Search PubMed⌕ Search

Biomedical subjects

D M Conroy

Publications and source records attributed to D M Conroy.

At least 19 recordsLinked to original sources
PubMed1995

Effect of tumor necrosis factor receptor binding protein on cell infiltration induced by lipopolysaccharide and Sephadex beads in guinea pig lung.

In the present study, the effect of a tumor necrosis factor receptor binding protein (TNFbp) on the cell infiltration induced by lipopolysaccharide (LPS) and Sephadex beads in guinea pig lung was examined. The intratracheal injection of LPS (2.5 micrograms) induced a six-fold increase in total cell number recovered in bronchoalveolar lavage (BAL) fluid at 24 hr. This increase in bronchopulmonary inflammation was mainly due to a neutrophil and macrophage infiltration, representing 60% and 35% of the total cells, respectively. The intravenous or intratracheal injection of Sephadex beads to guinea pigs induced a three-fold increase in total cell number recovered in BAL at 24 h and was characterized by a prominent eosinophil, macrophage, and neutrophil infiltration representing 36%, 42%, and 16% of the total cells, respectively. In addition, bronchial tissues isolated from Sephadex-treated guinea pigs showed an increased in vitro reactivity to both histamine and acetylcholine. TNFbp (1-50 micrograms) induced a dose-dependent inhibition of cell infiltration induced by LPS. In contrast TNFbp neither attenuated the bronchopulmonary cell infiltration observed 24 h following intravenous or intratracheal administration of Sephadex beads nor inhibited the increase in bronchial reactivity. These results show that TNF plays an important role in cell infiltration induced by LPS, but not that induced by Sephadex, in the guinea pig lung.

Animals↗
PubMed1993

Inhibition by rapamycin of leukocyte migration and bronchial hyperreactivity induced by injection of Sephadex beads to guinea-pigs.

1. The effect of rapamycin (0.001 to 5 mg kg-1) on the increased leukocyte counts in bronchoalveolar lavage (BAL) fluid and hyperreactivity of isolated bronchial strips to histamine and acetylcholine (ACh) was studied following the intravenous injection of Sephadex beads to guinea-pigs. 2. The intramuscular (i.m.) injection of rapamycin (0.012 to 5 mg kg-1) dose-dependently inhibited the increase in leukocyte counts in BAL fluid. Rapamycin (5 mg kg-1) reduced the numbers of eosinophils neutrophils, macrophages and lymphocytes in BAL fluid by 64, 55, 19 and 50% respectively. In addition, rapamycin (0.012 to 5 mg kg-1) significantly inhibited the Sephadex-induced hyperreactivity of bronchial tissue to both histamine and ACh. 3. At a dose of 0.001 mg kg-1, rapamycin did not significantly reduce leukocyte infiltration or bronchial hyperreactivity. 4. Cyclosporin (5 mg kg-1) significantly reduced both lymphocyte and eosinophil numbers in BAL fluid of Sephadex-injected guinea-pigs whereas dexamethasone (1 mg kg-1) significantly reduced lymphocyte numbers. Neither drug affected the bronchial hyperreactivity to histamine and ACh. 5. It is concluded that the new immunosuppressive drug, rapamycin, is a potent inhibitor of leukocyte migration and bronchial hyperreactivity observed following the intravenous injection of Sephadex beads to guinea-pigs. Rapamycin also appears to be more effective than cyclosporin or dexamethasone in reducing leukocyte counts and bronchial hyperreactivity in this model. 6. Our results suggest that inflammatory mechanisms which are inhibited by rapamycin may be important in the induction of Sephadex-induced hyperreactivity.

Acetylcholine↗
PubMed1993

Reduction of Sephadex-induced lung inflammation and bronchial hyperreactivity by rapamycin.

Rapamycin is a macrolide antibiotic whose potent immunosuppressor activity was recently described in vivo and in vitro. The aim of the present work was to determine if rapamycin could affect an established inflammatory response. Conscious pathogen-free Dunkin-Hartley guinea pigs (300-400 g) were injected intravenously with Sephadex beads (G50, superfine, 10 to 40 microns, 24 mg/kg) to induce lung inflammation and bronchial hyperreactivity. Bronchoalveolar lavage (BAL) fluid was collected 2, 12 and 24 h after Sephadex administration and the cells were counted. Bronchial tissue was used to construct dose-response (contraction, g) curves to histamine and acetylcholine 24 h after the Sephadex injection, using a cascade system. Results are presented as area under the log dose-response curves. Test animals were injected with rapamycin (5 mg/kg) or its vehicle by the intramuscular route either 2 or 12 h after Sephadex injection and BAL fluid collected 24 h after Sephadex administration. Rapamycin administration 2 h after Sephadex reduced eosinophil and lymphocyte numbers in BAL by 52 and 55%, respectively, but not ex vivo bronchial hyperreactivity induced by Sephadex injection. However, rapamycin administration 12 h after Sephadex reduced BAL eosinophil and lymphocyte numbers (55 and 62%, respectively) and bronchial hyperreactivity. The increase in neutrophil numbers in BAL induced by Sephadex injection was not modified by rapamycin. Since lymphocyte numbers in BAL were significantly increased in Sephadex-treated animals at 12 h but not at 2 h after Sephadex injection, the present results suggest that the inhibition of bronchial hyperreactivity by rapamycin may be dependent on the presence of lymphocytes elicited into the airways by Sephadex injection.

