title: Aldose reductase inhibition prevents allergic airway remodeling through PI3K/AKT/GSK3β pathway in mice.
abstract: BACKGROUND
  Long-term and unresolved airway inflammation and airway remodeling, characteristic features of chronic asthma, if not treated could lead to permanent structural changes in the airways. Aldose reductase (AR), an aldo-sugar and lipid aldehyde metabolizing enzyme, mediates allergen-induced airway inflammation in mice, but its role in the airway remodeling is not known. In the present study, we have examined the role of AR on airway remodeling using ovalbumin (OVA)-induced chronic asthma mouse model and cultured human primary airway epithelial cells (SAECs) and mouse lung fibroblasts (mLFs).
  
  
  METHODS
  Airway remodeling in chronic asthma model was established in mice sensitized and challenged twice a week with OVA for 6 weeks. AR inhibitor, fidarestat, was administered orally in drinking water after first challenge. Inflammatory cells infiltration in the lungs and goblet cell metaplasia, airway thickening, collagen deposition and airway hyper-responsiveness (AHR) in response to increasing doses of methacholine were assessed. The TGFβ1-induced epithelial-mesenchymal transition (EMT) in SAECs and changes in mLFs were examined to investigate AR-mediated molecular mechanism(s) of airway remodeling.
  
  
  RESULTS
  In the OVA-exposed mice for 6 wks inflammatory cells infiltration, levels of inflammatory cytokines and chemokines, goblet cell metaplasia, collagen deposition and AHR were significantly decreased by treatment with AR inhibitor, fidarestat. Further, inhibition of AR prevented TGFβ1-induced altered expression of E-cadherin, Vimentin, Occludin, and MMP-2 in SAECs, and alpha-smooth muscle actin and fibronectin in mLFs. Further, in SAECs, AR inhibition prevented TGFβ1- induced activation of PI3K/AKT/GSK3β pathway but not the phosphorylation of Smad2/3.
  
  
  CONCLUSIONS
  Our results demonstrate that allergen-induced airway remodeling is mediated by AR and its inhibition blocks the progression of remodeling via inhibiting TGFβ1-induced Smad-independent and PI3K/AKT/GSK3β-dependent pathway.
authors: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors: Umesh C S
authors: UC
authors: Yadav
authors: Amarjit S
authors: AS
authors: Naura
authors: Leopoldo
authors: L
authors: Aguilera-Aguirre
authors: Istvan
authors: I
authors: Boldogh
authors: Hamid A
authors: HA
authors: Boulares
authors: William J
authors: WJ
authors: Calhoun
authors: Kota V
authors: KV
authors: Ramana
authors: Satish K
authors: SK
authors: Srivastava
mesh_terms: D056151:Airway Remodeling / Q000187:drug effects; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001249:Asthma / Q000188:drug therapy / Q000201:enzymology; D015415:Biomarkers / Q000378:metabolism; D002908:Chronic Disease; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D006967:Hypersensitivity / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology*; D048289:Imidazolidines / Q000494:pharmacology / Q000627:therapeutic use; D007249:Inflammation / Q000473:pathology; D008168:Lung / Q000201:enzymology / Q000473:pathology; D008679:Metaplasia; D051379:Mice; D009093:Mucus / Q000378:metabolism; D010047:Ovalbumin; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D015415:Biomarkers; D004791:Enzyme Inhibitors; D048289:Imidazolidines; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; C077139:fidarestat; D010047:Ovalbumin; D000449:Aldehyde Reductase; D019869:Phosphatidylinositol 3-Kinases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3