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Biomedical subjects

W M Abraham

Publications and source records attributed to W M Abraham.

At least 109 records · Page 6Linked to original sources
PubMed1989

Effect of nedocromil sodium on antigen-induced airway responses in allergic sheep.

We studied the effects of nedocromil sodium and sodium cromoglycate on early and late bronchial responses, the airway inflammation associated with the late response to inhaled Ascaris suum antigen in allergic sheep in vivo, and the antigen-induced contractile responses of sheep tracheal smooth muscle in vitro. In addition, we examined the effect of nedocromil sodium on the development of antigen-induced airway hyper-responsiveness in this model. Pretreatment with either nedocromil sodium or sodium cromoglycate was effective in blocking antigen-induced early and late responses in allergic sheep. Both drugs also prevented the influx of eosinophils into the airways as assessed by bronchoalveolar lavage, observed during the late response in this model. No difference in drug potency was observed in vivo, but in vitro nedocromil sodium was 10-fold more potent than sodium cromoglycate against antigen-induced contractions of sheep tracheal smooth muscle. Nedocromil sodium was effective in blocking antigen-induced late responses and the subsequent development of airway hyper-responsiveness irrespective of whether the drug was given before antigen challenge or after the immediate response to antigen but before the late response. These findings indicate that nedocromil sodium is effective in the sheep model of asthma and therefore may be beneficial in the treatment of reversible obstructive airway disease in man.

Animals↗
PubMed1989

Lectin-detectable effects of localized pneumonia on airway mucous cell populations: role of cyclooxygenase metabolites.

We examined the airway secretory apparatus of adult sheep with experimental pneumonia to look for morphologic and lectin-binding correlates of increased mucus production. The animals were inoculated in the right caudal lobar bronchus either with starch broth containing Pasteurella haemolytica (INF, n = 6), starch broth alone (SHAM, n = 6), or with P. haemolytica and subsequently treated (INF/T, n = 5) with 2 mg/kg indomethacin, subcutaneously three times daily for 6 days. In the INF and INF/T groups, a localized pneumonic infiltrate containing P. haemolytica organisms was present. The bronchi (18-23rd generation) adjacent to the pneumonic lesion had an increased gland volume fraction (6.3 +/- 3.7% in INF, 11.3 +/- 2.4% in INF/T, and 3.1 +/- 1.9% in SHAM, p less than 0.05 among the three). The mean population densities of BSA-reactive (identifying alpha-D-gal) cells were 41.9 +/- 2.7% in the INF, 40.1 +/- 5.6% in the INF/T, versus 14.3 +/- 1.5% in the SHAM group (p less than 0.05), while the corresponding values for PNA-reactive [identifying beta-D-gal(1----3)-D-galNAc] cells were 28.8 +/- 5.1%, 0%, and 0%, respectively. Nor morphologic abnormalities were seen in the trachea, but BSA staining was shifted to morphologically different mucous cells in the INF and INF/T. We conclude that in localized P. haemolytica pneumonia in sheep (1) there are morphologic changes of the airway secretory apparatus adjacent to the lesion, (2) the glycoconjugate profile of secretory cells adjacent to and remote from the lesion is altered, and (3) cyclooxygenase products influence the chemical composition of secretory cells.

Animals↗
PubMed1989

Effects of ozone on lamb tracheal mucosa. Quantitative glycoconjugate histochemistry.

