The effects of a cysteinyl leukotriene antagonist (ONO-1078) on antigen-induced responses in allergic sheep

W. M. Abraham, A. Ahmed, A. Cortes, M. Sielczak, J. Hallmon

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

The cysteinyl leukotrienes (LTC4/D4/E4) are putative mediators of asthma. In this study we used sheep allergic to Ascaris suum antigen to examine the effects of a novel orally active cysteinyl LT antagonist, ONO-1078, on antigen-induced early and late responses, airway inflammation, post challenge (24 h) airway hyperresponsiveness (AHR) and mucociliary clearance. Airway responses to antigen were determined by measuring specific lung resistance (SRL) before and for 8 h after challenge, bronchoalveolar lavage (BAL) was used to estimate airway inflammation, and airway responsiveness was measured by determining the carbachol dose that increased SRL by 400% (PC400). We also used a radiographic technique to measure the antigen-induced change in tracheal mucus velocity (TMV), a marker of mucociliary clearance. In two trials separated by at least 21 days, sheep were treated once with ONO-1078 (30 mg/kg, p.o.) and once with placebo (0.5% methylcellulose), 2 h before and 4 h after antigen challenge. Treatment with ONO-1078 (n = 7) provided 40% protection (p < 0.10) against the peak early increase in SRL, resulted in a more rapid reversal of the early response, and provided 96% protection against the peak late (6-8 h) increase in SRL. ONO-1078 also inhibited the AHR 24 h after challenge. In the drug trial, PC400 was unchanged as compared to pre-challenge, whereas in the placebo trial, PC400 was decreased 1.4-fold (p < 0.05). Treatment however, did not affect BAL cell numbers or differential. Antigen challenge caused a reduction in TMV (n = 7) which was less severe in the drug trial as compared to the placebo trial, but this difference was not significant. These results confirm our previous findings that the cysteinyl LT contribute to the antigen-induced early and late bronchial responses and the AHR that follows on the days after antigen challenge in allergic sheep. Our results do not support a major role for the cysteinyl LT in the airway inflammatory cell influx or the antigen-induced changes in TMV in this animal model.

Original languageEnglish
Pages (from-to)233-239
Number of pages7
JournalProstaglandins, Leukotrienes and Essential Fatty Acids
Volume48
Issue number3
DOIs
StatePublished - Jan 1 1993
Externally publishedYes

Fingerprint

Leukotriene Antagonists
Sheep
Antigens
Mucus
Mucociliary Clearance
Placebos
Bronchoalveolar Lavage
Bridge clearances
Ascaris suum
Inflammation
Leukotriene D4
cysteinyl-leukotriene
pranlukast
Leukotriene C4
Methylcellulose
Carbachol
Pharmaceutical Preparations
Animals
Asthma
Animal Models

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Endocrinology, Diabetes and Metabolism

Cite this

The effects of a cysteinyl leukotriene antagonist (ONO-1078) on antigen-induced responses in allergic sheep. / Abraham, W. M.; Ahmed, A.; Cortes, A.; Sielczak, M.; Hallmon, J.

In: Prostaglandins, Leukotrienes and Essential Fatty Acids, Vol. 48, No. 3, 01.01.1993, p. 233-239.

Research output: Contribution to journalArticle

Abraham, W. M. ; Ahmed, A. ; Cortes, A. ; Sielczak, M. ; Hallmon, J. / The effects of a cysteinyl leukotriene antagonist (ONO-1078) on antigen-induced responses in allergic sheep. In: Prostaglandins, Leukotrienes and Essential Fatty Acids. 1993 ; Vol. 48, No. 3. pp. 233-239.
@article{5994aae8e9b6415aa88d7a0d04671d33,
title = "The effects of a cysteinyl leukotriene antagonist (ONO-1078) on antigen-induced responses in allergic sheep",
abstract = "The cysteinyl leukotrienes (LTC4/D4/E4) are putative mediators of asthma. In this study we used sheep allergic to Ascaris suum antigen to examine the effects of a novel orally active cysteinyl LT antagonist, ONO-1078, on antigen-induced early and late responses, airway inflammation, post challenge (24 h) airway hyperresponsiveness (AHR) and mucociliary clearance. Airway responses to antigen were determined by measuring specific lung resistance (SRL) before and for 8 h after challenge, bronchoalveolar lavage (BAL) was used to estimate airway inflammation, and airway responsiveness was measured by determining the carbachol dose that increased SRL by 400{\%} (PC400). We also used a radiographic technique to measure the antigen-induced change in tracheal mucus velocity (TMV), a marker of mucociliary clearance. In two trials separated by at least 21 days, sheep were treated once with ONO-1078 (30 mg/kg, p.o.) and once with placebo (0.5{\%} methylcellulose), 2 h before and 4 h after antigen challenge. Treatment with ONO-1078 (n = 7) provided 40{\%} protection (p < 0.10) against the peak early increase in SRL, resulted in a more rapid reversal of the early response, and provided 96{\%} protection against the peak late (6-8 h) increase in SRL. ONO-1078 also inhibited the AHR 24 h after challenge. In the drug trial, PC400 was unchanged as compared to pre-challenge, whereas in the placebo trial, PC400 was decreased 1.4-fold (p < 0.05). Treatment however, did not affect BAL cell numbers or differential. Antigen challenge caused a reduction in TMV (n = 7) which was less severe in the drug trial as compared to the placebo trial, but this difference was not significant. These results confirm our previous findings that the cysteinyl LT contribute to the antigen-induced early and late bronchial responses and the AHR that follows on the days after antigen challenge in allergic sheep. Our results do not support a major role for the cysteinyl LT in the airway inflammatory cell influx or the antigen-induced changes in TMV in this animal model.",
author = "Abraham, {W. M.} and A. Ahmed and A. Cortes and M. Sielczak and J. Hallmon",
year = "1993",
month = "1",
day = "1",
doi = "10.1016/0952-3278(93)90091-A",
language = "English",
volume = "48",
pages = "233--239",
journal = "Prostaglandins Leukotrienes and Essential Fatty Acids",
issn = "0952-3278",
publisher = "Churchill Livingstone",
number = "3",

