A bradykinin antagonist modifies allergen-induced mediator release and late bronchial responses in sheep

W. M. Abraham, R. M. Burch, S. G. Farmer, M. W. Sielczak, A. Ahmed, A. Cortes

Research output: Contribution to journalArticle

70 Citations (Scopus)

Abstract

We assessed the role of bradykinin (BK) in allergen-induced early and late bronchial responses, airway inflammation, mediator release, and antigen-induced airway hyperresponsiveness in allergic sheep by studying the effects of the BK B2 receptor antagonist, NPC-567 (D-Arg-[Hyp3, D-Phe7]-BK), on these parameters. Antigen challenge was performed on two occasions > 3 wk apart, once with placebo (control) and once after high-dose (10 mg/ml) and low-dose (5 mg/ml) treatments with aerosol NPC-567. In the control trials (n = 14) antigen challenge resulted in an early and late increase in specific lung resistance (SRL). The early response was associated with increases (p < 0.05) in prostaglandin (PG) D2, immunoreactive kinin, tosyl-L-arginine methyl ester (TAME)-esterase, and PGE2 in bronchoalveolar lavage (BAL) fluid. The late response was associated with increase (p < 0.05) in leukotrienes (LT) B4 and C4, thromboxane (TX) B2, 6-keto-PGF(1α), and PGE2. There was a significant influx of neutrophils in the BAL fluid during the late response, and airway hyperresponsiveness to carbachol aerosol was apparent 4 h after challenge. In six sheep the high-dose NPC-567 treatment (given before, during, and 4 h after antigen challenge) did not attenuate the early bronchoconstrictor response or the early release of mediators but caused a significant reduction in the late response (p < 0.05). This protective effect was accompanied by reductions (p < 0.05) in both the concentrations of all the mediators associated with the late response and the severity of the BAL neutrophilia. High-dose NPC-567 did not attenuate the airway hyperresponsiveness or the cellular inflammatory response seen 24 h after challenge. In eight sheep treated with the low dose of NPC-567 (given before, during, and 4, 8, and 24 h after challenge) the early response was not blocked but the late response was again inhibited, as were the mediators associated with the late response. At the low dose the drug did not prevent the airway inflammation at 8 or 24 h. The additional treatments did, however, prevent the 24 h hyperresponsiveness. These data suggest that kinin generation during antigen-induced airway anaphylaxis may be important for controlling the release of arachidonic acid metabolites from airway inflammatory cells that contribute to the development of the late response in the allergic sheep model.

Original languageEnglish
Pages (from-to)787-796
Number of pages10
JournalAmerican Review of Respiratory Disease
Volume143
Issue number4 I
StatePublished - Jan 1 1991
Externally publishedYes

Fingerprint

Allergens
Sheep
Antigens
Kinins
Bronchoalveolar Lavage Fluid
Bradykinin
Aerosols
Bronchoconstrictor Agents
Prostaglandin D2
Inflammation Mediators
Leukotriene C4
Thromboxane B2
Leukotriene B4
Carbachol
Prostaglandins F
Bronchoalveolar Lavage
Anaphylaxis
Esterases
Dinoprostone
Arachidonic Acid

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

Abraham, W. M., Burch, R. M., Farmer, S. G., Sielczak, M. W., Ahmed, A., & Cortes, A. (1991). A bradykinin antagonist modifies allergen-induced mediator release and late bronchial responses in sheep. American Review of Respiratory Disease, 143(4 I), 787-796.

A bradykinin antagonist modifies allergen-induced mediator release and late bronchial responses in sheep. / Abraham, W. M.; Burch, R. M.; Farmer, S. G.; Sielczak, M. W.; Ahmed, A.; Cortes, A.

In: American Review of Respiratory Disease, Vol. 143, No. 4 I, 01.01.1991, p. 787-796.

Research output: Contribution to journalArticle

Abraham, WM, Burch, RM, Farmer, SG, Sielczak, MW, Ahmed, A & Cortes, A 1991, 'A bradykinin antagonist modifies allergen-induced mediator release and late bronchial responses in sheep', American Review of Respiratory Disease, vol. 143, no. 4 I, pp. 787-796.
Abraham WM, Burch RM, Farmer SG, Sielczak MW, Ahmed A, Cortes A. A bradykinin antagonist modifies allergen-induced mediator release and late bronchial responses in sheep. American Review of Respiratory Disease. 1991 Jan 1;143(4 I):787-796.
Abraham, W. M. ; Burch, R. M. ; Farmer, S. G. ; Sielczak, M. W. ; Ahmed, A. ; Cortes, A. / A bradykinin antagonist modifies allergen-induced mediator release and late bronchial responses in sheep. In: American Review of Respiratory Disease. 1991 ; Vol. 143, No. 4 I. pp. 787-796.
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