Animals↗
PubMed1992

Vasoactive intestinal peptide and helodermin inhibit the release of cyclo-oxygenase products induced by leukotriene D4 and bradykinin from guinea-pig perfused lung.

Vasoactive intestinal peptide (VIP, 10 nM) inhibited the release of cyclo-oxygenase products, detected by both bioassay and radioimmunoassay, induced by leukotriene (LT) D4 (3-30 pmol) and bradykinin (BK, 3-30 nmol) from guinea-pig isolated perfused lung. Helodermin (10 nM), a peptide that is structurally related to VIP, and salbutamol (10 nM), a beta 2-adrenoceptor agonist, evoked a similar inhibitory effect on LTD4-induced release of cyclo-oxygenase products. The generation of TxB2 and 6-keto-PGF1 alpha following stimulation with exogenously administered arachidonic acid (30-300 nmol) was not significantly attenuated in the presence of either VIP, helodermin or salbutamol. These results show that VIP, helodermin and salbutamol are potent inhibitors of the release of cyclo-oxygenase products induced by agonists known to activate endogenous arachidonic acid metabolism in guinea-pig lung. Since the metabolism of exogenously administered arachidonic acid was not inhibited these results suggest that the inhibitory effect may be exerted on events preceding the mobilisation of arachidonic acid and may involve cyclic AMP.

Albuterol↗
PubMed1992

Betel-nut chewing and asthma.

Two Asian patients admitted to hospital with acute severe asthma had been chewing betel nut immediately before the attacks. Arecoline, a cholinergic alkaloid, is a major constituent of Areca catechu (betel) nut and causes the euphoric effects. We sought an association between betel-nut chewing and bronchoconstriction in asthmatic patients. In vitro, arecoline caused dose-related contraction of human bronchial smooth-muscle strips, with one-tenth the potency of methacholine. In a double-blind challenge study, inhalation of arecoline caused bronchoconstriction in six of seven asthmatic patients and one of six healthy subjects; methacholine caused bronchoconstriction in all the asthmatic patients and in five controls. The geometric mean concentrations of arecoline and methacholine that caused 20% falls in the forced expiratory volume in 1 s (PC20 FEV1) in the asthmatic subjects were 5.2 mg/ml and 1.6 mg/ml, respectively. We then studied four Bengali asthmatic patients, regular users of betel nut, during a betel-nut challenge. Three showed no adverse effects, but one showed a 30% fall in FEV1 by 150 min after chewing; the effect was reproducible. In the UK, the rate of hospital admission for acute asthma is higher among Asians than among other groups in the population; betel-nut chewing may be one of several factors that affect asthma control and severity of attacks.

Adult↗
PubMed1991

Effects of vasoactive intestinal peptide, helodermin and galanin on responses of guinea-pig lung parenchyma to histamine, acetylcholine and leukotriene D4.

1. The effect of vasoactive intestinal peptide (VIP) was studied on the contractile response of guinea-pig lung parenchymal strips (GPP) induced by bronchoconstrictor agonists, such as leukotriene D4 (LTD4), histamine and acetylcholine (ACh). This effect of VIP was compared with helodermin, a peptide that is structurally related to VIP, and galanin, another neuropeptide that is thought to co-exist with VIP. 2. VIP (10 nM) induced a potent and reversible inhibition of the contractions of GPP induced by LTD4 (1-30 pmol) but did not affect those due to ACh (1-100 nmol) or histamine (1-30 nmol). A ten fold higher concentration of VIP (100 nM) did not further inhibit LTD4-induced responses or reduce those induced by histamine or ACh. 3. Helodermin (10 nM) had a similar inhibitory effect on contractions of GPP induced by LTD4 (3-30 pmol) but did not affect contractions induced by histamine (1-10 nmol). 4. Indomethacin (2.8 microM) and salbutamol (10 nM) significantly reduced responses elicited by LTD4 and histamine but not those due to ACh. A ten fold higher concentration of salbutamol (100 nM) further inhibited the contractions due to LTD4 and histamine and at this concentration responses induced by ACh were inhibited. 5. VIP (10 nM) and helodermin (10 nM) significantly reduced the LTD4-induced release of thromboxane A2 (TXA2), measured as TxB2 by radioimmunoassay, from GPP. The smaller release of TxA2 induced by histamine was not significantly reduced in the presence of VIP. 6. In comparative studies, galanin (10-100 nM) did not affect contractions of GPP induced by either LTD4, histamine or ACh. In contrast to VIP and helodermin, both at 0.1-3 nmol, which induced doserelated relaxations of guinea-pig trachea, galanin was inactive on this preparation in doses of up to 3 nmol.7. In conclusion, our results show that contractions of GPP induced by LTD4 are more sensitive to inhibition by VIP and helodermin than are contractions due to histamine or ACh. This inhibition appears to be associated with the different contribution of released TxA2 to contractions evoked by the agonists. VIP and helodermin inhibit the cyclo-oxygenase-dependent component of the LTD4-induced response, as in the case of indomethacin.

