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Biomedical subjects

W M Abraham

Publications and source records attributed to W M Abraham.

At least 127 records · Page 7Linked to original sources
PubMed1986

The effect of an orally active leukotriene D4/E4 antagonist, LY171883, on antigen-induced airway responses in allergic sheep.

Leukotriene (LT) D4 is a putative mediator of allergic asthma: inhaled LTD4 produces early and late increases in specific lung resistance (SRL) and slows tracheal mucus velocity (TMV) similar to inhaled antigen. In this study we examined the effects of an orally active LTD4/LTE4 antagonist, LY171883 [1-less than 2-Hydroxy-3-propyl-4-less than 4-(1H-Tetrazol-5-yl) Butoxy greater than Phenyl greater than Ethanone], on early and late changes in SRL and TMV following airway challenge with Ascaris suum antigen in conscious allergic sheep. SRL and TMV were measured before and up to 8 h and 24 h after antigen challenge after either LY171883 (30 mg/kg, p.o. 2 h before challenge) or placebo pretreatment. After placebo pretreatment antigen challenge resulted in significant early (483% over baseline) and late (221% over baseline) increases in SRL (n = 9). LY171883 pretreatment, however, significantly reduced the early increase in SRL (163% over baseline) and blocked the late response. LY171883 did not prevent the antigen-induced fall in TMV from 5-8 h post challenge (n = 6), but TMV recovered more rapidly in the drug trial returning to baseline values by 24 h. These results suggest that the generation of LTD4, and its metabolite LTE4, during airway anaphylaxis contributes to the early increase in SRL and is important for eliciting the late increase in SRL as well as contributing to the fall in TMV.

Acetophenones↗
PubMed1986

Ciliary responsiveness in allergic and nonallergic airways.

Allergic asthma is associated with airway (smooth muscle) hyperresponsiveness to several chemical mediators of anaphylaxis; however, it is not known whether this is accompanied by mucociliary hyperresponsiveness. The purpose of this study was therefore to determine if airway ciliary activity, a component function of mucociliary clearance, exhibits exaggerated responses to prostaglandin E1 (PGE1), prostaglandin E2 (PGE2), and leukotriene D4 (LTD4) in allergic sheep when compared with nonallergic sheep, and the effects of LTD4 are direct or involve the generation of cyclooxygenase products of arachidonate metabolism. Ciliary beat frequency (CBF) was measured in a perfusion chamber with a microscopic technique using tracheal epithelial cells obtained from brushing of "allergic" (positive cutaneous reaction and previous bronchospastic response to inhaled specific antigen) and "nonallergic" (negative cutaneous reaction, no previous inhalation challenge with antigen) sheep. Mean base-line CBF was not different among the groups; PGE1, PGE2, and LTD4 induced dose-dependent increases in CBF, and these increases were not different in allergic and nonallergic sheep. At the highest agonist concentration the mean increase in CBF from base line varied between 13 and 16% (P less than 0.05). The ciliostimulatory effect of LTD4 was significantly blunted by both the sulfidopeptide leukotriene antagonist FPL-55712 and the cyclooxygenase inhibitor indomethacin. These results suggest that allergic sheep fail to exhibit ciliary hyperresponsiveness to selected chemical mediators of anaphylaxis and the ciliostimulatory effect of LTD4 depends on the activation of cyclooxygenase and possibly the generation of prostaglandins.

Alprostadil↗
PubMed1986

Indomethacin and FPL-57231 inhibit antigen-induced airway hyperresponsiveness in sheep.

We compared the development of antigen-induced airway hyperresponsiveness (AHR) 24 h after challenge with Ascaris suum antigen in allergic sheep with acute (n = 7) and with dual (n = 7) airway responses and then attempted to modify this AHR. Cholinergic airway responsiveness was determined by measuring the carbachol dose required to increase specific lung resistance (sRL) 150% (i.e., PC150). Subsequently the sheep were challenged with antigen and sRL was measured at predetermined times to document the presence or absence of a late response. PC150 was redetermined 24 h later followed by bronchoalveolar lavage (BAL) to assess inflammation. Only dual responders developed AHR (PC150 decreased, P less than 0.05). There were no significant differences in BAL between the two groups. Six dual responders were then, on separate occasions (greater than or equal to 3 wk), pretreated with placebo, indomethacin (2 mg/kg iv), or a leukotriene antagonist, FPL-57231 (30 mg inhaled). Neither agent significantly affected the acute response to antigen. Only FPL pretreatment blocked the late response, but both agents blocked the antigen-induced AHR 24 h later. BAL at 24 h showed no significant differences. These results indicate that only dual responders develop AHR 24 h after antigen challenge. This AHR appears independent of the late increase in sRL or the severity of pulmonary inflammation. AHR appears to be sensitive to agents that interfere with the early release or actions of cyclooxygenase and lipoxygenase metabolites in dual responders.

