Aldose Reductase Inhibition Prevents Allergic Airway Remodeling through PI3K/AKT/GSK3b Pathway in Mice Umesh C. S. Yadav 1. , Amarjit S. Naura 4. , Leopoldo Aguilera-Aguirre 2 , Istvan Boldogh 2 , Hamid A. Boulares 3 , William J. Calhoun 5 , Kota V. Ramana 1 , Satish K. Srivastava 1 * 1 Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas, United States of America, 2 Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America, 3 Department of Pharmacology and Experimental Therapeutics and Stanley Scot Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States of America, 4 Department of Medicine and Stanley Scot Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States of America, 5 Department of Internal Medicine-Pulmonary/Critical Care, University of Texas Medical Branch, Galveston, Texas, United States of America 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 TGFb1-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 TGFb1-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 TGFb1- induced activation of PI3K/AKT/GSK3b 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 TGFb1-induced Smad-independent and PI3K/AKT/GSK3b-dependent pathway. Citation: Yadav UCS, Naura AS, Aguilera-Aguirre L, Boldogh I, Boulares HA, et al. (2013) Aldose Reductase Inhibition Prevents Allergic Airway Remodeling through PI3K/AKT/GSK3b Pathway in Mice. PLoS ONE 8(2): e57442. doi:10.1371/journal.pone.0057442 Editor: Bernhard Ryffel, French National Centre for Scientific Research, France Received December 19, 2012; Accepted January 21, 2013; Published February 27, 2013 Copyright: ß 2013 Yadav et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This study was supported by funds from American Asthma Foundation grant (AAF 08-0219) to SKS. SKS is a William Bowes Senior Fellow of the American Asthma Foundation. HAB is supported by grants from National Institutes of Health (HL072889) and from American Cancer Society (RSG-116608). IB is supported from National Institute of Environmental Health Sciences (NIEHS) grant (ES018948). This study was also supported by NIEHS core facility grant (ES00667616A1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: ssrivast@utmb.edu . These authors contributed equally to this work. Introduction Airway hyper-responsiveness (AHR) in asthma, one of the most prevalent chronic diseases [1], has been linked with airway inflammation and remodeling [2]. Age-related rapid decline in lung function has been found to be related to airway remodeling in asthmatics [3]. Mucous cells metaplasia and mucus hyper- secretion, epithelial-to-mesenchymal transition (EMT), collagen deposition and thickening of basement membrane in the airway are major contributing factors associated with chronic asthma- related airway hyper-responsiveness (AHR) in asthma patients [4– 6]. Although many studies suggest the role of uncontrolled chronic inflammation and free radicals in the mediation of airway remodeling, a clear mechanism remains unknown [7,8]. Further, airway remodeling leads to development of airway obstruction which occurs in many asthmatic patients with long-standing disease and present corticosteroid therapies are ineffective in preventing or treating this critical condition of asthma. We have shown previously that aldose reductase (AR) mediates early airway inflammatory response in ragweed pollen extract (RWE) and ovalbumin (OVA)-induced asthma and IL-13-induced mucous cell metaplasia [9–11]. However the role of AR in long term persisting PLOS ONE | www.plosone.org 1 February 2013 | Volume 8 | Issue 2 | e57442