Journal Article

Aldose Reductase Inhibition Prevents Metaplasia of Airway Epithelial Cells

Boldogh, Istvan, Srivastava, Satish K., Ramana, Kota V., Yadav, Umesh C. S., Aguilera-Aguirre, Leopoldo

2010

Overview

Goblet cell metaplasia that causes mucus hypersecretion and obstruction in the airway lumen could be life threatening in asthma and chronic obstructive pulmonary disease patients. Inflammatory cytokines such as IL-13 mediate the transformation of airway ciliary epithelial cells to mucin-secreting goblet cells in acute as well as chronic airway inflammatory diseases. However, no effective and specific pharmacologic treatment is currently available. Here, we investigated the mechanisms by which aldose reductase (AR) regulates the mucus cell metaplasia in vitro and in vivo. Metaplasia in primary human small airway epithelial cells (SAEC) was induced by a Th2 cytokine, IL-13, without or with AR inhibitor, fidarestat. After 48 h of incubation with IL-13 a large number of SAEC were transformed into goblet cells as determined by periodic acid-schiff (PAS)-staining and immunohistochemistry using antibodies against Mucin5AC. Further, IL-13 significantly increased the expression of Mucin5AC at mRNA and protein levels. These changes were significantly prevented by treatment of the SAEC with AR inhibitor. AR inhibition also decreased IL-13-induced expression of Muc5AC, Muc5B, and SPDEF, and phosphorylation of JAK-1, ERK1/2 and STAT-6. In a mouse model of ragweed pollen extract (RWE)-induced allergic asthma treatment with fidarestat prevented the expression of IL-13, phosphorylation of STAT-6 and transformation of epithelial cells to goblet cells in the lung. Additionally, while the AR-null mice were resistant, wild-type mice showed goblet cell metaplasia after challenge with RWE. The results show that exposure of SAEC to IL-13 caused goblet cell metaplasia, which was significantly prevented by AR inhibition. Administration of fidarestat to mice prevented RWE-induced goblet cell metaplasia and AR null mice were largely resistant to allergen induced changes in the lung. Thus our results indicate that AR inhibitors such as fidarestat could be developed as therapeutic agents to prevent goblet cell metaplasia in asthma and related pathologies.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Acids / Airway management / Aldehyde reductase / Aldehyde Reductase - antagonists & inhibitors / Aldose reductase / Allergens / Allergies / Analysis / Animals / Antibodies / Asthma / Biochemistry / Biochemistry/Cell Signaling and Trafficking Structures / Chemical compounds / Chronic obstructive pulmonary disease / Cytokines / Diabetic neuropathy / Drug dosages / Enzyme Activation / Enzyme Inhibitors - pharmacology / Epidermal growth factor / Epithelial cells / Epithelial Cells - cytology / Gene expression / Goblet cells / Goblet Cells - cytology / Humans / Immunohistochemistry / Immunology / Immunology/Allergy and Hypersensitivity / In vitro methods and tests / In vivo methods and tests / Incubation / Inflammation / Inflammatory diseases / Inhibition / Inhibitors / Intensive care / Interleukin 13 / Interleukin-13 - metabolism / Kinases / Lipids / Lung - cytology / Lung diseases / Lungs / Lymphocytes T / Metaplasia / Metaplasia - pathology / Metaplasia - prevention & control / Mice / Molecular biology / Monosaccharides / mRNA / Mucin / Mucins / Mucous membrane / Mucus / Nitric oxide / Obstructive lung disease / Oxidation-Reduction / Oxidative stress / Pharmacology / Phosphorylation / Pollen / Prevention / Reactive Oxygen Species / Respiratory Medicine/Asthma / Respiratory system agents / Respiratory tract / Respiratory tract diseases / Rodents / Small intestine / STAT6 Transcription Factor - metabolism / Transcription factors / Transformation / Ventilators / Vitamin E