title: Airway hyperresponsiveness: a story of mice and men and cytokines.
abstract: Bronchial hyperresponsiveness (BHR) is an essential part of the definition of asthma. Although our understanding of the allergic inflammatory and immunologic mechanisms of asthma have markedly increased, the mechanism of BHR remains to be elucidated. Increased BHR is associated temporally with exposure to allergens, certain respiratory viruses, pollutants such as ozone, and certain occupational chemicals. An important research use of determining the degree of BHR to direct and indirect challenge is to determine the efficacy of pharmacologic and immunodulatory agents. Beta-adrenergic agents inhibit BHR and certain genetic polymorphisms of the beta-adrenergic receptor are associated with increased BHR. When beta-adrenergic receptors are blocked, sensitivity to allergens is markedly increased in patients with asthma and animal models of asthma. Allergen challenge and clinical asthma are associated with synthesis and release of pro-inflammatory cytokines such as IL-1 and TNF-alpha which have been shown to decrease the response to beta-agonists and increased the reactivity to methacholine and the airways neutrophils and alveolar macrophages. The Th2 cytokine IL-13 is increased in the airways of asthmatics and increases BHR in normal unsensitized animals. The mechanisms of this effect of IL-13 are being intensively investigated. Our group has shown that IL-13 induced BHR persisted for at least 7 days and the soluble receptor IL-13R2alpha protected against their BHR. Other investigators have demonstrated that IL-13 is necessary and sufficient for the induction of BHR and that eosinophilic airway inflammation in the absence of IL-13 fails to induce BHR. These studies indicate that treatment of human asthma with antagonists of IL-13 may be very effective.
authors.affiliation: Department of Medicine, Creighton University School of Medicine, Omaha, NE, USA. rtownley@creighton.edu
authors.forename: Robert G
authors.initials: RG
authors.lastname: Townley
authors.forename: Masahide
authors.initials: M
authors.lastname: Horiba
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D001249:Asthma / Q000175:diagnosis / Q000276:immunology* / Q000517:prevention & control; D001980:Bronchi / Q000276:immunology; D016535:Bronchial Hyperreactivity / Q000175:diagnosis / Q000276:immunology* / Q000517:prevention & control; D001985:Bronchial Provocation Tests; D016085:Bronchoconstrictor Agents / Q000008:administration & dosage; D005541:Forced Expiratory Volume; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis / Q000502:physiology; D018793:Interleukin-13 / Q000096:biosynthesis / Q000502:physiology; D053661:Interleukin-13 Receptor alpha1 Subunit; D016676:Macrophages, Alveolar / Q000187:drug effects; D016210:Methacholine Chloride / Q000008:administration & dosage; D008969:Molecular Sequence Data; D009154:Mutation; D009504:Neutrophils / Q000187:drug effects; D011110:Polymorphism, Genetic; D011943:Receptors, Adrenergic, beta / Q000737:chemistry / Q000235:genetics; D018123:Receptors, Interleukin / Q000502:physiology; D053660:Receptors, Interleukin-13; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D000318:Adrenergic beta-Agonists; D016085:Bronchoconstrictor Agents; C508181:IL13RA1 protein, human; D007375:Interleukin-1; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D011943:Receptors, Adrenergic, beta; D018123:Receptors, Interleukin; D053660:Receptors, Interleukin-13; D014409:Tumor Necrosis Factor-alpha; D016210:Methacholine Chloride