Abstract
BackgroundChildhood hospitalization related to asthma remains at historically high levels, and its incidence is on the rise world-wide. Previously, we have demonstrated that aldose reductase (AR), a regulatory enzyme of polyol pathway, is a major mediator of allergen-induced asthma pathogenesis in mouse models. Here, using AR null (AR-/-) mice we have investigated the effect of AR deficiency on the pathogenesis of ragweed pollen extract (RWE)-induced allergic asthma in mice and also examined the efficacy of enteral administration of highly specific AR inhibitor, fidarestat.MethodsThe wild type (WT) and AR-/- mice were sensitized and challenged with RWE to induce allergic asthma. AR inhibitor, fidarestat was administered orally. Airway hyper-responsiveness was measured in unrestrained animals using whole body plethysmography. Mucin levels and Th2 cytokine in broncho-alveolar lavage (BAL) were determined using mouse anti-Muc5A/C ELISA kit and multiplex cytokine array, respectively. Eosinophils infiltration and goblet cells were assessed by H&E and periodic acid Schiff (PAS)-staining of formalin-fixed, paraffin-embedded lung sections. T regulatory cells were assessed in spleen derived CD4+CD25+ T cells population.ResultsDeficiency of AR in mice led to significantly decreased PENH, a marker of airway hyper-responsiveness, metaplasia of airway epithelial cells and mucus hyper-secretion following RWE-challenge. This was accompanied by a dramatic decrease in infiltration of eosinophils into sub-epithelium of lung as well as in BAL and release of Th2 cytokines in response to RWE-challenge of AR-/- mice. Further, enteral administration of fidarestat significantly prevented eosinophils infiltration, airway hyper-responsiveness and also markedly increased population of T regulatory (CD4+CD25+FoxP3+) cells as compared to RWE-sensitized and challenged mice not treated with fidarestat.ConclusionOur results using AR-/- mice strongly suggest the role of AR in allergic asthma pathogenesis and effectiveness of oral administration of AR inhibitor in RWE-induced asthma in mice supports the use of AR inhibitors in the treatment of allergic asthma.
Highlights
Childhood hospitalization related to asthma remains at historically high levels, and its incidence is on the rise world-wide
The results shown here demonstrate that ragweed pollen extract (RWE) sensitization and challenge increased airway resistance, mucus hypersecretion, eosinophils infiltration and inflammatory cytokines and chemokines in wild-type (WT) mice and these changes were significantly decreased in aldose reductase (AR)-/- mice
AR deficiency protects against RWE-induced airway hyper-responsiveness in mice Since inflammatory changes in allergic asthma lead to blockage of airway passages and cause airway resistance leading to hyper-responsiveness, we first subjected the RWE-sensitized and challenged mice to whole body unrestrained plethysmography and quantitatively measured airway responsiveness in response to methacholine inhalation
Summary
Childhood hospitalization related to asthma remains at historically high levels, and its incidence is on the rise world-wide. We have demonstrated that aldose reductase (AR), a regulatory enzyme of polyol pathway, is a major mediator of allergen-induced asthma pathogenesis in mouse models. In spite of the identification of several factors associated with the development of allergic airway inflammation, a clear causative factor or mediator remains elusive. Cellular oxidative stress induced by ROS plays a fundamental role in inflammation through the activation of inflammatory signals which activate stress kinases such as ERK1/2, p38 and JNK, which in turn activate redox-sensitive transcription factors such as NF-B that transcribe pro-inflammatory genes [9,10,11,12]. We have recently demonstrated that ROSderived lipid aldehydes - glutathione (GSH) conjugates and their metabolic products are mediators of redox sensitive signaling. Inhibition of AR significantly decreases the activation of these kinases and transcription factors, which results in decreased inflammation caused by various stimuli including high glucose, cytokines, growth factors, allergens and carcinogens
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