Effect of zafirlukast (Accolate) on cellular mediators of inflammation: bronchoalveolar lavage fluid findings after segmental antigen challenge.

The effect of zafirlukast (Z) to alter the inflammatory response to segmental antigen challenge (SAC) was assessed by bronchoalveolar lavage (BAL) in this double-blind, placebo-controlled, two-period, crossover trial in 11 allergic asthmatic patients. Patients with asthma and positive skin tests to antigen received 7 d of treatment with Z (20 mg twice daily) or placebo (P) during two trial periods 14 to 21 d apart. At steady state (Day 5), patients underwent SAC followed by BAL immediately after challenge and 48 h later. Purified alveolar macrophages were analyzed ex vivo for phorbol myristate acetate (PMA)-driven superoxide release. Results were analyzed by analysis of variance (ANOVA). Forty-eight hours after SAC, Z therapy was associated with significantly reduced BAL lymphocytes and alcian blue-positive cells (presumably basophils) compared with P (p < 0.01), with a trend toward reduced numbers of alveolar macrophages (p = 0.06). PMA-driven superoxide release by purified alveolar macrophages was significantly reduced 48 h after SAC in the Z versus P arms (p < 0.05). Reduction of basophil influx, mediator release, and cellular activation may be important in attenuating the late phase of asthma. Collectively, the data suggest that zafirlukast therapy alters cellular infiltration and activation associated with antigen challenge.

[1]  J. Murray,et al.  A controlled trial of the effect of the 5-lipoxygenase inhibitor, zileuton, on lung inflammation produced by segmental antigen challenge in human beings. , 1996, The Journal of allergy and clinical immunology.

[2]  S. Peters,et al.  Pulmonary inflammation after segmental ragweed challenge in allergic asthmatic and nonasthmatic subjects. , 1995, American journal of respiratory and critical care medicine.

[3]  S. Wenzel,et al.  Effect of 5-lipoxygenase inhibition on bronchoconstriction and airway inflammation in nocturnal asthma. , 1995, American journal of respiratory and critical care medicine.

[4]  H. Kita,et al.  Eosinophil major basic protein induces degranulation and IL-8 production by human eosinophils. , 1995, Journal of immunology.

[5]  W. Busse,et al.  A common cold virus, rhinovirus 16, potentiates airway inflammation after segmental antigen bronchoprovocation in allergic subjects. , 1994, The Journal of clinical investigation.

[6]  R. Krell,et al.  Preclinical Exploration of the Potential Antiinflammatory Properties of the Peptide Leukotriene Antagonist ICI 204,219 (Accola™) , 1994, Annals of the New York Academy of Sciences.

[7]  I. Rodger,et al.  Leukotriene D4-induced increases in cytosolic calcium in THP-1 cells: dependence on extracellular calcium and inhibition with selective leukotriene D4 receptor antagonists. , 1994, The Journal of pharmacology and experimental therapeutics.

[8]  S. Galli,et al.  Identification of IgE-bearing cells in the late-phase response to antigen in the lung as basophils. , 1994, American journal of respiratory cell and molecular biology.

[9]  C. Andresen,et al.  Leukotriene D4 receptor antagonism reduces airway hyperresponsiveness in monkeys. , 1994, Pulmonary pharmacology.

[10]  T. Takishima,et al.  Involvement of superoxide in ozone-induced airway hyperresponsiveness in anesthetized cats. , 1993, The American review of respiratory disease.

[11]  P. Ward,et al.  Tumor necrosis factor α regulates in vivo intrapulmonary expression of ICAM-1 , 1993 .

[12]  W. Busse,et al.  Increased airway inflammation with segmental versus aerosol antigen challenge. , 1993, The American review of respiratory disease.

[13]  T. Haahtela,et al.  Leukotriene E4 and granulocytic infiltration into asthmatic airways , 1993, The Lancet.

