thromboxane-b2 and Lung-Diseases--Obstructive

Patients with Down syndrome (DS) and a left-to-right shunt often develop early severe pulmonary hypertension (PH) and pulmonary vascular obstructive disease (PVOD); the pathophysiological mechanisms underlying the development of these complications are yet to be determined. To investigate the mechanisms, we evaluated the biosynthesis of thromboxane (TX) A(2) and prostacyclin (PGI(2)) in four groups of infants, cross-classified as shown below, by measuring the urinary excretion levels of 11-dehydro-TXB(2) and 2,3-dinor-6-keto-PGF(1alpha): DS infants with a left-to-right shunt and PH (D-PH, n = 18), DS infants without congenital heart defect (D-C, n = 8), non-DS infants with a left-to-right shunt and PH (ND-PH, n = 12), and non-DS infants without congenital heart defect (ND-C, n = 22). The urinary excretion ratios of 11-dehydro-TXB(2) to 2,3-dinor-6-keto-PGF(1alpha) in the D-PH, D-C, ND-PH, and ND-C groups were 7.69, 4.71, 2.10, and 2.27, respectively. The ratio of 11-dehydro-TXB(2) to 2,3-dinor-6-keto-PGF(1alpha) was higher in the presence of DS (P < 0.001), independently of the presence of PH (P = 0.297). The predominant biosynthesis of TXA(2) over PGI(2), leading to vasoconstriction, was observed in DS infants, irrespective of the presence/absence of PH. This imbalance in the biosynthesis of vasoactive eicosanoids may account for the rapid progression of PVOD in DS infants with a left-to-right shunt.

Topics: 6-Ketoprostaglandin F1 alpha; Child, Preschool; Cross-Sectional Studies; Down Syndrome; Epoprostenol; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Infant; Lung Diseases, Obstructive; Male; Prognosis; Pulmonary Heart Disease; Radioimmunoassay; Thromboxane A2; Thromboxane B2

Oxidative stress has been suggested as a potential mechanism in the pathogenesis of chronic obstructive pulmonary disease (COPD). It has been difficult to address this hypothesis because of the limitations of conventional indices of lipid peroxidation in vivo. F2-isoprostanes (iPs) are prostaglandin isomers formed by free radical dependent peroxidation of arachidonic acid. Urinary iPF2alpha-III is a relatively abundant iPs produced in humans. In the present study, we investigated whether COPD is associated with enhanced oxidative stress by measuring urinary levels of this compound. Urinary excretion of iPF2alpha-III was determined in 38 patients with COPD and 30 sex- and age-matched healthy control subjects. Levels of iPF2alpha-III were significantly higher in patients with COPD (median, 84 pmol/ mmol creatinine; range, 38 to 321) than in healthy controls (median, 35.5 pmol/mmol creatinine; range, 15 to 65) (p < 0.0001). This elevation was independent of age, sex, smoking history, or duration of the disease. An inverse relationship was observed with the level of PaO2 (r = -0.38, p = 0. 019). Aspirin treatment failed to decrease urinary levels of iPF2alpha-III (102 +/- 8 versus 99.2 +/- 7.3 pmol/ mmol creatinine), whereas 11-dehydro TxB2 was significantly reduced (695 +/- 74 versus 95 +/- 10 pmol/mmol creatinine) (p < 0.0001). Elevated levels of iPF2alpha-III (median, 125 pmol/mmol creatinine; range, 110 to 170) in five patients with COPD declined (median, 90 pmol/mmol creatinine; range, 70 to 110) (p < 0.001) as an acute exacerbation in their clinical condition resolved. Increased urinary iPF2alpha-III is consistent with the hypothesis that oxidative stress occurs in COPD. This provides a basis for dose finding and evaluation of antioxidant therapy in the treatment of this disease.

Topics: Age Factors; Aged; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Arachidonic Acids; Aspirin; Case-Control Studies; Creatinine; Cross-Sectional Studies; Cyclooxygenase Inhibitors; Dinoprost; Female; Follow-Up Studies; Free Radicals; Humans; Lipid Peroxidation; Lung Diseases, Obstructive; Male; Middle Aged; Oxidative Stress; Oxygen; Sex Factors; Smoking; Thromboxane B2; Time Factors

