Title: Rapamycin attenuates airway hyperreactivity, goblet cells, and IgE in experimental allergic asthma.
Authors: Mushaben, Elizabeth M; Kramer, Elizabeth L; Brandt, Eric B; Khurana Hershey, Gurjit K; Le Cras, Timothy D
Published In J Immunol, (2011 Dec 1)
Abstract: The mammalian target of rapamycin (mTOR) signaling pathway integrates environmental cues, promotes cell growth/differentiation, and regulates immune responses. Although inhibition of mTOR with rapamycin has potent immunosuppressive activity, mixed effects have been reported in OVA-induced models of allergic asthma. We investigated the impact of two rapamycin treatment protocols on the major characteristics of allergic asthma induced by the clinically relevant allergen, house dust mite (HDM). In protocol 1, BALB/c mice were exposed to 10 intranasal HDM doses over a period of 24 d and treated with rapamycin simultaneously during the sensitization/exposure period. In protocol 2, rapamycin was administered after the mice had been sensitized to HDM (i.p. injection) and prior to initiation of two intranasal HDM challenges over 4 d. Airway hyperreactivity (AHR), IgE, inflammatory cells, cytokines, leukotrienes, goblet cells, and activated T cells were assessed. In protocol 1, rapamycin blocked HDM-induced increases in AHR, inflammatory cell counts, and IgE, as well as attenuated goblet cell metaplasia. In protocol 2, rapamycin blocked increases in AHR, IgE, and T cell activation and reduced goblet cell metaplasia, but it had no effect on inflammatory cell counts. Increases in IL-13 and leukotrienes were also blocked by rapamycin, although increases in IL-4 were unaffected. These data demonstrated that rapamycin can inhibit cardinal features of allergic asthma, including increases in AHR, IgE, and goblet cells, most likely as a result of its ability to reduce the production of two key mediators of asthma: IL-13 and leukotrienes. These findings highlight the importance of the mTOR pathway in allergic airway disease.
PubMed ID: 22021618
MeSH Terms: Animals; Asthma/drug therapy*; Asthma/immunology; Blotting, Western; Bronchial Hyperreactivity/drug therapy*; Bronchial Hyperreactivity/immunology; Cell Separation; Cytokines/biosynthesis; Disease Models, Animal; Female; Flow Cytometry; Goblet Cells/drug effects*; Goblet Cells/immunology; Hypersensitivity/drug therapy; Hypersensitivity/immunology; Immunoglobulin E/biosynthesis*; Immunohistochemistry; Immunosuppressive Agents/pharmacology*; Mice; Mice, Inbred BALB C; Pyroglyphidae/immunology; Real-Time Polymerase Chain Reaction; Signal Transduction/immunology; Sirolimus/pharmacology*; TOR Serine-Threonine Kinases/antagonists & inhibitors