6-ketoprostaglandin-f1-alpha and Bronchial-Hyperreactivity

We investigated the effect of thromboxane (TX) synthetase inhibitor, OKY-046, on bronchial hypersensitivity in 16 asthmatics by a double-blind, placebo-controlled, crossover trial. Bronchial sensitivity to methacholine was measured by Astograph. Blood samples were taken to measure plasma levels of TX metabolites. No significant differences of forced expiratory volume in 1 sec (FEV1), bronchial sensitivity, or bronchial reactivity were observed after OKY-046 administration, compared to baseline or after placebo. However, responders showed a significant decrease in the plasma TXB2/6-keto-PGF1alpha ratio as compared to nonresponders. Our data failed to confirm an inhibitory effect of OKY-046 on bronchial hypersensitivity, but suggested the importance of its therapeutic dose monitoring.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Asthma; Bronchial Hyperreactivity; Double-Blind Method; Enzyme Inhibitors; Female; Forced Expiratory Volume; Humans; Male; Methacrylates; Placebos; Spirometry; Thromboxane B2; Thromboxane-A Synthase

Both smoking and asthma are associated with inflammatory changes in the lung, which may be suppressed with the help of exogenous anti-inflammatory drugs or by the endogenous defense system. Lipocortin-1 (LC-1; annexin-1) is an anti-inflammatory protein present in respiratory tract secretions. We report an inverse correlation between extracellular LC-1 concentration and the bronchoconstrictor prostaglandin (PG) D2 [n = 15, Spearman rank correlation coefficient (rS) = -0.597, P < 0.05] in bronchoalveolar lavage fluid (BALF) from allergic asthmatic patients, together with positive correlations between extracellular LC-1 per milliliter BALF and the prostacyclin (PGI2) metabolite 6-keto-PGF1 alpha (n = 15, rS = 0.480, P < 0.05) and between LC-1 per milliliter BALF and concentration of histamine causing a 20% decrease in forced expired volume in 1 s (n = 15, rS = 0.720, P < 0.01) in these subjects. We found no significant difference between the LC-1 concentration in BALF from nonsmoking asthmatic patients who were receiving inhaled glucocorticoid therapy (2 x 100 micrograms beclomethasone 4 times/day for 2.5 yr; median 186 ng LC-1/mg albumin; n = 6) and those who were not (median 126 ng LC-1/mg albumin; n = 12), perhaps because inhaled drugs deposit predominantly in central airways, which are poorly represented in bronchoalveolar lavage. Both asthmatic and healthy volunteers who smoked had higher levels of LC-1 in their BALF than did their nonsmoking counterparts (e.g., asthmatic smokers, median 317 ng LC-1/mg albumin, n = 10; asthmatic nonsmokers, median 162 ng LC-1/mg albumin, n = 18; P < 0.05), perhaps because smokers' lungs contain more alveolar macrophages, cells that release LC-1. We observed a positive correlation between BALF LC-1 and bronchoalveolar lavage cell number (n = 16, rS = 0.821, P < 0.001). Increased extracellular LC-1 may be part of a protective response of the lung to inflammatory insult. Regulation of prostanoid levels might be one mechanism by which LC-1 suppresses inflammation.

Topics: 6-Ketoprostaglandin F1 alpha; Administration, Inhalation; Adult; Annexin A1; Anti-Inflammatory Agents; Asthma; Beclomethasone; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Eicosanoids; Female; Glucocorticoids; Histamine; Humans; Male; Middle Aged; Pulmonary Alveoli; Respiratory Function Tests; Smoking