Whether or not the previously reported O3-induced abnormality in the postnatal development of tracheal secretory function in lambs is accompanied by changes in epithelial cell populations and their glycoconjugate composition was determined. Six lambs were killed at birth and 12 lambs at age 2 weeks. Of the latter 12, six were exposed to O3 (1 ppm, 4 hours daily for 5 days during the 1st week of life) and five had air-sham exposures (controls). Tracheal glycoconjugates were localized in situ with lectins to detect N-acetyl-galactosamine (galNAc), alpha-D-galactose (alpha-gal), beta-D-gal(1----3)-galNAc (beta-gal), and fucose (fuc). Mean (+/- SD) epithelial cell density (cells/mm basal lamina) was 418 +/- 57 in the newborns, 385 +/- 63 in controls (P was not significant), and 342 +/- 47 in O3-exposed lambs (P less than 0.05). Mucous cell density was 87 +/- 12 in newborns, 63 +/- 10 in controls (P less than 0.05), and 76 +/- 10 in O3 exposed lambs (P was not significant). Ciliated cells remained unchanged from birth to 2 weeks (P was not significant), but decreased (P less than 0.05) in O3-exposed lambs. All counted mucous cells contained fuc and galNAc at birth and retained these residues after sham and O3 exposure. The alpha-gal-containing mucous cells declined from 97 +/- 13 to 7 +/- 1 (P less than 0.05) and beta-gal containing cells from 39 +/- 5 to 25 +/- 4 in controls. In contrast, cells containing alpha-gal 71 +/- 10 remained at newborn levels (97 +/- 13) and beta-gal-containing cells increased from 40 +/- 5 at birth to 58 +/- 8 in O3-exposed animals (P less than 0.05). It was concluded that early postnatal exposure of lambs to O3 causes a decrease in epithelial cell density, but retards the developmental decrease in the number of tracheal mucous cells and alters the lectin detectable carbohydrate composition of mucus in these cells. These developmental defects were interpreted to be the morphologic correlates of the previously shown effects of O3 on the maturation of secretory function and mucus transport.

Acetylgalactosamine↗
PubMed1989

Effect of picumast dihydrochloride on antigen-induced early and late airway responses in allergic sheep.

In this study the effects of picumast dihydrochloride (3,4-dimethyl-7-[4-(4-chlorobenzyl)piperazine-1-yl]propoxycoumarine++ + dihydrochloride) a novel antiallergic agent, on antigen-induced early and late responses in allergic sheep were examined. For all studies picumast dihydrochloride was administered as an aerosol approximately 20 min before airway challenge with Ascaris suum antigen. Allergic sheep were challenged on four occasions each greater than or equal to 14 days apart: one placebo trial and after 1 mg, 2.5 mg, and 5 mg picumast dihydrochloride aerosol (total dose nebulized). Specific lung resistance (SRL) was used as an index of the airway response to antigen and was measured before and serially after antigen challenge. In the placebo trial (n = 11) antigen challenge resulted in significant early and late airway responses (i.e. 382% and 185% increases in SRL, respectively). Picumast dihydrochloride at 1.0 mg (n = 7) did not protect against the antigen-induced increases in SRL. At 2.5 mg (n = 7), picumast dihydrochloride gave 48% and 55% (both p less than 0.05) protection against the early and late airway responses, respectively. These effects were slightly enhanced with 5 mg picumast dihydrochloride (n = 7) giving 63% protection against the early response and 81% against the late response. These results suggest that the antiallergic agent picumast dihydrochloride may provide some benefit in the treatment of allergic airway disease.

Administration, Oral↗
PubMed1988

The effect of an orally active leukotriene (LT) D4 antagonist WY-48, 252 on LTD4 and antigen-induced bronchoconstrictions in allergic sheep.

In this study we examined the effects of a new orally active leukotriene (LT) D4 receptor antagonist, WY-48,252 (1,1,1-trifluoro-N-[3-(2-quinolinylmethoxy)phenyl]methanesulfonamide), on LTD4-induced bronchoconstriction and antigen-induced early and late responses in allergic sheep. For all studies WY-48,252 10 mg/kg, was administered via intragastric tube 1 h prior to airway challenge. In seven sheep, airway challenge with LTD4 [delivered dose mean +/- SE, 53 +/- 2 micrograms] resulted in an immediate increase in SRL to 600 +/- 18% over baseline. When these same sheep were treated with WY-48,252, airway challenge with LTD4 (delivered dose, 61 +/- 5 micrograms) resulted in only a 220 +/- 50% increase in SRL (p less than 0.05 vs placebo). The drug had no effect on baseline SRL. WY-48,252 was also effective in reducing early responses and blocking late responses to inhaled antigen in allergic sheep (n = 7). In the control trial, airway challenge with Ascaris suum antigen resulted in immediate and late (i.e. 6-8 h) increases in SRL of 499% and 138% over baseline (both responses, p less than 0.05). When these same sheep were pretreated with WY-48,252 the immediate antigen-induced increase in SRL was 171% and the late response was 49% over baseline (both responses p less than 0.05 vs control). These results indicate that WY-48,252 is a LTD4 antagonist in allergic sheep. The ability of this compound to modify antigen-induced early responses and to block antigen-induced late responses suggests that the generation of LTD4 during airway anaphylaxis contributes to both responses.