Acetylcholine↗
PubMed1990

Relaxations of guinea-pig isolated trachea induced by platelet-activating factor are epithelial-dependent and are antagonised by WEB 2086.

Platelet-activating factor (PAF, 10-1000 pmol) induced dose-dependent relaxations of the basal tone of superfused strips of epithelium-intact guinea-pig trachea. Indomethacin (1.4 microM) completely inhibited and WEB 2086 (1 and 10 nM) effectively antagonised these relaxations. Following epithelial removal PAF evoked a single contraction. These results show that the PAF-induced relaxations of guinea-pig trachea are dependent on an intact epithelial layer and are mediated by a cyclo-oxygenase product.

Albuterol↗
PubMed1990

Verapamil inhibits phosphatidic acid formation and modifies phosphoinositide metabolism in stimulated platelets.

Rabbit platelet-rich plasma was incubated with [32P]orthophosphate, after which the platelets were washed, further incubated in the absence or presence of verapamil and subsequently stimulated with PAF-acether or thrombin. In the absence of verapamil, a rapid increase in radioactivity in phosphatidic acid was observed in platelets stimulated with PAF-acether or thrombin. This was inhibited by verapamil over the concentration range 10(-7) to 10(-4) M, at which concentration the rise in phosphatidic acid was completely abolished. In unstimulated platelets, 10(-4) M verapamil induced an increase in radioactivity in polyphosphoinositides but not significantly in phosphatidylinositol. When these verapamil-treated platelets were stimulated with PAF-acether or thrombin, there was a rapid, sustained loss of the additional radioactivity induced in the polyphosphoinositides by verapamil. Polyphosphoinositide radioactivity remained unchanged in platelets stimulated in the absence of verapamil. Verapamil may stimulate formation of a separate pool of polyphosphoinositide which is susceptible to agonist-induced phospholipase C, and failure to re-synthesize this polyphosphoinositide could result from inhibition of phosphatidic acid synthesis.

Animals↗
PubMed1989

Pharmacological profile of leukotrienes E4, N-acetyl E4 and of four of their novel omega- and beta-oxidative metabolites in airways of guinea-pig and man in vitro.

1, The biological effects of metabolites of leukotriene E4 (LTE4) i.e. N-acetyl LTE4 (N-AcLTE4), 20-COOH-LTE4, 20-COOH-N-AcLTE4, as well as 18-COOH-19,20-dinor-LTE4 (dinor-LTE4) and 16-COOH-17,18,19,20-tetranor-14,15-dihydro-LTE4 (tetranor-LTE4) were investigated on superfused strips of guinea-pig trachea (GPT) and lung parenchyma (GPP) in vitro. 2. The actions of LTE4 were studied in isolated, superfused strips of human lung parenchyma (HP) and bronchus (HBr), in comparison with LTD4 and histamine. Effects of N-AcLTE4, the 20-carboxy metabolites, dinor-LTE4 and tetranor-LTE4 were also investigated in HBr. 3. N-AcLTE4 (0.1-10 nmol) induced dose-related contractions of GPT and was approximately 100 times less active than LTD4 (3-100 pmol). 4. In GPP, N-AcLTE4 (0.01-3 nmol) was equiactive with LTE4 (0.01-1 nmol) and approximately one order of magnitude less active than LTD4 (1-300 pmol). Contractions caused by N-AcLTE4 and LTE4 were very similar and approximately twice as sustained as those due to LTD4. 5. LTE4 (0.1-30 nmol) contracted strips of HP and HBr and was about 2-3 orders of magnitude less active than LTD4. As in GPP, the effect of LTE4 was more protracted than that of LTD4. Actions of N-AcLTE4 were similar to those of LTE4 in HBr. 6. 20-carboxy-LTE4, 20-carboxy-N-AcLTE4, dinor-LTE4 and tetranor-LTE4, all at 0.3-30 nmol, were inactive in GPT, GPP and HBr. 7. Indomethacin (2.8 microM) potentiated the effect of N-AcLTE4 in GPT, inhibited its contraction in GPP but did not affect that due to LTE4 in either HP or HBr. FPL 55712 (1.9 microM) antagonised leukotriene-induced contractions in GPT, GPP and HBr. 8. In conclusion, the metabolism of LTD4 to LTE4 or N-AcLTE4 may represent a detoxification but not an inactivation of cysteinyl-containing leukotrienes, since both metabolites still retain considerable biological activity in guinea-pig and human airways in vitro. However, further metabolism of LTE4 and N-AcLTE4 appears to result in inactivation of leukotrienes.