This study investigated the capacity of conjugated linoleic acids (CLA) to reduce ex vivo antigen-induced release of eicosanoids in a type I hypersensitivity model. Guinea pigs were fed a diet containing 0.25% safflower oil (control) or 0.25% CLA [43% trans (t)10, cis (c)12; 41% c9, t11/t9, c11 18:2] for 2 wk before and during sensitization to ovalbumin (OVA). Lungs, tracheas, and bladders were incubated in physiological saline solution (PSS) for 1 h (basal mediator release) and challenged with OVA (0.01 g/l PSS) for 1 h (mediator release in response to antigen). Eicosanoids were quantified by HPLC/tandem mass spectrometry or enzyme immunoassay. CLA feeding resulted in no change in basal release but decreased eicosanoid release from sensitized tissues in response to antigen challenge in the following manner: thromboxane B(2), 6-keto-prostaglandin (PG)F(1alpha), PGF(2alpha), PGD(2), PGE(2) by 57-75% in lung, 45-65% in trachea, and 38-60% in bladder; and leukotriene C(4)/D(4)/E(4) by 87, 90, and 50% in lung, trachea, and bladder, respectively. These data indicate that feeding CLA reduces lipid-derived inflammatory mediators produced by this type I hypersensitivity model.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blotting, Western; Bronchial Hyperreactivity; Cyclooxygenase 2; Dinoprost; Dinoprostone; Eicosanoids; Female; Guinea Pigs; Hypersensitivity, Immediate; Isoenzymes; Linoleic Acid; Ovalbumin; Prostaglandin D2; Prostaglandin-Endoperoxide Synthases; Trachea; Urinary Bladder

Lipopolysaccharide (LPS) and interleukin (IL)-1beta have been reported to induce airway hyperresponsiveness in several animal models. This study investigated the effect of LPS or IL-1beta on bradykinin-induced human isolated bronchi contraction. LPS (100 ng x mL(-1) for 3-6 h) and IL-1beta (3x10(-10) and 3x10(-9) M for 20 min to 3 h) time-dependently potentiated bradykinin-induced contraction. This contraction was abolished, as in control experiments, by indomethacin (10(-6) M) or by the thromboxane (Tx) receptor antagonist GR 32191 but not by the cyclo-oxygenase-2 inhibitor, CGP28238. In contrast, the Tx mimetic U46619-induced contraction of human bronchi was not enhanced IL-1beta pretreatment. In the presence of GR 32191 (10(-6) M), bradykinin induced a prostanoid dependent relaxation that was not significantly modified by IL-1beta pretreatment. Determination of prostanoids in the organ bath fluid showed that bradykinin induced TxB2, the stable metabolite of TxA2, and 6-keto prostaglandin F1alpha, the stable metabolite of PGI2, release. Only TxA2 release was potentiated by IL-1beta. Taken together our results suggest that interleukin-1beta (1-3 h)-induced potentiation of the effect of bradykinin is linked to an increased activity of thromboxane synthase and, in turn, to increased thromboxane synthesis.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; 6-Ketoprostaglandin F1 alpha; Aged; Biphenyl Compounds; Bradykinin; Bronchi; Bronchial Hyperreactivity; Bronchoconstriction; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Heptanoic Acids; Humans; In Vitro Techniques; Indomethacin; Interleukin-1; Lipopolysaccharides; Middle Aged; Receptors, Thromboxane; Thromboxanes

1. IgG1-mediated anaphylactic bronchoconstriction was elicited by intravenous administration of antigen to guinea-pig 2 days after passive sensitization with IgG1-rich serum, and this response was not affected by heating the serum (at 56 degrees C, for 4 h). IgE-mediated bronchoconstriction, provoked 14 days after passive sensitization with IgE-rich serum, was completely abolished by the heating of the serum. 2. S-1452 (10 mg kg-1, p.o.), a selective thromboxane (Tx) A2 antagonist, significantly but incompletely suppressed the IgG1-mediated bronchoconstriction, but did not affect the IgE-mediated one, while diphenhydramine (5 mg kg-1, i.v.), a histamine antagonist, almost completely inhibited both IgG1- and IgE-mediated bronchoconstriction. 3. Pretreatment with propranolol (1 mg kg-1, i.v.), a beta-adrenergic blocker, in addition to diphenhydramine, caused a long-lasting bronchoconstriction following antigen challenge in both animal models. This histamine-independent bronchoconstriction was markedly suppressed by S-1452 at a low dose of 0.1 mg kg-1. 4. A significant increase in bronchial responsiveness to i.v. acetylcholine (ACh), compared to the prechallenge value, occurred as early as 3 min and persisted for 24 h after antigen challenge in the IgG1 model, but was not observed in the IgE model. S-1452 (10 mg kg-1, p.o.) inhibited the IgG1-mediated bronchial hyperresponsiveness, as assessed 60 min after antigen challenge. 5. A marked elevation of TxB2 levels was observed in bronchoalveolar lavage fluid (BALF) 3 min after antigen challenge in the IgG1 model, while levels were not changed in the IgE model. In contrast, the plasma TxB2 level assessed 1 min after antigen challenge was increased in both the IgGI and IgE models.6. The results indicate that the inhibition of IgGl- but not IgE-mediated bronchoconstriction by higher doses of S-1452 may result from the suppression of increased bronchial responsiveness to allergic mediators such as histamine, which is probably due to TxA2 generated in the airway lumen rather than in plasma. In both the IgGI and IgE models, plasma TxA2 appeared to contribute directly to the bronchoconstriction, its action being almost completely masked by histamine-mediated bronchoconstriction.

