Aldose Reductase Inhibition Prevents Metaplasia of Airway Epithelial Cells

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

Research output: Contribution to journalArticle

25 Citations (Scopus)

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, 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. Conclusions: 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.

Original languageEnglish (US)
Article numbere14440
JournalPLoS One
Volume5
Issue number12
DOIs
StatePublished - 2010

Fingerprint

aldehyde reductase
metaplasia
Aldehyde Reductase
Goblet Cells
goblet cells
Metaplasia
Interleukin-13
epithelial cells
Epithelial Cells
asthma
Phosphorylation
Asthma
mice
pollen
Mucus
mucus
phosphorylation
extracts
cytokines
lungs

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Aldose Reductase Inhibition Prevents Metaplasia of Airway Epithelial Cells. / Yadav, Umesh C S; Aguilera-Aguirre, Leopoldo; Ramana, Kota; Boldogh, Istvan; Srivastava, Satish.

In: PLoS One, Vol. 5, No. 12, e14440, 2010.

Research output: Contribution to journalArticle

Yadav, Umesh C S ; Aguilera-Aguirre, Leopoldo ; Ramana, Kota ; Boldogh, Istvan ; Srivastava, Satish. / Aldose Reductase Inhibition Prevents Metaplasia of Airway Epithelial Cells. In: PLoS One. 2010 ; Vol. 5, No. 12.
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