Aerosols↗
PubMed1988

Effect of gallopamil, a calcium channel blocker, on carbachol- and histamine-induced bronchoconstriction in sheep.

We compared the in vivo effectiveness of the calcium channel blockers, gallopamil and verapamil, in inhibiting carbachol- and histamine-induced bronchoconstriction in conscious sheep. In 13 sheep, specific lung resistance (SRL) was measured before and after aerosol challenge with histamine (50 breaths; 5% solution) and carbachol (10 breaths; 2.5% solution), without and with pretreatment with intravenous and aerosolized gallopamil and verapamil. Histamine increased mean SRL by 213%. Intravenous (20 micrograms/kg) and aerosolized (5 mg) gallopamil markedly inhibited the histamine-induced bronchoconstriction. Mean SRL increased by 19% and 23%, respectively, whereas 2.5 mg of aerosolized gallopamil partly inhibited the histamine-induced response with SRL increasing by 115% (p less than 0.05). Carbachol increased mean SRL by 380%. Pretreatment with 2.5 mg of aerosolized gallopamil had no effect on carbachol-induced bronchoconstriction, whereas intravenous and 5 mg of aerosolized gallopamil partly attenuated the carbachol response; mean SRL increased by 204% and 177%, respectively (p less than 0.05). Intravenous (150 micrograms/kg) and aerosolized (10 mg and 20 mg) verapamil did not prevent either histamine- or carbachol-induced bronchoconstriction. These results indicate that gallopamil (parenteral and aerosol) attenuates carbachol- and histamine-induced bronchoconstriction, is more potent than verapamil, and may be of therapeutic potential.

Aerosols↗
PubMed1988

The role of leukotrienes in allergen-induced late responses in allergic sheep.

Evidence has been presented that lipoxygenase products of arachidonic acid metabolism released during the early stages of allergic reactions play an important role in the subsequent development of late bronchial responses. Moreover, because of this, the activity of the lipoxygenase pathway and sensitivity to the products generated may be important factors that distinguish between dual and acute responders. We recognize that these studies were performed in an experimental animal model of allergic airway disease. If the same mechanisms that are active in sheep are proven active in humans, then pharmacologic modification of the lipoxygenase pathway or its products (or both) may be important for the treatment of some forms of asthma.

Allergens↗
PubMed1988

Modification of bronchial blood flow during allergic airway responses.

Ascaris suum antigen effects on mean airflow resistance (RL) and bronchial arterial blood flow (Qbr) were studied in allergic anesthetized sheep with documented airway responses. Qbr was measured with electromagnetic flow probes, and supplemental O2 prevented antigen-induced hypoxemia. Aerosol challenge with this specific antigen increased RL and Qbr significantly. Cromolyn sodium aerosol pretreatment prevented antigen-induced increases in RL but not in Qbr. Intravenous cromolyn, however, prevented increases in Qbr and RL, suggesting a role for mast cell degranulation in both bronchomotor and bronchovascular responses to antigen. Antigen-induced increases in Qbr were not solely attributable to histamine release. Indomethacin pretreatment attenuated the antigen-induced increase in Qbr, thus suggesting that vasodilator cyclooxygenase products contribute to the vascular response. Antigen challenge significantly decreased Qbr after indomethacin and metiamide pretreatment, which suggests that vasoconstrictor substances released after antigen exposure also modulate Qbr; however, released vasodilators overshadow vasoconstrictor effects. Thus antigen challenge affects Qbr by locally releasing histamine and vasodilator prostaglandins as well as vasoconstrictor substances. These effects were independent of antigen-induced changes in systemic and pulmonary hemodynamics.

Airway Resistance↗
PubMed1988

Nedocromil sodium in allergen-induced bronchial responses and airway hyperresponsiveness in allergic sheep.