Animals↗
PubMed1986

The effects of dietary (n-3) fatty acid supplementation on lipid dynamics and composition in rat lymphocytes and liver microsomes.

Rats were fed diets devoid of (n-3) fatty acids (olive oil supplementation) or high in (n-3) fatty acids (fish oil supplementation) for a period of 10 days. In spleen lymphocytes and liver microsomes derived from animals fed fish oil diets, relatively high levels of (n-3) eicosapentaenoic (20:5), docosapentaenoic (22:5) and docosahexaenoic acids (22:6) were obtained compared to minimal levels when fed the olive oil diet. When the average lipid motional properties were examined by measuring the fluorescence anisotropy of diphenylhexatriene, no significant different was found between intact liver microsomes from animals fed the two diets. However, when lipid motion was examined in vesicles of phosphatidylcholine, isolated from the microsomes from fish oil fed animals (21.4% (n-3) fatty acids), the fluorescence anisotropy was significantly less than the corresponding phosphatidylcholine from olive oil fed animals (5.6% (n-3) fatty acids), indicating a more disordered or fluid bilayer in the presence of higher levels of (n-3) fatty acids. Phosphatidylethanolamine (n-3) fatty acids were also elevated after fish oil supplementation (41.3% of total fatty acids), compared to the level after olive oil supplementation (21.4%). The major effect of the fish oil supplementation was a replacement of (n-6) arachidonic acid by the (n-3) fatty acids and when this was 'modeled', using liposomes of synthetic lipids, 1-palmitoyl-2-arachidonyl(n-6) or docosahexaenoyl(n-3)-phosphatidylcholine, significant differences in lipid motional properties were found, with the docosahexaenoate conferring a more disordered or fluid lipid environment. Thus it appears that although lipid order/fluidity can be significantly decreased by increases in the highly unsaturated (n-3) fatty acid levels, alterations in membrane domain organization and/or phospholipid molecular species composition effectively compensated for the changes, at least as far as average lipid motional properties in the intact membranes was concerned.

Animals↗
PubMed1986

Influence of dietary lipids on the effect of chlorpromazine on membrane properties of rabbit red cells.

The effect of diets containing different types of common natural oils on physical properties of red cells was investigated by using rabbits. The rabbits were fed for 18 months on a standard diet in which 8% of its energy content was provided by safflower oil and 32% energy by either more safflower oil or fish oil, linseed oil, olive oil or palm oil. Erythrocyte deformability was significantly decreased by the fish oil diet compared with each of the other diets. Osmotic fragility was significantly less (66 mM) for red cells from rabbits fed on the linseed oil diet, and significantly greater (71 mM) for red cells from rabbits on the fish oil diet, than for red cells from rabbits on the other three diets which did not differ significantly from each other (68 mM). With rabbits on the standard diet, the resistance of their erythrocytes to osmotic haemolysis was increased by chlorpromazine at concentrations below and decreased by concentrations above 30 microM. The dietary oils caused significant changes in the effects of chlorpromazine on osmotic fragility. The concentration at which the effect of chlorpromazine reversed from antihaemolytic to prohaemolytic was decreased by the safflower and linseed oil diets and increased by the fish oil diet, compared with the olive and palm oil diets. Analysis of the fatty acid compositions of the dietary oils on the one hand and of the red cell phospholipids on the other established, specifically, that in the presence of 30 microM chlorpromazine the percentage haemolysis was directly proportional to the linoleate content of the red cell phospholipids.

Animals↗
PubMed1984

Unsaturated fatty acids stimulate the formation of lipoxygenase and cyclooxygenase products in rat spleen lymphocytes.

Rat spleen lymphocytes prelabelled with [14C] arachidonate were suspended in fresh medium in the presence or absence of exogenous non-radioactive fatty acids added in ethanol. It was found that fatty acids stimulate thromboxane B2, PGE2, HHT and HETE formation. The effect is specific for unsaturated fatty acids. It occurs at 50 micron concentrations and is apparent after 20 minutes incubation. Unsaturated fatty acids may serve an important role in the regulation of prostaglandin and hydroxy fatty acid metabolism in vivo. This may indicate a mechanism for the action of fatty acids on the immune response.

Animals↗