aldose reductase inhibition prevents metaplasia of airway epithelial cells醛糖还原酶抑制防止气道上皮细胞化生.pdfVIP

Aldose Reductase Inhibition Prevents Metaplasia of Airway Epithelial Cells 1 2 1 2 Umesh C. S. Yadav , Leopoldo Aguilera-Aguirre , Kota V. Ramana , Istvan Boldogh , Satish K. Srivastava1* 1 Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas, United States of America, 2 Department of Microbiology and Immunology and Sealy Center for Molecular Medicine, University of Texas Medical Branch, Galveston, Texas, United States of America Abstract Background: 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. Methodology/Findings: 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, an