Yu, M., Tsai, M., Tam, S.Y., Jones, C., Zehnder, J. & Galli, S.J. Mast cells can promote the development of multiple features of chronic asthma in mice. J. Clin. Invest. 116, 1633-1641

Department of Pathology, Stanford University School of Medicine, Stanford, California 94305-5324, USA.
Journal of Clinical Investigation (Impact Factor: 13.22). 07/2006; 116(6):1633-41. DOI: 10.1172/JCI25702
Source: PubMed


Bronchial asthma, the most prevalent cause of significant respiratory morbidity in the developed world, typically is a chronic disorder associated with long-term changes in the airways. We developed a mouse model of chronic asthma that results in markedly increased numbers of airway mast cells, enhanced airway responses to methacholine or antigen, chronic inflammation including infiltration with eosinophils and lymphocytes, airway epithelial goblet cell hyperplasia, enhanced expression of the mucin genes Muc5ac and Muc5b, and increased levels of lung collagen. Using mast cell-deficient (Kit(W-sh/W-sh) and/or Kit(W/W-v)) mice engrafted with FcRgamma+/+ or FcRgamma-/- mast cells, we found that mast cells were required for the full development of each of these features of the model. However, some features also were expressed, although usually at less than wild-type levels, in mice whose mast cells lacked FcRgamma and therefore could not be activated by either antigen- and IgE-dependent aggregation of Fc epsilonRI or the binding of antigen-IgG1 immune complexes to Fc gammaRIII. These findings demonstrate that mast cells can contribute to the development of multiple features of chronic asthma in mice and identify both Fc Rgamma-dependent and Fc Rgamma-independent pathways of mast cell activation as important for the expression of key features of this asthma model.

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Available from: James L Zehnder, Jan 15, 2015
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    • "Mast cells release three groups of mediators76, including preformed granule products, such as histamine, tryptase, chymase and heparin; newly synthesized arachidonic acid products, such as leukotriene C4 (LTC4) and prostaglandin D2 (PGD2)77; and cytokines, such as IL-4, IL-13, and eotaxin78. These products greatly contribute to pathological damage in different tissues (Table 2)79,80. "
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    ABSTRACT: The current definition of allergy is a group of IgE-mediated diseases. However, a large portion of patients with clinical manifestations of allergies do not exhibit elevated serum levels of IgE (sIgEs). In this article, three key factors, i.e. soluble allergens, sIgEs and mast cells or basophils, representing the causative factors, messengers and primary effector cells in allergic inflammation, respectively, were discussed. Based on current knowledge on allergic diseases, we propose that allergic diseases are a group of diseases mediated through activated mast cells and/or basophils in sensitive individuals, and allergic diseases include four subgroups: (1) IgE dependent; (2) other immunoglobulin dependent; (3) non-immunoglobulin mediated; (4) mixture of the first three subgroups. According to our proposed definition, pseudo-allergic-reactions, in which mast cell or basophil activation is not mediated via IgE, or to a lesser extent via IgG or IgM, should be non-IgE-mediated allergic diseases. Specific allergen challenge tests (SACTs) are gold standard tests for diagnosing allergies in vivo, but risky. The identification of surface membrane activation markers of mast cells and basophils (CD203c, CCR3, CD63, etc.) has led to development of the basophil activation test (BAT), an in vitro specific allergen challenge test (SACT). Based on currently available laboratory allergy tests, we here propose a laboratory examination procedure for allergy.
    Full-text · Article · Aug 2013 · Acta Pharmacologica Sinica
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    • "Our data indicate that adiponectin overexpression results in a significant reduction in inflammatory cell recruitment to the airspaces (Figure 2) and in the induction of genes known to drive airway inflammation (Figure 3) after acute OVA challenge. A similar reduction in BAL inflammatory cells as well as reductions in BAL eotaxin and IL-13 with adiponectin overexpression was observed (Figure 4) when we used a chronic OVA challenge protocol in which inflammation is dependent on mast cells [31], a feature relevant to human allergic asthma. Importantly, others have previously reported that adiponectin deficiency results in increased allergic airways inflammation in this chronic challenge protocol, likely as a result of effects on chemokine expression, especially eotaxin [12]. "
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    ABSTRACT: Obesity is an important risk factor for asthma. Obese individuals have decreased circulating adiponectin, an adipose-derived hormone with anti-inflammatory properties. We hypothesized that transgenic overexpression of adiponectin would attenuate allergic airways inflammation and mucous hyperplasia in mice. To test this hypothesis, we used mice overexpressing adiponectin (Adipo Tg). Adipo Tg mice had marked increases in both serum adiponectin and bronchoalveolar lavage (BAL) fluid adiponectin. Both acute and chronic ovalbumin (OVA) sensitization and challenge protocols were used. In both protocols, OVA-induced increases in total BAL cells were attenuated in Adipo Tg versus WT mice. In the acute protocol, OVA-induced increases in several IL-13 dependent genes were attenuated in Adipo Tg versus WT mice, even though IL-13 per se was not affected. With chronic exposure, though OVA-induced increases in goblet cells numbers per millimeter of basement membrane were greater in Adipo Tg versus WT mice, mRNA abundance of mucous genes in lungs was not different. Also, adiponectin overexpression did not induce M2 polarization in alveolar macrophages. Our results indicate that adiponectin protects against allergen-induced inflammatory cell recruitment to the airspaces, but not development of goblet cell hyperplasia.
    Full-text · Article · Jun 2013 · Journal of Allergy
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    • "Although there is considerable evidence concerning the roles of mast cells in the pathogenesis of asthma, little is known about the role of basophils in this disease. It has been reported that chronic airway antigen challenge resulted in the development of mast cell hyperplasia in the lungs of sensitized mice (Ikeda et al., 2003; Yu et al., 2006); however, the potential roles of basophils in murine asthma remain incompletely defined. As a technique to assess the roles of basophils in allergy and helminthic infection, basophil-depleting antibodies have been utilized (Obata et al., 2007; Denzel et al., 2008; Sokol et al., 2008). "
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    ABSTRACT: Background and purpose: Mast cell hyperplasia has been observed in the lungs of mice with experimental asthma, but few reports have studied basophils. Here, we attempted to discriminate and quantify mast cells and basophils in the lungs in a murine asthma model, determine if both cells were increased by multiple antigen challenges and assess the roles of those cells in asthmatic responses. Experimental approach: Sensitized Balb/c mice were intratracheally challenged with ovalbumin four times. Mast cells and basophils in enzymatically digested lung tissue were detected by flow cytometry. An anti-FcεRI monoclonal antibody, MAR-1, was i.p. administered during the multiple challenges. Key results: The numbers of both mast cells (IgE(+) C-kit(+) ) and basophils (IgE(+) C-kit(-) CD49b(+) ) increased in the lungs after three challenges. Treatment with MAR-1 completely abolished the increases; however, a late-phase increase in specific airway resistance (sRaw), and airway eosinophilia and neutrophilia were not affected by the treatment, although the early-phase increase in sRaw was suppressed. MAR-1 reduced antigen-induced airway IL-4 production. Basophils infiltrating the lung clearly produced IL-4 after antigen stimulation in vitro; however, histamine and murine mast cell protease 1 were not increased in the serum after the challenge, indicating that mast cell activation was not evoked. Conclusion and implications: Both mast cells and basophils infiltrated the lungs by multiple intratracheal antigen challenges in sensitized mice. Neither mast cells nor basophils were involved in late-phase airway obstruction, although early-phase obstruction was mediated by basophils. Targeting basophils in asthma therapy may be useful for an early asthmatic response.
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