Airway Resistance↗
PubMed1986

Preliminary report on the effect of nedocromil sodium on antigen-induced early and late reactions in allergic sheep.

Allergic sheep may be considered in many respects to be an animal model of human bronchial asthma. This study investigated the effects of pretreatment with nedocromil sodium and sodium cromoglycate on antigen-induced smooth muscle contraction in vitro, and antigen-induced early and late bronchial responses and inflammatory cell influx in allergic sheep in vivo. Nedocromil sodium was found to be more potent than sodium cromoglycate against the antigen-induced smooth muscle contraction in vitro. Both drugs appeared equally effective against acute antigen-induced bronchoconstriction in sheep; both gave protection against the late response, and both agents had a similar effect on the antigen-induced response in cells obtained by bronchoalveolar lavage.

Airway Resistance↗
PubMed1986

Impairment of tracheal mucociliary clearance but not ciliary beat frequency by a combination of low level ozone and sulfur dioxide in sheep.

We used conscious sheep to determine the effect of a combined exposure to ozone (O3) and sulfur dioxide (SO2) on tracheal mucus velocity (TMV) and ciliary beat frequency (CBF). TMV was measured in vivo by tracking the movement of radiopaque particles which had been deposited on the tracheal mucosa. CBF of tracheal epithelial cells, obtained by brushing, was measured in vitro with phase contrast microscopy. On two separate occasions, six sheep were exposed by mask to either a combination of 0.3 ppm O3 and 3 ppm SO2 or air (control) for 5 h on each of three consecutive days. TMV and CBF were measured prior to the first exposure, and immediately and 24 h after the last exposure. The combination of O3 and SO2 depressed mean TMV by 40% immediately after and by 25%, 24 h after exposure. Both values were different from the corresponding values after air exposure (p less than 0.05). However, this depression in TMV was not associated with an impairment in CBF. We conclude that in conscious sheep, exposure to a combination of low level O3 and SO2 causes a depression in TMV, and changes in CBF are probably not a primary cause of this mucociliary dysfunction.

Animals↗
PubMed1985

Production of early and late pulmonary responses with inhaled leukotriene D4 in allergic sheep.

Some allergic sheep respond to inhalation of Ascaris suum antigen with both immediate and late increases in airflow resistance (late response). The mechanism of the late response is unknown but recent evidence suggests that the initial generation of slow-reacting substance of anaphylaxis (SRS-A) immediately after antigen challenge is a necessary pre-requisite for the physiologic expression of this late response. Based on this evidence we hypothesized that airway challenge with leukotriene D4 (LTD4), an active component of SRS-A would produce acute and late airway responses in allergic sheep similar to those observed with antigen. In five allergic sheep with documented early and late pulmonary responses to Ascaris suum antigen, inhalation of leukotriene D4 aerosol (delivered dose (mean +/- SE) 0.55 +/- 0.08 ug) resulted in significant early and late increases in specific lung resistance (SRL). In three allergic sheep which only demonstrated acute responses to antigen, LTD4 aerosol (delivered dose 0.59 +/- 0.09 ug) only produced an acute increase in SRL. In the late responders pretreatment with aerosol cromolyn sodium (1 mg/kg) did not affect the acute response but blunted the late increase in SRL. Pretreatment with aerosol FPL-57231 (1% w/v solution) completely blocked both the acute and late responses. These data support the hypothesis that initial release of LTD4 in the airways of sensitive animals is important for the physiologic expression of the late response.

Aerosols↗
PubMed1985

Effects of histamine on bronchial artery blood flow and bronchomotor tone.

