PMID- 23460857 OWN - NLM STAT- MEDLINE DCOM- 20130903 LR - 20211021 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 8 IP - 2 DP - 2013 TI - Aldose reductase inhibition prevents allergic airway remodeling through PI3K/AKT/GSK3beta pathway in mice. PG - e57442 LID - 10.1371/journal.pone.0057442 [doi] LID - e57442 AB - 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 TGFbeta1-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 TGFbeta1-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 TGFbeta1- induced activation of PI3K/AKT/GSK3beta 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 TGFbeta1-induced Smad-independent and PI3K/AKT/GSK3beta-dependent pathway. FAU - Yadav, Umesh C S AU - Yadav UC AD - Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas, United States of America. FAU - Naura, Amarjit S AU - Naura AS FAU - Aguilera-Aguirre, Leopoldo AU - Aguilera-Aguirre L FAU - Boldogh, Istvan AU - Boldogh I FAU - Boulares, Hamid A AU - Boulares HA FAU - Calhoun, William J AU - Calhoun WJ FAU - Ramana, Kota V AU - Ramana KV FAU - Srivastava, Satish K AU - Srivastava SK LA - eng GR - P01 AI062885/AI/NIAID NIH HHS/United States GR - R01 ES018948/ES/NIEHS NIH HHS/United States GR - ES018948/ES/NIEHS NIH HHS/United States GR - R01 HL072889/HL/NHLBI NIH HHS/United States GR - ES00667616A1/ES/NIEHS NIH HHS/United States GR - HL072889/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20130227 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Biomarkers) RN - 0 (Enzyme Inhibitors) RN - 0 (Imidazolidines) RN - 0 (Smad Proteins) RN - 0 (Transforming Growth Factor beta1) RN - 8SH8T1164U (fidarestat) RN - 9006-59-1 (Ovalbumin) RN - EC 1.1.1.21 (Aldehyde Reductase) RN - EC 2.7.1.- (Phosphatidylinositol 3-Kinases) RN - EC 2.7.11.1 (GSK3B protein, human) RN - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta) RN - EC 2.7.11.1 (Gsk3b protein, mouse) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.26 (Glycogen Synthase Kinase 3) SB - IM MH - *Airway Remodeling/drug effects MH - Aldehyde Reductase/*antagonists & inhibitors/metabolism MH - Animals MH - Asthma/drug therapy/enzymology MH - Biomarkers/metabolism MH - Chronic Disease MH - Disease Models, Animal MH - Enzyme Inhibitors/pharmacology/therapeutic use MH - Epithelial Cells/drug effects/enzymology/pathology MH - Epithelial-Mesenchymal Transition/drug effects MH - Glycogen Synthase Kinase 3/*metabolism MH - Glycogen Synthase Kinase 3 beta MH - Humans MH - Hypersensitivity/*enzymology/pathology/*physiopathology MH - Imidazolidines/pharmacology/therapeutic use MH - Inflammation/pathology MH - Lung/enzymology/pathology MH - Metaplasia MH - Mice MH - Mucus/metabolism MH - Ovalbumin MH - Phosphatidylinositol 3-Kinases/*metabolism MH - Phosphorylation/drug effects MH - Proto-Oncogene Proteins c-akt/*metabolism MH - Signal Transduction/drug effects MH - Smad Proteins/metabolism MH - Transforming Growth Factor beta1/metabolism PMC - PMC3584054 COIS- Competing Interests: The authors have declared that no competing interests exist. EDAT- 2013/03/06 06:00 MHDA- 2013/09/04 06:00 PMCR- 2013/02/27 CRDT- 2013/03/06 06:00 PHST- 2012/12/19 00:00 [received] PHST- 2013/01/21 00:00 [accepted] PHST- 2013/03/06 06:00 [entrez] PHST- 2013/03/06 06:00 [pubmed] PHST- 2013/09/04 06:00 [medline] PHST- 2013/02/27 00:00 [pmc-release] AID - PONE-D-12-40517 [pii] AID - 10.1371/journal.pone.0057442 [doi] PST - ppublish SO - PLoS One. 2013;8(2):e57442. doi: 10.1371/journal.pone.0057442. Epub 2013 Feb 27.