}

TY - JOUR

T1 - The effects of a cysteinyl leukotriene antagonist (ONO-1078) on antigen-induced responses in allergic sheep

AU - Abraham, W. M.

AU - Ahmed, A.

AU - Cortes, A.

AU - Sielczak, M.

AU - Hallmon, J.

PY - 1993/1/1

Y1 - 1993/1/1

N2 - The cysteinyl leukotrienes (LTC4/D4/E4) are putative mediators of asthma. In this study we used sheep allergic to Ascaris suum antigen to examine the effects of a novel orally active cysteinyl LT antagonist, ONO-1078, on antigen-induced early and late responses, airway inflammation, post challenge (24 h) airway hyperresponsiveness (AHR) and mucociliary clearance. Airway responses to antigen were determined by measuring specific lung resistance (SRL) before and for 8 h after challenge, bronchoalveolar lavage (BAL) was used to estimate airway inflammation, and airway responsiveness was measured by determining the carbachol dose that increased SRL by 400% (PC400). We also used a radiographic technique to measure the antigen-induced change in tracheal mucus velocity (TMV), a marker of mucociliary clearance. In two trials separated by at least 21 days, sheep were treated once with ONO-1078 (30 mg/kg, p.o.) and once with placebo (0.5% methylcellulose), 2 h before and 4 h after antigen challenge. Treatment with ONO-1078 (n = 7) provided 40% protection (p < 0.10) against the peak early increase in SRL, resulted in a more rapid reversal of the early response, and provided 96% protection against the peak late (6-8 h) increase in SRL. ONO-1078 also inhibited the AHR 24 h after challenge. In the drug trial, PC400 was unchanged as compared to pre-challenge, whereas in the placebo trial, PC400 was decreased 1.4-fold (p < 0.05). Treatment however, did not affect BAL cell numbers or differential. Antigen challenge caused a reduction in TMV (n = 7) which was less severe in the drug trial as compared to the placebo trial, but this difference was not significant. These results confirm our previous findings that the cysteinyl LT contribute to the antigen-induced early and late bronchial responses and the AHR that follows on the days after antigen challenge in allergic sheep. Our results do not support a major role for the cysteinyl LT in the airway inflammatory cell influx or the antigen-induced changes in TMV in this animal model.

AB - The cysteinyl leukotrienes (LTC4/D4/E4) are putative mediators of asthma. In this study we used sheep allergic to Ascaris suum antigen to examine the effects of a novel orally active cysteinyl LT antagonist, ONO-1078, on antigen-induced early and late responses, airway inflammation, post challenge (24 h) airway hyperresponsiveness (AHR) and mucociliary clearance. Airway responses to antigen were determined by measuring specific lung resistance (SRL) before and for 8 h after challenge, bronchoalveolar lavage (BAL) was used to estimate airway inflammation, and airway responsiveness was measured by determining the carbachol dose that increased SRL by 400% (PC400). We also used a radiographic technique to measure the antigen-induced change in tracheal mucus velocity (TMV), a marker of mucociliary clearance. In two trials separated by at least 21 days, sheep were treated once with ONO-1078 (30 mg/kg, p.o.) and once with placebo (0.5% methylcellulose), 2 h before and 4 h after antigen challenge. Treatment with ONO-1078 (n = 7) provided 40% protection (p < 0.10) against the peak early increase in SRL, resulted in a more rapid reversal of the early response, and provided 96% protection against the peak late (6-8 h) increase in SRL. ONO-1078 also inhibited the AHR 24 h after challenge. In the drug trial, PC400 was unchanged as compared to pre-challenge, whereas in the placebo trial, PC400 was decreased 1.4-fold (p < 0.05). Treatment however, did not affect BAL cell numbers or differential. Antigen challenge caused a reduction in TMV (n = 7) which was less severe in the drug trial as compared to the placebo trial, but this difference was not significant. These results confirm our previous findings that the cysteinyl LT contribute to the antigen-induced early and late bronchial responses and the AHR that follows on the days after antigen challenge in allergic sheep. Our results do not support a major role for the cysteinyl LT in the airway inflammatory cell influx or the antigen-induced changes in TMV in this animal model.

UR - http://www.scopus.com/inward/record.url?scp=0027478876&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0027478876&partnerID=8YFLogxK

U2 - 10.1016/0952-3278(93)90091-A

DO - 10.1016/0952-3278(93)90091-A

M3 - Article

VL - 48

SP - 233

EP - 239

JO - Prostaglandins Leukotrienes and Essential Fatty Acids

JF - Prostaglandins Leukotrienes and Essential Fatty Acids

SN - 0952-3278

IS - 3

ER -