Paradoxical Effects of Rapamycin on Experimental House Dust Mite-Induced Asthma

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

Apolipoprotein E Negatively Regulates House Dust Mite–induced Asthma via a Low-Density Lipoprotein Receptor–mediated Pathway

Rationale: Distinct sets of corticosteroid-unresponsive genes modulate disease severity in asthma

Paradoxical Effect of Rapamycin on Lung C-C Chemokine Expression in Induction and Treatment Models of House Dust Mite-induced Asthma.

<p>Quantification of lung mRNA levels for CCL11, CCL24, CCL7 and CCL17 by qRT-PCR presented as relative mRNA expression. Results for the induction experiment are shown in Panel A (n = 6 animals per group, * P<0.01), while results for the treatment experiment are shown in Panel B (n = 5–10 animals per group, * P<0.05). Results are representative of 2 independent experiments.</p

Human apolipoprotein E genotypes differentially modify house dust mite-induced airway disease in mice

Apolipoprotein E (apoE) is an endogenous negative regulator of airway hyperreactivity (AHR) and mucous cell metaplasia in experimental models of house dust mite (HDM)-induced airway disease. The gene encoding human apoE is polymorphic, with three common alleles (ε2, ε3, and ε4) reflecting single amino acid substitutions at amino acids 112 and 158. The objective of this study was to assess whether the human apoE alleles modify airway responses to repeated nasal HDM challenges. Mice expressing the human apoE ε2 (huApoE2), ε3 (huApoE3), or ε4 (huApoE4) alleles received nasal HDM challenges, and airway responses were compared with mice expressing the endogenous murine apoE gene (muApoE). huApoE3 mice displayed significant reductions in AHR, mucous cell metaplasia, and airway inflammation compared with muApoE mice. The attenuated severity of airway inflammation in huApoE3 mice was associated with reductions in lung mRNA levels of Th2 and Th17 cytokines, as well as chemokines (CCL7, CCL11, CCL24). huApoE4 mice had an intermediate phenotype, with attenuated AHR and IgE production, compared with muApoE mice, whereas airway inflammation and mucous cell metaplasia were not reduced. In contrast, HDM-induced airway responses were not modified in mice expressing the huApoE2 allele. We conclude that the polymorphic huApoE alleles differentially modulate HDM-induced airway disease, which can be stratified, in rank order of increasing disease severity, ε3 < ε4 < ε2. These results raise the possibility that the polymorphic apoE alleles may modify disease severity in human asthma

Paradoxical Effect of Rapamycin on Lung Th2 and Th17 Cytokine Expression in Induction and Treatment Models of House Dust Mite-induced Asthma.

<p>Quantification of lung mRNA levels for IL-4, IL-13, and IL-17A by qRT-PCR presented as relative mRNA expression. Results for the induction experiment are shown in Panel A (n = 6–8 animals per group, * P<0.05, HDM+Vehicle vs. HDM+Rapamycin), while results for the treatment experiment are shown in Panel B (n = 6–10 animals per group, * P<0.001). Results are representative of 2 independent experiments.</p

Paradoxical Effect of Rapamycin on Plasma Immunoglobulin Levels in House Dust Mite-induced Asthma.

<p>Plasma levels of IgE, IgG1 and IgG2a were quantified. Results for the induction experiment are shown in Panels A, C and E, while results for the treatment experiment are shown in Panels B, D and F (n = 8–20 animals per group, * P<0.05 vs. Saline+Vehicle, ** P<0.001).</p

Paradoxical Effect of Rapamycin on Airway Hyperreactivity in House Dust Mite-induced Asthma.

<p>Airway resistance (cm H₂0/ml/s) was directly measured following administration of increasing doses of nebulized methacholine. Results for the induction experiment are shown in Panel A (n = 10 animals per group, * P<0.05), while results form the treatment experiment are shown in Panel B (n = 9–10 animals per group, * P<0.05). Results are representative of 2 independent experiments.</p