Abstract
The mammalian target of rapamycin (mTOR) modulates immune responses and cellular proliferation. The objective of this study was to assess whether inhibition of mTOR with rapamycin modifies disease severity in two experimental murine models of house dust mite (HDM)-induced asthma. In an induction model, rapamycin was administered to BALB/c mice coincident with nasal HDM challenges for 3 weeks. In a treatment model, nasal HDM challenges were performed for 6 weeks and rapamycin treatment was administered during weeks 4 through 6. In the induction model, rapamycin significantly attenuated airway inflammation, airway hyperreactivity (AHR) and goblet cell hyperplasia. In contrast, treatment of established HDM-induced asthma with rapamycin exacerbated AHR and airway inflammation, whereas goblet cell hyperplasia was not modified. Phosphorylation of the S6 ribosomal protein, which is downstream of mTORC1, was increased after 3 weeks, but not 6 weeks of HDM-challenge. Rapamycin reduced S6 phosphorylation in HDM-challenged mice in both the induction and treatment models. Thus, the paradoxical effects of rapamycin on asthma severity paralleled the activation of mTOR signaling. Lastly, mediastinal lymph node re-stimulation experiments showed that treatment of rapamycin-naive T cells with ex vivo rapamycin decreased antigen-specific Th2 cytokine production, whereas prior exposure to in vivo rapamycin rendered T cells refractory to the suppressive effects of ex vivo rapamycin. We conclude that rapamycin had paradoxical effects on the pathogenesis of experimental HDM-induced asthma. Thus, consistent with the context-dependent effects of rapamycin on inflammation, the timing of mTOR inhibition may be an important determinant of efficacy and toxicity in HDM-induced asthma.
Highlights
Rapamycin (Sirolimus, RapamuneH) is a macrolide product of Streptomyces hygroscopius that was initially discovered in a soil sample from Easter Island (Rapa Nui) in the early 1970s [1]
house dust mite (HDM) was purchased from Greer Laboratories (Lenoir, NC), while the rapamycin oral solution was from Wyeth (Philadelphia, PA) and Phosal 50 PGH was from the American Lecithin Company (Oxford, CT)
HDM challenges were performed for 6 weeks, whereas treatment with rapamycin or vehicle was administered during weeks 4 through 6 (Figure S1)
Summary
Rapamycin (Sirolimus, RapamuneH) is a macrolide product of Streptomyces hygroscopius that was initially discovered in a soil sample from Easter Island (Rapa Nui) in the early 1970s [1]. The rapamycin derivative, 32-deoxorapamycin (SAR 943), was shown to be as effective as corticosteroids in inhibiting eosinophilic and lymphocytic airway inflammation, Th2 cytokine production, epithelial cell proliferation, goblet cell hyperplasia, and airway hyperreactivity in a murine model of ovalbumin (OVA)-induced asthma [5]. Intratracheal administration of 32deoxorapamycin prior to a single OVA challenge in sensitized Brown-Norway rats, did not inhibit the number of bronchoalveolar lavage fluid eosinophils, lymphocytes or neutrophils, nor did it suppress airway hyperreactivity [6] In another Brown-Norway rat model, repeated oral administration of 32-deoxyrapamycin to sensitized animals that had already begun to receive multiple OVA challenges, inhibited airway smooth muscle and epithelial cell proliferation and reduced the number of CD4+ T cells, but did not inhibit airway hyperreactivity or pulmonary eosinophilia [7]. Previous studies report conflicting results regarding the utility of mTOR inhibitors for the treatment of asthma
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