calcimycin and Airway-Obstruction

To evaluate leukotriene (LT) biosynthetic capacity in lung tissue from healthy horses and horses with recurrent airway obstruction (RAO).. Lung parenchyma and airway specimens from 8 RAO-affected and 5 healthy horses.. Horses were stabled for > or = 72 hours. Blood was drawn before euthanasia, after which lung specimens were collected. Tissue strips from small airways and parenchyma were incubated in organ baths with the precursor LTA4 or stimulated with calcium ionophore A23187 or the tripeptide N-formyl-Met-Leu-Phe (fMLP), with or without exogenous arachidonic acid, in the presence of isolated blood neutrophils.. Stabling induced typical clinical signs of airway obstruction in RAO-affected horses but not control horses. When lung parenchyma or airway specimens from both groups of horses were incubated with calcium ionophore, with or without arachidonic acid, they did not form LT. In contrast, addition of LTA4 to both tissues resulted in conversion to LTB4, although concentrations of LTC4 were negligible in airways and parenchymal strips from healthy and RAO-affected horses. Incubation of airway and parenchymal strips with suspensions of autologous neutrophils did not influence formation of LT stimulated by calcium ionophore or fMLP, with or without exogenous arachidonic acid.. Results suggest that lung parenchyma and airway tissues themselves are not of substantial importance for LT formation in the lungs, although these tissues possessed some LTA4 hydrolase activity, enabling LTB4 formation. It may be speculated that LTB4 originates primarily from neutrophils and may play a role in the inflammatory events of RAO.

Topics: Airway Obstruction; Animals; Arachidonic Acid; Calcimycin; Female; Horse Diseases; Horses; In Vitro Techniques; Ionophores; Leukotrienes; Lung; Male; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils

We examined the in vivo actions of LY293111 sodium (2-[2-propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy]pro poxy]phenoxy] benzoic acid sodium salt). Guinea pigs were used to evaluate the effect of this agent on (1) acute airway obstruction produced by intravenous leukotriene B4, (2) pulmonary granulocyte infiltration and delayed onset airway obstruction resulting from a 4-h leukotriene B4 inhalation and (3) lung inflammation after aerosol challenge with the divalent cationic ionophore A23187 (6S-[6alpha(2S*,3S*),8beta(R*),9beta,11alpha]-5- (methylamino)-2-[[3,9,11-trimethyl-8-[1-methyl-2-oxo-2-(1H-pyrrol-2-yl)e thyl]-1,7-dioxaspiro[5.5]undec-2-yl]methyl]-4-benzoxazole carboxylic acid). Airway obstruction was quantitated using pulmonary gas trapping measurements and lung inflammation was evaluated by bronchoalveolar lavage (BAL) and histology. LY293111 sodium produced a dose-related inhibition of acute leukotriene B4-induced airway obstruction when administered i.v. (ED50=14 microg/kg) or p.o. (ED50=0.4 mg/kg). In contrast, LY293111 sodium did not inhibit the pulmonary gas trapping caused by aerosols of histamine, leukotriene D4, or the thromboxane mimetic U46619 (15 [(S)-hydroxy11a,9a-(epoxymethano)prosta-5Z,13E-dienoic acid]). Oral LY293111 sodium inhibited leukotriene B4-induced bronchoalveolar lavage granulocyte infiltration and delayed onset airway obstruction at doses as low as 0.3 mg/kg. In A23187-challenged animals, pulmonary inflammation was markedly inhibited at 1 h, but not 2 h and 4 h post-exposure. We conclude that LY293 11 sodium is a selective leukotriene B4 receptor antagonist with potent pulmonary anti-inflammatory activity.