The effects of aerosolized 5% histamine (10 breaths) on bronchial artery blood flow (Qbr), airflow resistance (RL), and pulmonary and systemic hemodynamics were studied in mechanically ventilated sheep anesthetized with pentobarbital sodium. Histamine increased mean Qbr and RL to 252 +/- 45 and 337 +/- 53% of base line, respectively. This effect was significantly different from base line for 30 min after challenge. The histamine-induced increase in RL was blocked by pretreatment with the histamine H1 receptor antagonist, chlorpheniramine, whereas the histamine-induced elevation in Qbr was prevented by the H2 antagonist, metiamide. Both responses were blocked only when both antagonists were present. Changes in Qbr were not directly associated with alterations in systemic and pulmonary hemodynamics or arterial blood gas composition. In vitro histamine caused a dose-dependent contraction of ovine bronchial artery strips that was prevented by H1 antagonist. The H2 agonist, impromidine, caused relaxation of precontracted arterial strips and was more potent and efficacious than histamine, whereas H1 agonists failed to elicit a relaxant response. Thus these findings indicate that histamine aerosol induces a vasodilation in the bronchial vascular bed; histamine has a direct effect on Qbr that is independent of alterations in RL, systemic and pulmonary hemodynamics, or arterial blood gas composition; and, histamine-induced bronchoconstriction is mediated predominantly by H1-receptors, whereas increased Qbr is controlled predominantly by H2-receptors, probably located in resistance vessels. This local effect of histamine on Qbr may have important implications in the pathophysiology of bronchial asthma and pulmonary edema.

Animals↗
PubMed1985

Effects of leukotriene D4 on mucociliary and respiratory function in allergic and nonallergic sheep.

We determined the effect of aerosol challenge with leukotriene D4 (LTD4) on specific lung resistance (sRL) and tracheal mucous velocity (TMV) in conscious sheep with (allergic) and without (nonallergic) Ascaris suum hypersensitivity. In allergic sheep LTD4 in concentrations of 50, 100, and 150 micrograms/ml produced dose-dependent increases in mean sRL by 44 (P = NS), 154 (P less than 0.05), and 233% (P less than 0.05), respectively. The increase in sRL produced by 150 micrograms/ml LTD4 was prevented by FPL 55712, an antagonist of slow-reacting substance of anaphylaxis. In nonallergic sheep 150 micrograms/ml LTD4 failed to elicit a significant change in sRL. In contrast to the changes in airway mechanics, concentrations of LTD4 as low as 25 micrograms/ml produced significant decreases in TMV in allergic sheep. The maximum decrease in TMV at this dose occurred 2 h after challenge; with larger doses of LTD4 (100 and 150 micrograms/ml) the maximum effect was observed 3 h after challenge. Furthermore, 150 micrograms/ml LTD4 reduced TMV in nonallergic sheep (mean decrease 43%, P less than 0.05). FPL 55712 only had a minor effect on the LTD4-induced decreases in TMV. We conclude that allergic sheep exhibit greater airway responsiveness to inhaled LTD4 than nonallergic sheep but that this difference is not evident for the concomitant changes in mucociliary transport. This suggests that the allergic state is associated with an increased responsiveness to LTD4 in tissues controlling airway caliber but not in those contributing to mucociliary function.

Aerosols↗
PubMed1985

Influence of two-phase gas-liquid interaction on aerosol deposition in airways.

Many patients with chronic simple bronchitis, viz., chronic productive cough without major airway obstruction, frequently show enhanced aerosol deposition in the airways. We hypothesized that this phenomenon might relate in part to wave motion of an accumulated layer of mucus caused by dynamic, two-phase gas-liquid interactions. In the present investigation, two-phase gas-liquid interaction was demonstrated in vivo by observing wave motion during tidal breathing of radiopaque-labeled viscous and viscoelastic fluids that had been added to distal tracheas of conscious sheep. Total aerosol deposition in the lung and mean pulmonary resistance (RL) were measured after addition of 4 to 10 ml of viscoelastic or viscous fluids to the distal main bronchi of conscious sheep. Change in aerosol deposition over baseline after fluid addition was compared with change in RL. In 21 experiments, 5 for each of 3 viscoelastic fluids with varying characteristics and 6 for a viscous fluid, aerosol deposition was significantly enhanced in every experiment, irrespective of the type of fluid added. This increase in aerosol deposition ranged from 13 to 66% above baseline. The RL increased in 5 of the 6 experiments with viscous fluid and in 4 of the 15 experiments with viscoelastic fluids. There was less wavelike motion with viscous than with viscoelastic fluids. These results suggest that two-phase gas-liquid interaction in the airways can account for increased aerosol deposition with little alteration in airway resistance.