Topics: 6-Ketoprostaglandin F1 alpha; Adrenergic beta-Antagonists; Animals; Antibodies, Monoclonal; Antigens; Asthma; Bridged Bicyclo Compounds; Bronchial Hyperreactivity; Bronchoconstriction; Diphenhydramine; Fatty Acids, Monounsaturated; Guinea Pigs; Immunoglobulin E; Immunoglobulin G; Male; Receptors, Prostaglandin; Thromboxane A2; Thromboxane B2

Nedocromil sodium, a disodium salt of a pyroquinolinedicarboxylic acid, raises the bronchial hyperresponsiveness threshold, because it inhibits the mediators released by the various cells, and reduces the involvement and activation of inflammatory cells. The aim of this study was to evaluate the state of activation of the immunocompetent cells and the main chemical mediators present in the bronchoalveolar lavage (BAL) fluid from 10 atopic asthmatic patients, before and after treatment with nedocromil sodium. The following examinations were performed before treatment and after 120 days of therapy with nedocromil sodium at 16 mg/day (two 2-mg puffs x 4): the level of chemical mediators and the state of activation of immunocompetent cells in BAL fluid; immunological analytes in activation of immunocompetent cells in BAL fluid; immunological analytes in peripheral blood; aspecific bronchial challenge test with ultrasonicated bidistilled H2O fog to evaluate variations in the hyperreactivity threshold; questionnaire to determine any adverse effects of treatment (cough, breathlessness, sleep disorders). Our findings demonstrate that nedocromil sodium prevents the release of chemotactic and inflammatory mediators by the effector cells and thus stabilizes microvascular permeability and epithelial damage, so raising the threshold of response to bronchoconstriction stimuli. Lastly, nedocromil sodium is associated with a better preventive therapeutic efficacy and good tolerance and can therefore be suggested as a valid drug to be used in the long-term treatment of bronchial asthma.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Albumins; Asthma; Blood Proteins; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoalveolar Lavage Fluid; Dinoprostone; Eosinophil Granule Proteins; Humans; Hypersensitivity; Immunoglobulins; Immunologic Factors; Leukocytes; Leukotriene B4; Lymphocytes; Macrophages; Male; Nedocromil; Peptide Hydrolases; Ribonucleases; Thromboxane B2

To investigate the role of thromboxane (Tx) A2 and prostaglandin (PG) I2 in the development of airway responsiveness after ozone exposure, we measured the airway responsiveness to inhaled methacholine (Mch), TxB2 and 6-keto-PGF1 alpha levels in bronchoalveolar lavage fluid (BALF) in 18 dogs after ozone exposure. Airway responsiveness to Mch was determined by Astograph (7 Hz oscillation method), and ozone exposure was carried out for 2 hr at an ozone level of 3.01 +/- 0.05 ppm (mean +/- SEM). Airway responsiveness to Mch increased significantly after ozone exposure (p less than 0.001). TxB2 levels in BALF were not affected by ozone exposure, but the levels of 6-keto-PGF1 alpha decreased significantly after ozone exposure (p less than 0.001). The ratio of TxB2/6-keto-PGF1 alpha increased significantly after ozone exposure, and the change in this ratio correlated significantly with the change of airway responsiveness to Mch (p less than 0.01, r = 0.654). These results suggest that airway hyperresponsiveness after ozone exposure is induced by the relative increase of TxA2 due to the decrease of PGI2.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Atmosphere Exposure Chambers; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Dogs; Epoprostenol; Female; Ozone; Thromboxane A2; Thromboxane B2