Topics: Airway Obstruction; Animals; Benzoates; Benzopyrans; Bronchoalveolar Lavage Fluid; Calcimycin; Chemotaxis, Leukocyte; Dinoprostone; Granulocytes; Guinea Pigs; Inflammation; Leukotriene Antagonists; Leukotriene B4; Lung; Male; Receptors, Leukotriene B4; Thromboxane B2

To determine the capacity of pulmonary mast cells (PMC) to degranulate in response to various potential allergens and other secretagogues in horses with recurrent airway obstruction (heaves) and clinically normal horses before and after exposure to moldy hay.. 5 horses with heaves and 5 clinically normal horses.. Heaves was characterized as an increased clinical respiratory score and maximum change in transpulmonary pressure of > 20 cm H2O after exposure. Bronchoalveolar lavage was performed during each period. Washed and resuspended cells were exposed for 20 minutes at 37 C with whole reconstituted freeze-dried preparations of Aspergillus fumigatus, Alternaria tenuis, and Ambrosia elatior, fungal extracts of Aspergillus fumigatus, Alternaria tenuis, and Micropolyspora faeni; A23187; and compound 48/80. Histamine release (HR) was used as a marker of degranulation.. Compared with clinically normal horses, HR was significantly greater from PMC from horses with heaves during remission and exacerbation in response to whole preparations and extracts of Aspergillus fumigatus and whole preparations of Alternaria tenuis. Extracts of Alternaria tenuis caused significantly greater HR from PMC from horses with heaves during exacerbation. Histamine was also released from PMC in response to A23187 and to changes in osmolality of the medium, but only as a result of cell lysis by compound 48/80.. Increased degranulation of PMC after antigenic challenge may contribute to the pathogenesis of heaves in horses.. Strategies for prevention and treatment that attenuate degranulation of PMC may assist in the clinical management of horses with heaves.

Topics: Airway Obstruction; Allergens; Alternaria; Animals; Aspergillus fumigatus; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Calcimycin; Cell Degranulation; Female; Fluorometry; Histamine; Histocytochemistry; Horse Diseases; Horses; Ionophores; Lung Diseases, Obstructive; Male; Mast Cells; Micromonosporaceae; p-Methoxy-N-methylphenethylamine; Respiratory Function Tests

Anandamide (arachidonylethanolamide), 5,8,11,14-eicosatetraenamide, (N-2-hydroxyethyl), was tested for bronchodilator and anti-inflammatory activities. Conscious guinea pigs were given cumulative i.v. doses of anandamide (1.0, 3.0, and 10.0 mg/kg) to assess its effect on dynamic compliance (Cdyn), total pulmonary resistance (RL), tidal volume (VT) and breathing frequency (f). Other guinea pigs were exposed to an aerosol of A23187 (6S-[6alpha(2S*,3S*),8beta(R*),9beta,11alpha]-5- (methylamino)-2-[[3,9,11-trimethyl-8-[1-methyl-2-oxo-2-(1H-pyrrol-2-yl)e thyl]-1,7-dioxaspiro[5.5]undec-2-yl]methyl]-4-benzoxazole carboxylic acid) until Cdyn decreased by 50% (approximately 5 min) and at 20 min, cumulative i.v. doses of anandamide (1.0, 3.0, and 10.0 mg/kg) were administered and reversal of Cdyn examined. After the final dose of anandamide, the animals were killed and excised lung gas volumes (ELGV), i.e., pulmonary gas trapping, measured. Other animals were treated i.v. with anandamide (10.0 mg/kg), exposed to an aerosol of A23187 until labored breathing began, and then killed 1 h later. Anandamide did not significantly affect Cdyn, RL, VT and f. ELGV values of anandamide-treated guinea pigs were not different from those of vehicle-treated animals. Anandamide failed to reverse A23187-induced decreases in Cdyn and to reduce A23187-associated ELGV increases. Also, it did not prevent the prolonged airway obstruction caused by A23187. Histological evaluation revealed that anandamide significantly reduced A23187-related airway epithelial injury and pulmonary leukocytosis. However, it did not prevent A23187-induced peribronchiolar granulocytic accumulation. Our results suggest that in vivo anandamide has minimal direct airway smooth muscle-related actions, however it may possess modest anti-inflammatory properties.