Aerosols↗
PubMed1984

Changes in airway permeability and responsiveness after exposure to ozone.

The purpose of this investigation was to examine the relationship between airway responsiveness and the permeability of histamine through the airways in conscious sheep after exposure to ozone (O3). Airway responsiveness was assessed by measuring the change from baseline in mean pulmonary flow resistance following a controlled 2-min inhalation challenge with 1% histamine, containing 200 microCi/ml of [3H]histamine. The rate of appearance of the [3H]histamine in the plasma during inhalation challenge was used to estimate airway permeability. To perturb the airways, conscious sheep were exposed to either 0.5 or 1.0 ppm O3 for 2 hr via an endotracheal tube. Airway responsiveness and airway permeability were measured prior to and 1 day after exposure. In six sheep exposed to 0.5 ppm O3, increased airway responsiveness and airway permeability were observed 1 day after exposure. Four of seven sheep exposed to 1.0 ppm O3 had enhanced airway responsiveness and airway permeability, while the remaining three sheep showed corresponding decreases in airway responsiveness and airway permeability. Since the O3-induced directional changes in airway responsiveness paralleled the directional changes in airway permeability in both the positive and negative directions, it was concluded that changes in airway responsiveness to inhaled histamine following exposure to O3 may be related to concomitant changes in airway permeability to this agent.

Airway Resistance↗
PubMed1984

Inhibition of antigen-induced bronchoconstriction by methylprednisolone succinate.

We investigated whether the glucocorticoid methylprednisolone succinate mg/kg) could prevent antigen-induced bronchoconstriction in conscious sheep. Ten allergic ewes were subjected to inhalation challenge with Ascaris suum antigen, with and without methylprednisolone pretreatment, administered intravenously either 20 min or 3 hr before antigen challenge. Antigen challenge alone resulted in increased airflow resistance, pulmonary hyperinflation, and decreases in dynamic lung compliance and arterial oxygen tension. Methylprednisolone administered 20 min before antigen challenge had no effect on these antigen-induced changes. In contrast, administration of methylprednisolone 3 hr before antigen challenge effectively prevented all the responses to antigen challenge. We suggest that pretreatment with glucocorticoids can attenuate airway anaphylaxis if sufficient time is allowed between the pretreatment and the antigen challenge.

Animals↗
PubMed1984

Late phase bronchial obstruction following nonimmunologic mast cell degranulation.

Immunologic degranulation of airway mast cells after antigen inhalation produces early and late airway obstructions in allergic sheep. In this study we determined whether nonimmunologic degranulation of airway mast cells by inhalation of compound 48/80 had similar effects. In five sheep, pulmonary flow resistance (RL), thoracic gas volume (Vtg), and arterial O2 tension (Pao2) were determined prior to and at predetermined times after inhalation of 48/80 aerosol. Immediately after challenge mean specific lung resistance (sRL = RL X Vtg) increased by 259% and mean Pao2 decreased by 29%. All values returned to normal by 3 h. By 5-h postchallenge sRL again increased significantly; this second increase in sRL (92% above base line) was maximal at 7 h and was accompanied by a 17% drop in Pao2. In these same sheep inhalation of Ascaris suum antigen produced comparable early changes in sRL, but the onset of the late response was somewhat delayed and more pronounced. In a second group of sheep (n = 5), pretreatment with the mast cell stabilizer cromolyn sodium prevented both early and late responses by compound 48/80. Pretreatment with the histamine H1-antagonist chlorpheniramine had no significant effect on either response, whereas pretreatment with FPL 55712, an antagonist of slow-reacting substance of anaphylaxis (SRS-A), slightly but not significantly attenuated the early response and completely prevented the late response. We conclude that, like immunologic stimuli, nonimmunologic mast cell degranulation produces early and late bronchial obstructions in allergic sheep; that these responses are mediator dependent; and that while histamine and SRS-A contribute to the early response, it is the early appearance of SRS-A which is an important prerequisite for the late response.

