title: A novel model of IgE-mediated passive pulmonary anaphylaxis in rats.
abstract: Mast cells are central effector cells in allergic asthma and are augmented in the airways of asthma patients. Attenuating mast cell degranulation and with it the early asthmatic response is an important intervention point to inhibit bronchoconstriction, plasma exudation and tissue oedema formation. To validate the efficacy of novel pharmacological interventions, appropriate and practicable in vivo models reflecting mast cell-dependent mechanisms in the lung, are missing. Thus, we developed a novel model of passive pulmonary anaphylaxis in rats. Rats were passively sensitized by concurrent intratracheal and intradermal (ear) application of an anti-DNP IgE antibody. Intravenous application of the antigen, DNP-BSA in combination with Evans blue dye, led to mast cell degranulation in both tissues. Quantification of mast cell degranulation in the lung was determined by (1) mediator release into bronchoalveolar lavage, (2) extravasation of Evans blue dye into tracheal and bronchial lung tissue and (3) invasive measurement of antigen-induced bronchoconstriction. Quantification of mast cell degranulation in the ear was determined by extravasation of Evans blue dye into ear tissue. We pharmacologically validated our model using the SYK inhibitor Fostamatinib, the H1-receptor antagonist Desloratadine, the mast cell stabilizer disodium cromoglycate (DSCG) and the β2-adrenergic receptor agonist Formoterol. Fostamatinib was equally efficacious in lung and ear. Desloratadine effectively inhibited bronchoconstriction and ear vascular leakage, but was less effective against pulmonary vascular leakage, perhaps reflecting the differing roles for histamine receptor sub-types. DSCG attenuated both vascular leakage in the lung and bronchoconstriction, but with a very short duration of action. As an inhaled approach, Formoterol was more effective in the lung than in the ear. This model of passive pulmonary anaphylaxis provides a tissue relevant readout of early mast cell activity and pharmacological benchmarking broadly reflects responses observed in patients with asthma.
authors.affiliation: Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Wex
authors.affiliation: Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Thaler
authors.affiliation: Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Blum
authors.affiliation: Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Lamb
mesh_terms: D000631:Aminopyridines; D000707:Anaphylaxis / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology*; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000627:therapeutic use; D018893:Bronchoalveolar Lavage; D016084:Bronchoconstriction / Q000187:drug effects; D015550:Cell Degranulation; D004205:Cromolyn Sodium / Q000627:therapeutic use; D004140:Dinitrophenols / Q000008:administration & dosage / Q000276:immunology; D004195:Disease Models, Animal; D039563:Histamine H1 Antagonists, Non-Sedating / Q000627:therapeutic use; D007073:Immunoglobulin E / Q000276:immunology*; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors; D017336:Loratadine / Q000031:analogs & derivatives / Q000627:therapeutic use; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000473:pathology*; D008407:Mast Cells / Q000187:drug effects / Q000473:pathology* / Q000502:physiology; D009025:Morpholines; D010078:Oxazines / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000627:therapeutic use; D011743:Pyrimidines; D051381:Rats; D017208:Rats, Wistar; D012710:Serum Albumin, Bovine / Q000008:administration & dosage / Q000276:immunology; D000072377:Syk Kinase
chemical_list: D000631:Aminopyridines; D018927:Anti-Asthmatic Agents; D004140:Dinitrophenols; D039563:Histamine H1 Antagonists, Non-Sedating; D047908:Intracellular Signaling Peptides and Proteins; D009025:Morpholines; D010078:Oxazines; D011725:Pyridines; D011743:Pyrimidines; C034638:dinitrophenyl-bovine serum albumin; D012710:Serum Albumin, Bovine; D007073:Immunoglobulin E; D017336:Loratadine; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606898:Syk protein, rat; C121345:desloratadine; D004205:Cromolyn Sodium; C523665:fostamatinib