Topics: Aerosols; Airway Obstruction; Airway Resistance; Animals; Anti-Inflammatory Agents; Arachidonic Acids; Bronchodilator Agents; Calcimycin; Endocannabinoids; Guinea Pigs; Injections, Intravenous; Lung; Lung Compliance; Male; Polyunsaturated Alkamides; Pulmonary Ventilation; Receptors, Cannabinoid; Receptors, Drug; Tidal Volume

We examined the effect of dexamethasone on A23187-induced bronchospasm, pulmonary inflammation and airway responses to substance P. Guinea pigs, dosed orally once a day for 4 days with dexamethasone (3.0, 10.0 or 30.0 mg/kg) or saline, were exposed to an aerosol of A23187 for 12 min or until labored breathing began. Postmortem pulmonary gas trapping was used as an indicator of in vivo airway obstruction and changes in bronchial responses. Dexamethasone did not alter airway obstruction or inflammation 1 h after A23187 exposure. However, dexamethasone reduced the enhanced airway responses to substance P and bronchiolar/peribronchiolar inflammation 24 h post-A23187. It is possible that glucocorticosteroid suppression of A23187-induced pulmonary inflammation was important in reducing the increased airway responses to substance P.

Topics: Administration, Inhalation; Administration, Oral; Airway Obstruction; Airway Resistance; Animals; Bronchial Hyperreactivity; Bronchial Spasm; Calcimycin; Dexamethasone; Dyspnea; Guinea Pigs; Lung; Male; Pulmonary Gas Exchange; Substance P

Heaves is a respiratory disorder of horses and ponies characterized by bouts of acute airway obstruction and airway hyperresponsiveness. We measured prostaglandin E2 (PGE2) and 15-hydroxyeicosatetraenoic acid (15-HETE) production in vitro in tracheal epithelium obtained from six affected horses at the time of acute airway obstruction as compared with six matched control horses. Strips of epithelium and subepithelial tissue were prepared and stimulated with A23187, histamine, and bradykinin. The PGE2 and 15-HETE in media from strips was quantitated by radioimmunoassay. 15-HETE above the limits of accurate detection was found in epithelial strips of only two principal animals and in none of the control horses, and the amount of 15-HETE was not increased when strips were stimulated. Epithelial strips from affected horses tended to produce less PGE2 than did strips from control horses, and there was a significant correlation between epithelial PGE2 production and the time taken for affected animals to develop airway obstruction. Subepithelial tissue strips from control horses produced significantly more PGE2 in response to A23187 and bradykinin than did strips from affected horses. We conclude that equine tracheal epithelium is not a significant source of 15-HETE. Airway mucosal PGE2 production is reduced in horses with heaves, which suggests that a relative decrease in this bronchorelaxant substance may be a factor in the pathogenesis of this model of asthma.

Topics: Airway Obstruction; Animals; Bradykinin; Calcimycin; Dinoprostone; Epithelium; Histamine; Horse Diseases; Horses; Hydroxyeicosatetraenoic Acids; Mucous Membrane; Radioimmunoassay; Respiratory Function Tests; Trachea

Conscious guinea pigs that were briefly exposed to an aerosol of A23187 developed a prolonged airway constrictive response that lasted at least 60 min. Cumulative i.v. doses of various drugs were given and reversal of dynamic compliance (Cdyn) examined. After the final dose of each agent, the animals were killed and excised lung gas volumes, i.e., pulmonary gas trapping, measured. Salbutamol, a beta-2 adrenoceptor agonist; phenidone, a 5-lipoxygenase inhibitor; aminophylline, a methylxanthine bronchodilator; dazoxiben, a thromboxane synthetase inhibitor; REV-6866, a 5-lipoxygenase inhibitor; LY53857, a 5-hydroxytryptamine receptor antagonist; and LY183001, a leukotriene D4/E4 antagonist, partially reversed Cdyn and reduced excised lung gas volume. Atropine, a cholinergic/muscarinic antagonist indomethacin, a cyclooxygenase inhibitor; pyrilamine, a histamine receptor antagonist; and SRI 63-072, a platelet activating factor antagonist, had little or no effect. For all animals, final Cdyn values were highly correlated with reduction of pulmonary gas trapping (r = -0.86, P less than .0001). We conclude that smooth muscle contraction is important in A23187-induced airway obstruction; 5-hydroxytryptamine, thromboxane A2 and lipoxygenase products may be involved in maintaining this response; and that this approach is useful for investigating reversal of ongoing airway constriction.

