Journal Article

Aldose reductase deficiency in mice protects from ragweed pollen extract (RWE)-induced allergic asthma

Ramana, Kota V, Boldogh, Istvan, Yadav, Umesh CS, Srivastava, Satish K, Aguilera-Aguirre, Leopoldo

2011

Overview

Background Childhood 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. Methods The 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. Results Deficiency 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. Conclusion Our 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.

• Publisher: BioMed Central,BioMed Central Ltd,Nature Publishing Group,BMC
• Subject: Aldehyde reductase / Aldehyde Reductase - antagonists & inhibitors / Aldehyde Reductase - deficiency / Aldehyde Reductase - metabolism / Aldehydes / Aldose reductase / Allergens / allergic asthma / Ambrosia - chemistry / Analysis / Animal models / Animals / Asthma / Asthma - enzymology / Asthma - prevention & control / CD25 antigen / CD4 antigen / Chemokines / Children / Cytokines / Drinking water / Enzyme-linked immunosorbent assay / Epithelial cells / Formaldehyde / Glucose / Helper cells / Imidazolidines - administration & dosage / Immunoregulation / Infiltration / inflammation / Kinases / Leukocytes (eosinophilic) / Lipids / Lung / Lungs / Lymphocytes T / Medicine / Medicine & Public Health / Metaplasia / Mice / Mice, Knockout / Monosaccharides / Mucus / Oxidative stress / Physiological aspects / Plant Extracts / Pneumology/Respiratory System / Pollen / Polyols / Proteins / ragweed pollen extract / Respiratory tract / Rhinitis, Allergic, Seasonal - enzymology / Rhinitis, Allergic, Seasonal - prevention & control / Rodents / Spleen / Studies / Sugars / T cells / Treatment Outcome