.08 in one or two hours after the administration, then increased progressively and reached a value of 1.04 +/- 0.27 in eight hours after the linoleic acid administration. In conclusion, this study demonstrates that therapeutical effects of ECMO against respiratory failure could be elevated by using PGI2 derivative.

Topics: Animals; Blood Gas Analysis; Dogs; Epoprostenol; Extracorporeal Membrane Oxygenation; Hemodynamics; Lung; Respiratory Insufficiency; Thromboxane A2

Escherichia coli hemolysin has been implicated as a pathogenicity factor in extraintestinal E. coli infections including sepsis. In the present study the effects of intravascular administration of hemolysin were investigated in isolated blood-free perfused rabbit lungs. Low concentrations of the toxin in the perfusate (0.05-5 hemolytic units/ml, corresponding to approximately 5-500 ng/ml), caused a dose- and time-dependent release of potassium, thromboxane A2, and prostaglandin I2, but not of lactate dehydrogenase, into the recirculating medium, as well as a dose-dependent liberation of the prostanoids into the bronchoalveolar space. These events were paralleled by a dose-dependent pulmonary hypertension, and studies with different inhibitors collectively indicated that the vasoconstrictor response was mediated predominantly by pulmonary thromboxane generation. In addition, E. coli hemolysin elicited a protracted, dose-dependent increase in the lung capillary filtration coefficient, which was independent of the prostanoid-mediated pressor response and resulted in severe pulmonary edema formation. We conclude that E. coli hemolysin can elicit thromboxane-mediated pulmonary hypertension combined with severe vascular leakage in isolated lungs in the absence of circulating inflammatory cells and humoral mediator systems, mimicking the key events in the development of acute respiratory failure in states of septicemia.

Topics: Animals; Arachidonic Acids; Calcium; Cyclooxygenase Inhibitors; Epoprostenol; Escherichia coli; Escherichia coli Infections; Hemolysin Proteins; Hypertension, Pulmonary; In Vitro Techniques; Lung; Organ Size; Potassium; Rabbits; Respiratory Insufficiency; Thromboxane A2

Topics: Adult; Aspirin; Dinoprost; Female; Humans; Middle Aged; Prostaglandins F; Pulmonary Alveoli; Respiration, Artificial; Respiratory Insufficiency; Thromboxane A2

Ischemia stimulates thromboxane (Tx) synthesis. This study tests the hypothesis that the cardiopulmonary dysfunction that may follow aortic declamping is related to Tx. Anesthetized dogs (N = 15) were subjected to 4 hours of infrarenal aortic cross-clamping. In untreated control animals (N = 7), plasma levels of TxB2 rose from 654 +/- 74 pg/mL to 1238 +/- 585 pg/mL at 5 min (p less than 0.05), and to 3174 +/- 912 pg/mL 3 hours after declamping (p less than 0.05). Mean pulmonary artery pressure (MPAP) rose 5 min after declamping from 13 +/- 2 mmHg to 21 +/- 2 mmHg (p less than 0.05). Cardiac Index (CI) declined during ischemia from 181 +/- 30 mL/kg.min to 128 +/- 16 mL/min.kg (p less than 0.05), and to 80 +/- 8 mL/min.kg after 4 hours of reperfusion (p less than 0.05). Platelet counts declined but platelets labeled with In 111 did not accumulate in the lungs, whereas quantitative counts of polymorphonuclear leukocytes (PMN) in the lungs 4 hours after declamping yielded 213 +/- 33 PMN/25 high power fields (HPF) in dependent areas of the lung and 153 +/- 26 PMN/25 HPF in nondependent areas. The wet/dry weight ratio of the lungs was not elevated, although foci of proteinaceous exudate and PMNs in alveoli were noted. Another group of dogs (N = 8) were pretreated by random choice with the Tx synthase inhibitor OKY-046 2 mg/kg IV every 2 hours, which led to: lower TxB2 levels at baseline 95 +/- 35 pg/mL (p less than 0.05), 5 min after ischemia 140 +/- 93 pg/mL and after 3 hours of reperfusion 122 +/- 36 (p less than 0.05); lower MPAP, 16 +/- 2 mmHg (p less than 0.05); higher CI throughout (p less than 0.05); normal histology and reduced pulmonary PMN sequestration both in dependent 127 +/- 15 PMN/25 HPF and nondependent areas of the lungs 95 +/- 11 PMN/25 HPF (p less than 0.05). In animals undergoing sham ischemia (N = 3), levels of TxB2 and cardiopulmonary function remained unchanged from baseline. There were 150 PMN/25 HPF in dependent and 85 PMN/25 HPF in nondependent lung areas. The results indicate that ischemia-generated Tx mediates a rise in MPAP, a fall in CI, and PMN entrapment in the lungs.

Topics: Animals; Blood Pressure; Cardiac Output; Dogs; Female; Hypertension, Pulmonary; Ischemia; Leg; Leukocyte Count; Lung; Methacrylates; Neutrophils; Platelet Count; Respiratory Insufficiency; Thromboxane A2; Thromboxane B2; Time Factors

Acute respiratory failure (ARF) with permeability edema and increased physiologic shunting (QS/QT) occurs after complement activation. Leukocytes aggregate, become entrapped in the lungs, and release vasotoxic agents. This study of 31 sheep infused with zymosan-activated plasma (ZAP) tests the hypothesis tha thromboxane (Tx) A2, a proaggregator and bronchoconstrictor, is an intermediate in complement-induced ARF. Group I animals (n = 11) were untreated controls. An imidazole infusion, 25 mg/kg . hr was started 1 hour before a ZAP infusion in group II (n = 10). Prostacyclin (PGi2) was given to group III sheep (n = 10) in a dose of 100 ng/kg . min 3- minutes before the ZAP infusion. Within 5 minutes ZAP led to a decrease in the leukocyte count to 2900/mm3 (P less than 0.001), a rise in plasma TxB2 concentration (the stable degradation product of TxA2) from 14 to 246 pg/ml (P less than 0.001), a rise in lymph TxB2 from 24 to 609 pg/ml (P less than 0.001), a rise in QS/QT from 13% to 31% (P less than 0.01), and a rise in mean pulmonary arterial pressure from 17 to 43 mm Hg. Both imidazole and PGI2 prevented the increase in TxB2 and QS/QT and limited the increases in MPAP to 25 and 30 mm Hg, respectively--values below those of untreated controls (P less than 0.05). Imidazole, but not PGI2, prevented the increase in lymph flow, which in controls increased from 2.8 +/- 8.5 ml/30 min (P less than 0.01), and lymph albumin clearance, which increased from 2.2 to 6.0 ml/30 min (P less than 0.01). The high lymph concentrations of TxA2 suggest a pulmonary site of production, and its bronchoconstrictive action may account for the increase in QS/QT. However, TxA2 is only partially responsible for the pulmonary hypertension and is apparently unrelated to changes in permeability. The protective action of infused imidazole against increased permeability appears to be independent of its inhibition of Tx synthetase.

Topics: Animals; Blood Platelets; Complement Activation; Epoprostenol; Imidazoles; Leukocyte Count; Lung; Lymph; Platelet Aggregation; Pulmonary Edema; Respiratory Insufficiency; Thromboxane A2; Zymosan

Topics: Acute Disease; Animals; Dogs; Prostaglandins F; Respiratory Insufficiency; Thromboxane A2; Thromboxanes