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Yu, M. et al. 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: 13.77). 07/2006; 116(6):1633-41. DOI: 10.1172/JCI25702
Source: PubMed

ABSTRACT 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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    • "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 4 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 interleukin (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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    • "Given the limitations of acute rodent models, efforts to develop chronic asthma models that use frequent exposures to lower allergen concentrations can better portray exposure histories of allergic subjects to seasonal and episodic exacerbations. Specifically, airway remodeling in these mice include key features of human asthma, such as intraepithelial eosinophils, collagen deposition, epithelial hyperplasia and metaplasia, smooth muscle hyperplasia and hypertrophy, and increases in myofibroblasts (Lloyd and Robinson 2007; Nials and Uddin 2008; Yu et al. 2006). "
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    • "Thus, although mouse " models " of asthma have provided insights into immunological processes, mice do not have asthma, much less chronic asthma. However, a model has recently been developed in which mice sensitized by repetitive and long-term intra-nasal challenge with Ag (ovalbumin) in the absence of artificial adjuvant develop mast-cell dependent AHR with many features of chronic asthma (Yu et al., 2006). A discussion of the limitations of mouse models is beyond the scope of this review but this is thoroughly reviewed elsewhere (Wenzel & Holgate, 2006). "
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    ABSTRACT: Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite involved in many cellular processes, acting not only as an extracellular ligand to its specific G protein-coupled receptors, but also as a putative intracellular messenger with yet unidentified targets. Mast cells are tissue-dwelling pivotal early effectors of allergic responses, which produce and secrete S1P that can bind to its receptors present on mast cells to influence their activation and functions. In this review, we will first discuss the current knowledge of S1P production by two isozymes of sphingosine kinase (SphK). Mechanisms of SphK activation will be discussed, with an emphasis on experimental approaches developed to study their differential activation and biological roles in the context of mast cells. The relevance of mast cells in the etiology of allergic disorders, asthma and anaphylaxis is well established. In this review, this concept will be revisited, focusing on the contribution of S1P production and secretion to the symptoms associated with dysregulated inflammatory responses. To conclude, counteracting the proinflammatory effects of S1P could be envisioned as a therapeutic strategy to treat allergic disorders, exacerbated airway inflammation, and anaphylactic reactions, and various options will be discussed, such as the development of pharmacological tools to inhibit SphKs, S1P neutralizing monoclonal antibody, and S1P receptor antagonists.
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