We examined the effects of nedocromil sodium, a new drug developed for the treatment of reversible obstructive airway disease, on allergen-induced early and late bronchial responses and the development of airway hyperresponsiveness 24 h after challenge in nine allergic sheep. On occasions greater than 2 wk apart the sheep were treated with 1) placebo aerosol (buffered saline) before and 3 h after antigen challenge, 2) an aerosol of nedocromil sodium (1 mg/kg in 3 ml buffered saline) before antigen challenge and placebo 3 h after challenge, and 3) placebo aerosol before and nedocromil sodium aerosol 3 h after challenge. Early and late bronchial responses were determined by measuring specific lung resistance (sRL) before and periodically after challenge. Airway responsiveness was assessed by determining from dose-response curves the carbachol concentration (in % wt/vol) that increased sRL to 5 cmH2O/s. In the placebo trial, antigen challenge resulted in early and late increases in sRL over a base line of 353 +/- 32 and 131 +/- 17% (SE), respectively. Both early and late increases in sRL were blocked (P less than 0.05) when the sheep were pretreated with nedocromil sodium. When nedocromil was given after the early response, the late response was reduced significantly. Eight of nine sheep developed airway hyperresponsiveness 24 h after antigen challenge. In these eight sheep, carbachol concentration before antigen challenge was 2.6 +/- 0.3%, 24 h later carbachol concentration was significantly lower (1.8 +/- 0.3%). Both nedocromil sodium treatments blocked (P less than 0.05) this antigen-induced airway hyperresponsiveness.(ABSTRACT TRUNCATED AT 250 WORDS)

Airway Resistance↗
PubMed1988

Cellular markers of inflammation in the airways of allergic sheep with and without allergen-induced late responses.

Allergic sheep respond to inhaled Ascaris suum antigen either with an acute bronchoconstriction alone (acute responders, AR) or both an acute and late bronchoconstriction (dual responders, DR). In this study, we determined if: (1) inflammatory cell composition of bronchoalveolar lavage (BAL) obtained during the late response differs between DR and AR; (2) the difference in inflammatory cells is dependent on the prechallenge BAL cell composition; and (3) drugs that block late airway responses also modify this airway inflammation. Antigen challenge caused significant immediate mean increases in specific lung resistance (SRL) both in DR (n = 28) and in AR (n = 14), but only DR had a late increase in SRL. There were no differences between the two groups in total cell returns or in the percentage of neutrophils in BAL 7.5 to 8 h after challenge, but DR had a 3.5-fold increase (p less than 0.05) in the percentage of eosinophils. Methylprednisolone succinate (15 mg/kg intravenously) given to DR (n = 7) 3 h after antigen challenge blocked the late airway response and the eosinophil response. When BAL was performed both before and after (i.e., 7.5 to 8 h) antigen challenge, similar results were observed: AR (n = 7) and DR (n = 14) exhibited characteristic airway responses. No significant differences in prechallenge BAL cell composition were observed between AR and DR; after challenge both groups showed increases in neutrophils, but only the DR showed an increase (p less than 0.05) in eosinophils. Pretreatment of DR with the antiallergic agents (cromolyn sodium or nedocromil sodium aerosol, 20 mg) blocked the immediate and late responses and the late increase in BAL eosinophils.(ABSTRACT TRUNCATED AT 250 WORDS)

Allergens↗
PubMed1988

A leukotriene and thromboxane inhibitor (Sch 37224) blocks antigen-induced immediate and late responses and airway hyperresponsiveness in allergic sheep.

Peptide leukotrienes and thromboxane A2 are putative mediators of allergen-induced late responses and allergen-induced airway hyperresponsiveness (AHR), respectively. Sch 37224 blocks antigen-induced leukotriene D4 and thromboxane B2 release in guinea pig lung fragments. It also inhibits leukotriene-mediated allergic guinea pig bronchospasm. Sch 37224 was, therefore, tested in allergic sheep (n = 6) with documented immediate and late airway responses and AHR to inhaled Ascaris suum antigen. For these studies, base-line airway dose-response curves to histamine and carbachol were determined on the same day. The sheep were challenged 1 to 2 days later with Ascaris suum antigen, once after placebo treatment and once after 10 mg/kg of Sch 37224, administered orally 18 and 2 hr before challenge (total dose, 20 mg/kg). Airway dose-response curves were subsequently performed 24 hr after antigen challenge. In the placebo trial, antigen challenge caused significant peak immediate and peak late increases over base line in specific lung resistance (SRL) of 286 +/- 51 and 196 +/- 29%, respectively. SRL returned to baseline values 24 hr later, but the sheep had AHR to both histamine and carbachol as indicated by 2.6- and 3.1-fold increases in the slopes of the dose-response curves (P less than .05). Sch 37224 treatment reduced the peak immediate and peak late increases in SRL to 128 +/- 32 and 43 +/- 17%, respectively (both P less than .05 vs. placebo). Furthermore, 24 hr later, the antigen-induced AHR to both histamine and carbachol was blocked (P less than .05 vs. placebo).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Bacterial pneumonia stimulates macromolecule secretion and ion and water fluxes in sheep trachea.

