title: Aldose reductase deficiency in mice protects from ragweed pollen extract (RWE)-induced allergic asthma.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors: Department of Biochemistry, 301 University Blvd., The University of Texas Medical Branch, Galveston, TX 77555, USA.
authors: Umesh C S
authors: UC
authors: Yadav
authors: Leopoldo
authors: L
authors: Aguilera-Aguirre
authors: Istvan
authors: I
authors: Boldogh
authors: Kota V
authors: KV
authors: Ramana
authors: Satish K
authors: SK
authors: Srivastava
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000378:metabolism; D031164:Ambrosia / Q000737:chemistry; D000818:Animals; D001249:Asthma / Q000201:enzymology* / Q000517:prevention & control*; D048289:Imidazolidines / Q000008:administration & dosage*; D051379:Mice; D018345:Mice, Knockout; D010936:Plant Extracts; D011058:Pollen; D006255:Rhinitis, Allergic, Seasonal / Q000201:enzymology* / Q000517:prevention & control*; D016896:Treatment Outcome
chemical_list: D048289:Imidazolidines; D010936:Plant Extracts; C077139:fidarestat; D000449:Aldehyde Reductase