Airway Obstruction↗
PubMed1984

The role of slow-reacting substance of anaphylaxis in the late bronchial response after antigen challenge in allergic sheep.

Allergic sheep respond to inhalation challenge with Ascaris suum antigen with an immediate bronchoconstriction that resolves within 2 to 4 h, followed by a second bronchial obstruction occurring 6.5 to 8 h after challenge. The purpose of this study was to determine if the antigen-induced late bronchial response in allergic sheep is mediator dependent and to determine the extent to which histamine and/or slow-reacting substance of anaphylaxis (SRS-A) are involved in this response. To do this, 10 conscious sheep with Ascaris suum hypersensitivity underwent an inhalation challenge with antigen, and the average increase in specific lung resistance (SRL = mean pulmonary flow resistance times thoracic gas volume) was determined for each animal between 6.5 and 8 h after challenge, i.e., the time of late bronchial response. On another occasion, separated by at least 14 days, the animals were rechallenged with antigen, but prior to the onset of the late response (5.5 h) the animals were treated with either the mast cell stabilizer cromolyn (1 mg/kg), the SRS-A antagonist FPL-55712 (3 ml of a 1% wt/vol solution), or the histamine H1. receptor antagonist chlorpheniramine (2 mg/kg). Compared with the control response, inhaled aerosols of cromolyn or FPL-55712 blocked the late increase in SRL (p less than 0.01). Intravenously administered chlorpheniramine alone, or in conjunction with atropine, had no effect on the late response. Finally, the late response was partially reversed by FPL-55712 inhalation. These results suggest that the late bronchial response after inhalation challenge in allergic sheep is mediator dependent, and that SRS-A is a principal mediator of this response.

Airway Resistance↗
PubMed1983

Histamine receptor blocking effects of cimetidine in the airways.

We investigated the modification of histamine-induced bronchoconstriction by the H2-antagonist cimetidine in conscious sheep. One hundred breaths of 5% histamine aerosol increased mean (SD) pulmonary resistance (RL) by 5.6 (1.4) cmH2O/l/sec. This increase in RL was completely blocked by intravenous clemastine (0.5 mg), a specific H1-antagonist, indicating that the histamine-induced bronchoconstriction was mediated by H1-receptors. Intravenous cimetidine caused a dose-dependent enhancement of the histamine response between 1 and 1000 mg with a mean peak delta RL of 15.3 (5) cmH2O/l/sec (p less than 0.05) at the 1000 mg dose, while it blocked the histamine response at a dose of 2400 mg [delta RL = 1.9 (2) cmH2O/l/sec, p = NS]. This paradoxic effect was not related to an anticholinergic mechanism as intravenous cimetidine (2400 mg) failed to block carbachol-induced (25 breaths of 1% solution) bronchoconstriction. We conclude that in the ovine airway, cimetidine is a selective H2-histamine receptor blocker at lower tissue concentrations, and a combined H2- and H1-histamine receptor blocker at high tissue concentrations.

Airway Resistance↗
PubMed1983

Effects of chemical mediators of anaphylaxis on ciliary function.

We assessed the effects of selected chemical mediators of anaphylaxis on CBF in vitro. Ciliated epithelial cells were obtained from the trachea of conscious sheep with a cytology brush and suspended in a perfusion chamber containing KH. Ciliary activity was viewed microscopically and recorded on videotape for subsequent slow-motion analysis of CBF. Prostaglandin E1 (10(-8) M to 10(-6) M), prostaglandin E2 (10(-10) M to 10(-6) M), and leukotriene-C4 (10(-8) M) increased CBF between 7% and 33%. Histamine caused ciliostimulation only at the relatively high concentrations above 10(-5) M (7% increase in CBF), whereas prostaglandin F2 alpha (10(-10) M and 10(-6) M) was without effect. In no preparation was ciliary discoordination observed. These findings indicate that several chemical mediators of anaphylaxis stimulate CBF and that the previously described impairment of mucociliary transport in stable allergic asthma or antigen-induced bronchoconstriction is probably not caused by a primary alteration of ciliary function.

Alprostadil↗