In vivo instillation of Pasteurella haemolytica (greater than or equal to 10(7) colony-forming units/kg) into a lobar bronchus of sheep produced bacterial pneumonia by 7 days postinoculation. Infection was verified bacteriologically and histologically. Macromolecule secretion and ion and water fluxes were subsequently measured in tracheal tissues in vitro and were compared with values from sham-infected sheep. Macromolecules were radiolabeled with 35SO4 and [3H]threonine, and we measured the secretion of macromolecule-bound radiolabel onto the mucosa. Unidirectional fluxes of Cl-, Na+, and water were measured with radioactive tracers under open-circuit and short-circuit conditions. Lung infection increased basal secretion of bound 35SO4 (by 189%) and bound [3H]-threonine (by 110%). It significantly increased net Na+ absorption under open- and short-circuit conditions and induced open-circuit net absorption of Cl- and water (16 +/- 29 microliters X cm-2 X h-1). These changes were associated with specific recruitment of neutrophils and elevated levels of arachidonate metabolites (thromboxane B2 and leukotriene B4) in the airways. Thus the bacterial pneumonia-induced changes in tracheal mucus secretion may be the result of airway inflammation.

Animals↗
PubMed1987

The effect of nedocromil sodium and cromolyn sodium on antigen-induced responses in allergic sheep in vivo and in vitro.

We studied the effects of nedocromil sodium and cromolyn sodium on early and late bronchial responses to inhaled Ascaris suum antigen in allergic sheep in vivo, and the antigen-induced contractile responses of sheep tracheal smooth muscle in vitro. For the in vivo studies the sheep were pretreated with aerosols of placebo (buffered saline solution), 20 mg of nedocromil sodium, or 20 mg of cromolyn sodium (both dissolved in 3 ml of buffered saline solution) and then challenged with aerosol antigen. Specific pulmonary resistance (SRL) was measured before and after challenge to document the responses of the airways. In the trial with placebo, challenge with antigen resulted in significant early and late increases in SRL. Treatment with nedocromil sodium significantly reduced the early response to antigen and blocked the late response. Cromolyn sodium gave the same results; there were no statistical differences between the responses of the airways for the two dogs. In vitro nedocromil sodium at doses of 10(-6)M and 10(-5)M inhibited significantly the contractile responses of sheep tracheal smooth muscle to A suum. Cromolyn sodium only showed efficacy at 10(-5)M. These results suggest that nedocromil sodium may be potentially useful in the treatment of reversible allergic disease of the airways.

Airway Resistance↗
PubMed1986

Differences in airway responsiveness to leukotriene D4 in allergic sheep with and without late bronchial responses.

Allergic sheep respond to inhaled Ascaris suum antigen with either acute and late bronchial obstructions (dual responders) or only acute bronchoconstriction (acute responders). In this study we tested the hypothesis that one factor which may distinguish between these two populations is the difference in sensitivity to a specific mediator of airway anaphylaxis, leukotriene (LT) D4 (a major component of slow reacting substance of anaphylaxis). We postulated that if the hypothesis was correct then dual responders should demonstrate increased airway responses to inhaled LTD4 and that this increased responsiveness should also be reflected by a more severe response to inhaled antigen. To test this we used animals from both groups with the same degree of non-specific airway responsiveness to carbachol and determined their airway responses to controlled inhalation challenges with synthetic LTD4 and Ascaris suum antigen. Airway responsiveness to carbachol was determined by measuring the change in specific lung resistance (SRL) to increasing concentrations of carbachol aerosol, and then identifying, by linear interpolation, the provocative carbachol concentration which produced a 150% increase (PC150) in SRL. Airway responses to LTD4, and antigen were determined by measuring the percentage change in SRL after a controlled inhalation challenge with either aerosol. Airway responsiveness to carbachol was not different between the two groups. There was, however, a difference (p less than 0.05) in the airway response to the same dose of LTD4 in the two groups. Dual responders showed a 297 +/- 72% increase in SRL as compared to a 90 +/- 13% increase in SRL in the acute responders. Dual responders also showed a greater immediate and more prolonged response to antigen than did acute responders. These results suggest that increased responsiveness to LTD4 may be one factor which may distinguish dual responders from acute responders.

Airway Resistance↗