Ological agents which antagonize the factions of certain MC-derived mediators179. Infection with the parasite T. spiralis increases paracellular permeability of the jejunum and decreases the expression of occludin in the tight AMN107 web junctions of enterocytes181. Treatment of WT mice with a c-kit blocking antibody abrogated MC hyperplasia during T. spiralis infection and blocked parasite-induced increases in intestinal permeability181. Mice deficientMucosal Immunol. Author manuscript; available in PMC 2016 February 03.Reber et al.Pagein the chymase MCPT1 also exhibited diminished intestinal permeability during T. spiralis infection, even though numbers of intestinal MMCs were higher during infection in Mcpt1-/- mice than in WT mice181. 1,1-Dimethylbiguanide hydrochloride chemical information Injection of the neuropeptide substance P induces intestinal ion secretion with increase in Isc responses. In intestinal preparations from MC-deficient KitW/W-v mice, substance P-induced Isc responses were diminished to about 50 of those observed in WT mice and were normalized by the adoptive transfer of WT BM cells, suggesting that MCs can contribute to substance P-induced changes in intestinal ion secretion184. By contrast, our group demonstrated that MCs can limit the toxicity associated with high concentrations of another neuropeptide, vasoactive intestinal polypeptide (VIP)82. In that setting, our evidence indicated that VIP induced MC degranulation, releasing the chymase MCPT4 which then degraded VIP82.Author Manuscript Author Manuscript Author Manuscript Author ManuscriptAsthmaRoles of mast cells in allergic responses at mucosal sitesAsthma is a multifaceted disorder characterized by reversible airway narrowing (in many patients in response to particular allergens), immunologically non-specific airway hyperresponsiveness (AHR), chronic inflammation of the airways, and airway remodeling, including fibrosis, goblet cell hyperplasia/metaplasia, increased mucus production, smooth muscle thickening and increased vascularity185?87. Early manifestations of the disorder can appear in childhood, and both genetic188 and environmental factors189 contribute to the development and progression of asthma. Rather than being a single “disease”, the disorder called asthma is likely comprised of distinct subphenotypes with different clinical characteristics and underlying mechanisms190?92. Analysis of lung epithelial brushes, bronchoalveolar lavage (BAL) fluids, lung biopsies, and autopsies have shown increased numbers of MCs in the airways of some asthmatic subjects54, 193?95 but not others194, 196, 197. One feature more often seen in asthmatic subjects than in those without the disease is the presence of MCs within the bronchial epithelium198?00. In subjects with asthma, B cell class switching to IgE occurs in the lymph nodes201, as well as locally in the respiratory mucosa202. IgE binds to FcRI, highly expressed on MCs and basophils, but also, in certain settings by eosinophils and neutrophils; evidence has been reported that FcRI also can be expressed by airway epithelial and smooth muscle cells and by certain nerves (reviewed in69). IgE not only permits allergen-dependent MC activation, but also enhances the stability of FcRI on the MC surface, thus increasing the levels of receptor expression of FcRI, contributing to the maintenance of a positive amplification loop (reviewed in6). Several mouse models of allergic airway inflammation have been developed to recapitulate many aspects of asthma. Studies using the MC knock.Ological agents which antagonize the factions of certain MC-derived mediators179. Infection with the parasite T. spiralis increases paracellular permeability of the jejunum and decreases the expression of occludin in the tight junctions of enterocytes181. Treatment of WT mice with a c-kit blocking antibody abrogated MC hyperplasia during T. spiralis infection and blocked parasite-induced increases in intestinal permeability181. Mice deficientMucosal Immunol. Author manuscript; available in PMC 2016 February 03.Reber et al.Pagein the chymase MCPT1 also exhibited diminished intestinal permeability during T. spiralis infection, even though numbers of intestinal MMCs were higher during infection in Mcpt1-/- mice than in WT mice181. Injection of the neuropeptide substance P induces intestinal ion secretion with increase in Isc responses. In intestinal preparations from MC-deficient KitW/W-v mice, substance P-induced Isc responses were diminished to about 50 of those observed in WT mice and were normalized by the adoptive transfer of WT BM cells, suggesting that MCs can contribute to substance P-induced changes in intestinal ion secretion184. By contrast, our group demonstrated that MCs can limit the toxicity associated with high concentrations of another neuropeptide, vasoactive intestinal polypeptide (VIP)82. In that setting, our evidence indicated that VIP induced MC degranulation, releasing the chymase MCPT4 which then degraded VIP82.Author Manuscript Author Manuscript Author Manuscript Author ManuscriptAsthmaRoles of mast cells in allergic responses at mucosal sitesAsthma is a multifaceted disorder characterized by reversible airway narrowing (in many patients in response to particular allergens), immunologically non-specific airway hyperresponsiveness (AHR), chronic inflammation of the airways, and airway remodeling, including fibrosis, goblet cell hyperplasia/metaplasia, increased mucus production, smooth muscle thickening and increased vascularity185?87. Early manifestations of the disorder can appear in childhood, and both genetic188 and environmental factors189 contribute to the development and progression of asthma. Rather than being a single “disease”, the disorder called asthma is likely comprised of distinct subphenotypes with different clinical characteristics and underlying mechanisms190?92. Analysis of lung epithelial brushes, bronchoalveolar lavage (BAL) fluids, lung biopsies, and autopsies have shown increased numbers of MCs in the airways of some asthmatic subjects54, 193?95 but not others194, 196, 197. One feature more often seen in asthmatic subjects than in those without the disease is the presence of MCs within the bronchial epithelium198?00. In subjects with asthma, B cell class switching to IgE occurs in the lymph nodes201, as well as locally in the respiratory mucosa202. IgE binds to FcRI, highly expressed on MCs and basophils, but also, in certain settings by eosinophils and neutrophils; evidence has been reported that FcRI also can be expressed by airway epithelial and smooth muscle cells and by certain nerves (reviewed in69). IgE not only permits allergen-dependent MC activation, but also enhances the stability of FcRI on the MC surface, thus increasing the levels of receptor expression of FcRI, contributing to the maintenance of a positive amplification loop (reviewed in6). Several mouse models of allergic airway inflammation have been developed to recapitulate many aspects of asthma. Studies using the MC knock.