Thrombotic complications of pulmonary circulation occur in patients with chronic obstructive pulmonary disease (COPD). In the present study, we sought to evaluate in vivo platelet activation through the measurement of 11/dehydro-thromboxane (Tx) B2 TxA2 major metabolite in the urine, in 29 patients with COPD, compared with 29 sex- and age-matched healthy subjects. The urinary excretion of 11-dehydro-TxB2 was significantly higher in patients with COPD than in control subjects: median (range), 753 (277-4,409) and 275 (129-612) pg/mg creatinine, respectively; p < 0.0001). Moreover, 11-dehydro-TxB2 excretion was inversely related with arterial oxygen tension (rho = -0.46; p = 0.0145). In five of the 29 patients a short-term therapeutic course with oxygen supplementation induced a significant decrease of urinary 11-dehydro-TxB2 excretion: median range, 941 (452-2,640) to 445 (166-1,560) pg/mg creatinine. Moreover, selective inhibition of platelet cyclooxygenase activity by low-dose aspirin was associated with more than 90% inhibition of thromboxane metabolite excretion, demonstrating its being of platelet origin. Plasma levels of prothrombin fragment F1 + 2 were higher in patients than in control subjects (2.6 +/- 1.5 versus 0.9 +/- 0.4 nM, p = 0.0001). No relation between 11-dehydro-TxB2 excretion and plasma F1 + 2 levels was found. We conclude that platelet TxA2 biosynthesis is enhanced in patients with COPD and may be influenced by arterial oxygen tension changes.

Topics: Aged; Aspirin; Blood Platelets; Creatinine; Cyclooxygenase Inhibitors; Female; Humans; Lung Diseases, Obstructive; Male; Middle Aged; Oxygen Inhalation Therapy; Peptide Fragments; Platelet Activation; Prothrombin; Thromboxane B2; Thromboxanes

One of the main causes of pulmonary hypertension in chronic obstructive pulmonary disease (COPD) is considered to be hypoxic pulmonary vasoconstriction, which may partly be mediated by angiotensin II. Ten patients with COPD were administered with captopril (25mg sublingually). Hemodynamics blood gases renin activity inducing angiotensin II and angiotension converting enzyme (ACE) and TXB2/6-ketone-PGF1 alpha were studied through Swan-Ganz catheter before and after administration of the drug. Captopril reduced mean pulmonary artery pressure and pulmonary vascular resistance by 22% and 30% respectively. Levels of ACE angiotension II and TXB2/6-ketone-PGF1 alpha were reduced. There was no significant change in blood gases. Heart rate and systemic arterial pressure did not change significantly. These results suggest that captopril is of value in reducing pulmonary artery pressure and pulmonary vascular resistance.

Topics: Angiotensin II; Captopril; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Lung Diseases, Obstructive; Male; Middle Aged; Peptidyl-Dipeptidase A; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Epoprostenol; Humans; Hypertension, Pulmonary; Lung Diseases, Obstructive; Thromboxane B2

Fourteen experimental indices were determined in 26 patients of chronic cor pulmonale due to COPD and in 32 healthy nonsmokers. It was found that elastase, TXB2, ATII, 5-HT, IgE, CTC and Ach were significantly higher whereas 6-keto -PGF1 alpha, C4 and cAMP lower in the blood from the patients. The roles played by these factors in the development of chronic cor pulmonale were discussed.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Angiotensin II; Antigen-Antibody Complex; Complement C4; Female; Humans; Lung Diseases, Obstructive; Male; Middle Aged; Pancreatic Elastase; Pulmonary Heart Disease; Serotonin; Thromboxane B2

Arachidonate metabolites were measured in bronchoalveolar lavage fluid (BALF) from horses with (N = 4) and without (N = 7) chronic obstructive pulmonary disease (COPD). Prostaglandin (PG) D2, leukotriene (LT) B4 and LTC4 were present in highest concentrations in BALF from clinically normal horses. Concentrations of PGE2 and PGF were significantly higher in BALF from horses with COPD than in BALF from normal horses, but no differences were detected in thromboxane B2, 6-keto-PGF1 alpha, PGD2, LTB4 or LTC4.

Topics: Animals; Arachidonic Acids; Bronchoalveolar Lavage Fluid; Horse Diseases; Horses; Leukocyte Count; Leukotrienes; Lung Diseases, Obstructive; Neutrophils; Prostaglandins; Thromboxane B2