Topics: Airway Obstruction; Airway Resistance; Albuterol; Animals; Calcimycin; Dose-Response Relationship, Drug; Ergolines; Guinea Pigs; Leukotrienes; Lung Compliance; Male; Platelet Activating Factor; Serotonin; Thromboxane A2

Exposure of conscious guinea pigs to A23187 aerosol produced a concentration-related increase of excised lung gas volumes (ELGV), i.e., postmortem pulmonary gas trapping. Measurements of ELGV were highly correlated with in vivo measurements of dynamic compliance (Cdyn) and total pulmonary resistance (RL) and were used as an indication of in vivo airway obstruction. We pretreated guinea pigs intravenously with the following drugs: atropine; LY163443, a selective LTD4/E4 antagonist; indomethacin; propranolol; and pyrilamine. The guinea pigs were exposed for 8 minutes to the A23187 aerosol, and ELGV measurements were then made. Atropine or pyrilamine prevented the A23187-induced gas trapping. Indomethacin or propranolol tended to potentiate the response and when combined, they potentiated the gas trapping by 80%. LY163443 had no effect alone, but when combined with indomethacin, propranolol, and pyrilamine, inhibited A23187-induced gas trapping by 67%. We conclude that cholinergic and histaminergic mechanisms play major roles in the ionophore-induced pulmonary gas trapping of the guinea pig. With appropriate pretreatment, sulfidopeptide leukotrienes may produce a substantial effect.

Topics: Aerosols; Airway Obstruction; Animals; Atropine; Calcimycin; Guinea Pigs; Histamine Release; Lung; Male; Pyrilamine

Male Hartley guinea pigs were exposed by inhalation to leukotriene B4 (LTB4) and challenged 5 min or 4 h later with bronchoconstrictive aerosols of histamine or the divalent cationic ionophore A23187. Pulmonary gas trapping measured in excised lungs indicated the severity of post-challenge airway obstruction. Airway granulocyte infiltration was scored by an observer who was unaware of animal assignments. Treatment with LTB4 produced a marked influx of eosinophils and neutrophils into tracheal and bronchial airways. Granulocyte scores for LTB4-treated groups were 1.9 to 3.3 times higher than those for vehicle-treated groups at 5 min after exposure and 3.3 to 10.7 times higher at 4 h after exposure. Leukotriene B4 itself did not produce hyperinflation. However, histamine-induced gas trapping was increased 5 min after LTB4 exposure. Histamine responsiveness was unaffected 4 h after LTB4 treatment. In contrast, A23187-induced gas trapping was unaffected at 5 min, but diminished at 4 h after LTB4. Nonchemotactic stereoisomers of LTB4 did not produce granulocyte influx, but did produce altered airway responses similar to those seen for LTB4. We conclude that inhaled LTB4 produces airway granulocyte infiltration in the guinea pig and alterations in airway responsiveness that vary with the challenge stimulus and time after exposure. Alterations in airway responses may result from granulocyte-independent effects of LTB4 and its stereoisomers.

Topics: Aerosols; Airway Obstruction; Animals; Calcimycin; Dimethyl Sulfoxide; Ethanol; Granulocytes; Guinea Pigs; Histamine; Immunization; Leukotriene B4; Lung; Male; Time Factors