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Paradoxical effects of rapamycin on experimental house dust mite-induced asthma.

Fredriksson K, Fielhaber JA, Lam JK, Yao X, Meyer KS, Keeran KJ, Zywicke GJ, Qu X, Yu ZX, Moss J, Kristof AS, Levine SJ - PLoS ONE (2012)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.

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.

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Paradoxical Effect of Rapamycin on Bronchoalveolar Lavage Fluid Inflammatory Cells in Induction and Treatment Models of House Dust Mite-induced Asthma.Balb/c mice received daily nasal challenges with HDM (25 µg) 5 days per week. In the induction model (Panel A), HDM challenges were initiated concurrent with rapamycin administration (3 mg/kg) by gavage 5 days per week for 3 weeks (n = 7–10 animals per group). In the treatment model (Panel B), HDM challenges were administered for 6 weeks and rapamycin administration was given during weeks 4 through 6 (n = 12–13 animals per group). * P<0.05 vs. Saline+Vehicle, ** P<0.001. Results are representative of two independent experiments.
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pone-0033984-g001: Paradoxical Effect of Rapamycin on Bronchoalveolar Lavage Fluid Inflammatory Cells in Induction and Treatment Models of House Dust Mite-induced Asthma.Balb/c mice received daily nasal challenges with HDM (25 µg) 5 days per week. In the induction model (Panel A), HDM challenges were initiated concurrent with rapamycin administration (3 mg/kg) by gavage 5 days per week for 3 weeks (n = 7–10 animals per group). In the treatment model (Panel B), HDM challenges were administered for 6 weeks and rapamycin administration was given during weeks 4 through 6 (n = 12–13 animals per group). * P<0.05 vs. Saline+Vehicle, ** P<0.001. Results are representative of two independent experiments.

Mentions: To induce airway disease, Balb/c mice received daily nasal administration of HDM (25 µg) for 5 days per week. In the induction model, mice received rapamycin or vehicle coincident with the initiation of HDM administration for 3 weeks. In the treatment model, HDM challenges were performed for 6 weeks, whereas treatment with rapamycin or vehicle was administered during weeks 4 through 6 (Figure S1). In the induction model (Figure 1A), mice that had received rapamycin had a significant decrease in the total number of bronchoalveolar lavage fluid (BALF) inflammatory cells, specifically in the number of BALF eosinophils and lymphocytes. In contrast, in the treatment model (Figure 1B), rapamycin significantly increased the total number of BALF inflammatory cells, specifically in the number of eosinophils, lymphocytes, neutrophils and macrophages. As shown in Figure 2, the magnitude of peri-bronchial inflammatory cell infiltrates reflected the opposite effects of rapamycin on the number of BALF inflammatory cells in the induction and treatment models.


Paradoxical effects of rapamycin on experimental house dust mite-induced asthma.

Fredriksson K, Fielhaber JA, Lam JK, Yao X, Meyer KS, Keeran KJ, Zywicke GJ, Qu X, Yu ZX, Moss J, Kristof AS, Levine SJ - PLoS ONE (2012)

Paradoxical Effect of Rapamycin on Bronchoalveolar Lavage Fluid Inflammatory Cells in Induction and Treatment Models of House Dust Mite-induced Asthma.Balb/c mice received daily nasal challenges with HDM (25 µg) 5 days per week. In the induction model (Panel A), HDM challenges were initiated concurrent with rapamycin administration (3 mg/kg) by gavage 5 days per week for 3 weeks (n = 7–10 animals per group). In the treatment model (Panel B), HDM challenges were administered for 6 weeks and rapamycin administration was given during weeks 4 through 6 (n = 12–13 animals per group). * P<0.05 vs. Saline+Vehicle, ** P<0.001. Results are representative of two independent experiments.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3368343&req=5

pone-0033984-g001: Paradoxical Effect of Rapamycin on Bronchoalveolar Lavage Fluid Inflammatory Cells in Induction and Treatment Models of House Dust Mite-induced Asthma.Balb/c mice received daily nasal challenges with HDM (25 µg) 5 days per week. In the induction model (Panel A), HDM challenges were initiated concurrent with rapamycin administration (3 mg/kg) by gavage 5 days per week for 3 weeks (n = 7–10 animals per group). In the treatment model (Panel B), HDM challenges were administered for 6 weeks and rapamycin administration was given during weeks 4 through 6 (n = 12–13 animals per group). * P<0.05 vs. Saline+Vehicle, ** P<0.001. Results are representative of two independent experiments.
Mentions: To induce airway disease, Balb/c mice received daily nasal administration of HDM (25 µg) for 5 days per week. In the induction model, mice received rapamycin or vehicle coincident with the initiation of HDM administration for 3 weeks. In the treatment model, HDM challenges were performed for 6 weeks, whereas treatment with rapamycin or vehicle was administered during weeks 4 through 6 (Figure S1). In the induction model (Figure 1A), mice that had received rapamycin had a significant decrease in the total number of bronchoalveolar lavage fluid (BALF) inflammatory cells, specifically in the number of BALF eosinophils and lymphocytes. In contrast, in the treatment model (Figure 1B), rapamycin significantly increased the total number of BALF inflammatory cells, specifically in the number of eosinophils, lymphocytes, neutrophils and macrophages. As shown in Figure 2, the magnitude of peri-bronchial inflammatory cell infiltrates reflected the opposite effects of rapamycin on the number of BALF inflammatory cells in the induction and treatment models.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.

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.

Show MeSH
Related in: MedlinePlus