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      A Novel Model of IgE-Mediated Passive Pulmonary Anaphylaxis in Rats

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          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 H 1-receptor antagonist Desloratadine, the mast cell stabilizer disodium cromoglycate (DSCG) and the β 2-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.

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          Most cited references20

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          Mouse models of allergic asthma: acute and chronic allergen challenge.

          Asthma is defined as a chronic inflammatory disease of the airways; however, the underlying physiological and immunological processes are not fully understood. Animal models have been used to elucidate asthma pathophysiology, and to identify and evaluate novel therapeutic targets. Several recent review articles (Epstein, 2004; Lloyd, 2007; Boyce and Austen, 2005; Zosky and Sly, 2007) have discussed the potential value of these models. Allergen challenge models reproduce many features of clinical asthma and have been widely used by investigators; however, the majority involve acute allergen challenge procedures. It is recognised that asthma is a chronic inflammatory disease resulting from continued or intermittent allergen exposure, usually via inhalation, and there has been a recent focus on developing chronic allergen exposure models, predominantly in mice. Here, we review the acute and chronic exposure mouse models, and consider their potential role and impact in the field of asthma research.
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            Mast cell-associated alveolar inflammation in patients with atopic uncontrolled asthma.

            A significant proportion of patients with asthma have persistent symptoms despite treatment with inhaled glucocorticosteroids. We hypothesized that in these patients, the alveolar parenchyma is subjected to mast cell-associated alterations. Bronchial and transbronchial biopsies from healthy controls (n = 8), patients with allergic rhinitis (n = 8), and patients with atopic uncontrolled asthma (symptoms despite treatment with inhaled glucocorticosteroids; mean dose, 743 μg/d; n = 14) were processed for immunohistochemical identification of mast cell subtypes and mast cell expression of FcεRI and surface-bound IgE. Whereas no difference in density of total bronchial mast cells was observed between patients with asthma and healthy controls, the total alveolar mast cell density was increased in the patients with asthma (P < .01). Division into mast cell subtypes revealed that in bronchi of patients with asthma, tryptase positive mast cells (MC(T)) numbers decreased compared with controls (P ≤ .05), whereas tryptase and chymase positive mast cells (MC(TC)) increased (P ≤ .05). In the alveolar parenchyma from patients with asthma, an increased density was found for both MC(T) (P ≤ .05) and MC(TC) (P ≤ .05). The increased alveolar mast cell densities were paralleled by an increased mast cell expression of FcεRI (P < .001) compared with the controls. The patients with asthma also had increased numbers (P < .001) and proportions (P < .001) of alveolar mast cells with surface-bound IgE. Similar increases in densities, FcεRI expression, and surface-bound IgE were not seen in separate explorations of alveolar mast cells in patients with allergic rhinitis. Our data suggest that patients with atopic uncontrolled asthma have an increased parenchymal infiltration of MC(T) and MC(TC) populations with increased expression of FcεRI and surface-bound IgE compared with atopic and nonatopic controls. Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.
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              Time course of appearance and disappearance of human mast cell tryptase in the circulation after anaphylaxis.

              Tryptase, a neutral protease of human mast cells, is a potentially important indicator of mast cell involvement in various clinical conditions. The current study examined the time course of appearance and disappearance of tryptase in the circulation after an anaphylactic event and the stability of both endogenous and exogenous tryptase in terms of freeze-thawing and temperature. The peak level of tryptase after an experimentally induced systemic anaphylactic reaction occurred 1-2 h after the initiating bee sting in each of three subjects, in contrast to histamine levels which peaked at 5-10 min. In some cases elevated levels of tryptase may not be detected during the initial 15-30 min. Tryptase levels then declined under apparent first order kinetics with a t1/2 of approximately 2h. Similar disappearance kinetics were observed for two subjects presenting in the emergency room with immediate type reactions, one with severe asthma after indomethacin ingestion, the other with systemic anaphylaxis after a bee sting. Histamine levels declined rapidly and were back to baseline by 15-60 min. Measured levels of tryptase in serum or plasma were not diminished by up to four freeze-thaw cycles. Incubation of serum samples taken from subjects with elevated levels of tryptase at 22 and 37 degrees C indicated that greater than 50% of endogenous tryptase was still detected after 4 d. Purified tryptase added to serum or plasma and incubated as above was less stable: approximately 50% of exogenous tryptase in serum and approximately 15% in plasma was detected after 2d of incubation. Therefore, optimally samples should be stored frozen, but even those stored at room temperature for up to 4 d should be satisfactory. The best time to obtain samples for tryptase determinations is 1-2 h after the precipitating event, but depending on the magnitude of the initial response elevated levels of tryptase may be present in the circulation for several hours.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                26 December 2014
                : 9
                : 12
                : e116166
                Affiliations
                [1]Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
                French National Centre for Scientific Research, France
                Author notes

                Competing Interests: The authors of this manuscript have the following competing interests: All authors are employees of Boehringer Ingelheim Pharma GmbH & Co. KG. The funder (Boehringer Ingelheim Pharma GmbH & Co. KG) provided support in the form of salaries for authors [EW, ET, SB, DL], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

                Conceived and designed the experiments: EW ET SB DL. Performed the experiments: EW ET SB. Analyzed the data: EW ET SB DL. Wrote the paper: EW ET SB DL.

                Article
                PONE-D-14-43728
                10.1371/journal.pone.0116166
                4277472
                25541997
                e2dc880c-fa75-4c14-9362-edce1337556f
                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 29 September 2014
                : 4 December 2014
                Page count
                Pages: 15
                Funding
                The funder (Boehringer Ingelheim Pharma GmbH & Co. KG) provided support in the form of salaries for authors [EW, ET, SB, DL], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.
                Categories
                Research Article
                Biology and Life Sciences
                Anatomy
                Respiratory System
                Cell Biology
                Cellular Types
                Animal Cells
                Connective Tissue Cells
                Mast Cells
                Immunology
                Clinical Immunology
                Anaphylaxis
                Medicine and Health Sciences
                Pharmacology
                Pulmonology
                Asthma
                Research and Analysis Methods
                Animal Studies
                Animal Models of Disease
                Custom metadata
                The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files.

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                Uncategorized

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