[14]  W. Calhoun,et al.  Enhanced superoxide production by alveolar macrophages and air-space cells, airway inflammation, and alveolar macrophage density changes after segmental antigen bronchoprovocation in allergic subjects. , 1992, The American review of respiratory disease.

[15]  K. Chung,et al.  Role of inflammatory mediators in asthma. , 1992, British medical bulletin.

[16]  W. Busse,et al.  Immediate and late airway response of allergic rhinitis patients to segmental antigen challenge. Characterization of eosinophil and mast cell mediators. , 1991, The American review of respiratory disease.

[17]  A. Kay,et al.  TNFα mRNA expression in allergic inflammation , 1991 .

[18]  A. Capron,et al.  Increased secretion of tumor necrosis factor alpha and interleukin-6 by alveolar macrophages consecutive to the development of the late asthmatic reaction. , 1991, The Journal of allergy and clinical immunology.

[19]  W. Busse,et al.  Elevated bronchoalveolar lavage fluid histamine levels in allergic asthmatics are associated with increased airway obstruction. , 1991, The American review of respiratory disease.

[20]  E. Bleecker,et al.  Immediate and late inflammatory responses to ragweed antigen challenge of the peripheral airways in allergic asthmatics. Cellular, mediator, and permeability changes. , 1991, The American review of respiratory disease.

[21]  F. Luscinskas,et al.  Adhesion of human basophils, eosinophils, and neutrophils to interleukin 1-activated human vascular endothelial cells: contributions of endothelial cell adhesion molecules , 1991, The Journal of experimental medicine.

[22]  C. Dollery,et al.  Effect of cysteinyl-leukotriene receptor antagonist ICI 204.219 on allergen-induced bronchoconstriction and airway hyperreactivity in atopic subjects , 1991, The Lancet.

[23]  D. Woodward,et al.  Studies on leukotriene D4 as an eosinophil chemoattractant. , 1991, Drugs under experimental and clinical research.

[24]  A. Ford-hutchinson,et al.  Eosinophil-eicosanoid interactions: inhibition of eosinophil chemotaxis in vivo by a LTD4-receptor antagonist. , 1990, European journal of pharmacology.

[25]  J. Kalden,et al.  Effects of IFN on human eosinophils in comparison with other cytokines. A novel class of eosinophil activators with delayed onset of action. , 1990, Journal of immunology.

[26]  R. Djukanović,et al.  Mucosal inflammation in asthma. , 1990, The American review of respiratory disease.

[27]  S. Wenzel,et al.  Elevated levels of leukotriene C4 in bronchoalveolar lavage fluid from atopic asthmatics after endobronchial allergen challenge. , 1990, The American review of respiratory disease.

[28]  R. Murphy,et al.  Mediator release after endobronchial antigen challenge in patients with respiratory allergy. , 1990, The Journal of allergy and clinical immunology.

[29]  S. Wenzel,et al.  Activation of pulmonary mast cells by bronchoalveolar allergen challenge. In vivo release of histamine and tryptase in atopic subjects with and without asthma. , 1988, The American review of respiratory disease.

[30]  M. Chavance,et al.  Seasonal patterns of circulating basophils. , 1988, International archives of allergy and applied immunology.

[31]  P. O'Byrne,et al.  Allergen-induced airway hyperresponsiveness. , 1988, The Journal of allergy and clinical immunology.

[32]  W. Fiers,et al.  Recombinant human tumour necrosis factor (rTNF)2 enhances leukotriene biosynthesis in neutrophils and eosinophils stimulated with the Ca2+ ionophore A23187. , 1987, Clinical and experimental immunology.

[33]  A. Togias,et al.  Inflammatory mediators in late antigen-induced rhinitis. , 1985, The New England journal of medicine.

[34]  C. Nathan,et al.  Identification of interferon-gamma as the lymphokine that activates human macrophage oxidative metabolism and antimicrobial activity , 1983, The Journal of experimental medicine.

[35]  R. Schleimer,et al.  Inhibition of basophil histamine release by anti-inflammatory steroids , 1981, Nature.