%0 Journal Article
%T Aldose Reductase Inhibition Prevents Allergic Airway Remodeling through PI3K/AKT/GSK3¦Â Pathway in Mice
%A Umesh C. S. Yadav
%A Amarjit S. Naura
%A Leopoldo Aguilera-Aguirre
%A Istvan Boldogh
%A Hamid A. Boulares
%A William J. Calhoun
%A Kota V. Ramana
%A Satish K. Srivastava
%J PLOS ONE
%D 2013
%I Public Library of Science (PLoS)
%R 10.1371/journal.pone.0057442
%X 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 TGF¦Â1-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 TGF¦Â1-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 TGF¦Â1- induced activation of PI3K/AKT/GSK3¦Â pathway but not the phosphorylation of Smad2/3. Conclusion Our results demonstrate that allergen-induced airway remodeling is mediated by AR and its inhibition blocks the progression of remodeling via inhibiting TGF¦Â1-induced Smad-independent and PI3K/AKT/GSK3¦Â-dependent pathway.
%U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0057442