Constriction of small pulmonary arteries and arterioles and focal vascular injury are features of pulmonary hypertension. Because thromboxane A2 is both a vasoconstrictor and a potent stimulus for platelet aggregation, it may be an important mediator of pulmonary hypertension. Its effects are antagonized by prostacyclin, which is released by vascular endothelial cells. We tested the hypothesis that there may be an imbalance between the release of thromboxane A2 and prostacyclin in pulmonary hypertension, reflecting platelet activation and an abnormal response of the pulmonary vascular endothelium.. We used radioimmunoassays to measure the 24-hour urinary excretion of two stable metabolites of thromboxane A2 and a metabolite of prostacyclin in 20 patients with primary pulmonary hypertension, 14 with secondary pulmonary hypertension, 9 with severe chronic obstructive pulmonary disease (COPD) but no clinical evidence of pulmonary hypertension, and 23 normal controls.. The 24-hour excretion of 11-dehydro-thromboxane B2 (a stable metabolite of thromboxane A2) was increased in patients with primary pulmonary hypertension and patients with secondary pulmonary hypertension, as compared with normal controls (3224 +/- 482, 5392 +/- 1640, and 1145 +/- 221 pg per milligram of creatinine, respectively; P less than 0.05), whereas the 24-hour excretion of 2,3-dinor-6-keto-prostaglandin F1 alpha (a stable metabolite of prostacyclin) was decreased (369 +/- 106, 304 +/- 76, and 644 +/- 124 pg per milligram of creatinine, respectively; P less than 0.05). The rate of excretion of all metabolites in the patients with COPD but no clinical evidence of pulmonary hypertension was similar to that in the normal controls.. An increase in the release of the vasoconstrictor thromboxane A2, suggesting the activation of platelets, occurs in both the primary and secondary forms of pulmonary hypertension. By contrast, the release of prostacyclin is depressed in these patients. Whether the imbalance in the release of these mediators is a cause or a result of pulmonary hypertension is unknown, but it may play a part in the development and maintenance of both forms of the disorder.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Lung Diseases, Obstructive; Male; Radioimmunoassay; Thromboxane A2; Thromboxane B2

We measured the pulmonary arterial pressure and the level of Thromboxane A2 (TXA2), and Prostacyclin (PGI2) in 30 stable COPD patients and the level of TXA2 and PGI2 in 10 normal subjects so as to investigate the changes of TXA2 and PGI2 in COPD patients with pulmonary hypertension. The results showed that the level of TXA2 increased significantly in COPD patients with dominant and latent pulmonary hypertension when compared with that in normal subjects (P less than 0.001, less than 0.01), and the level of TXA2 in COPD patients with dominant pulmonary hypertension was also higher than that in COPD patients with latent pulmonary hypertension (P less than 0.02), but there was no difference in the level of PGI2 among normal subjects and COPD patients with or without pulmonary hypertension. This indicates that TXA2 plays an important role in causing pulmonary hypertension in COPD patients.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Female; Humans; Hypertension, Pulmonary; Lung Diseases, Obstructive; Male; Middle Aged; Thromboxane B2

The present study was designed to assess the occurrence of small airways disease (SAD) in non-smoking sarcoidosis patients by pulmonary function measurement; and to investigate the possible mechanisms of SAD by measuring the in vitro production of arachidonic acid metabolites (PGE2 and LTB4) by peripheral blood mononucleocytes from sarcoidosis patients. SAD did in fact occur in 15 of the 32 sarcoid patients studied. The increase in LTB4 and decrease in PGE2 observed in SAD patients could imply a causative role for these arachidonic acid metabolites in SAD.

Topics: Arachidonic Acids; Dinoprostone; Forced Expiratory Flow Rates; Humans; Lung Diseases, Obstructive; Monocytes; Prostaglandins E; Sarcoidosis; Thromboxane B2

Topics: beta-Thromboglobulin; Dipyridamole; Female; Humans; Hypertension, Pulmonary; Lung Diseases, Obstructive; Male; Middle Aged; Platelet Aggregation; Thromboxane A2; Thromboxane B2; Thromboxanes

Topics: 6-Ketoprostaglandin F1 alpha; Aspirin; Blood Platelets; Female; Humans; Lung Diseases, Obstructive; Male; Middle Aged; Physical Exertion; Platelet Aggregation; Smoking; Thromboxane B2

A modification of the original thiobarbituric acid (TBA) method for malondialdehyde (MDA) assay is described. The improvement is essentially based on the clearing effect of KClO4 that makes measurements more simple and sensitive. MDA values obtained in normal subjects were almost eightfold higher than those obtainable with Stuart's original assay method, so that after cyclooxygenase block it was possible to assess platelet regeneration time even in thrombocytopenic patients with at least 60,000 platelets/microliter and MDA production early after aspirin intake. To challenge this modification, platelet regeneration time was studied in normal subjects as well as in thrombocytopenic patients, either hypoplastic or idiopathic, and in hypoxemic patients with increased platelet consumption. The initial disappearance kinetics of platelet MDA and thromboxane B2 production after aspirin suggests that TBA-reactive material is synthesized through the lipoxygenase pathway. The reversible block determined by acetylsalicylic acid and salicylate on hydroperoxi-eicosatetraenoic acid peroxidase can be responsible for the initial increase of this TBA-reactive material.

Topics: Adult; Aged; Aspirin; Blood Platelets; Cell Survival; Cyclooxygenase Inhibitors; Humans; Lung Diseases, Obstructive; Malonates; Malondialdehyde; Middle Aged; Prostaglandin-Endoperoxide Synthases; Thrombocytopenia; Thromboxane B2