Aldose reductase inhibition suppresses airway inflammation

Umesh C.S. Yadav, Kota V. Ramana, Satish K. Srivastava

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

Airway inflammation induced by reactive oxygen species (ROS)-mediated activation of redox-sensitive transcription factors is the hallmark of asthma, a prevalent chronic respiratory disease. In various cellular and animal models, we have recently demonstrated that, in response to multiple stimuli, aldose reductase (AKR1B1) regulates the inflammatory signals via NF-kappa B activation. Since NF-κB activation is implicated in asthma pathogenesis, we investigated whether AKR1B1 inhibition could prevent ovalbumin (Ova)- and ragweed pollen extract (RWE)-induced airway inflammation and hyper-responsiveness in mice models and tumor necrosis factor-alpha (TNF-α)-, lipopolysachharide (LPS)- and RWE-induced cytotoxic and inflammatory signals in primary human small airway epithelial cells (SAEC). Sensitization and challenge with Ova or RWE caused airway inflammation and production of inflammatory cytokines, accumulation of eosinophils in airways and sub-epithelial regions, mucin production in the bronchoalveolar lavage fluid, airway hyperresponsiveness, elevated IgE levels and release of Th2 cytokines in the airway and treatment with AKR1B1 inhibitors markedly reduced these pathological changes in mice. In SAEC, treatment with TNF-α, LPS or RWE induced apoptosis, reactive oxygen species generation, synthesis of inflammatory markers IL-6, IL-8, and PGE2 and activation of NF-κB and AP-1. Pharmacological inhibition prevented these changes suggesting that AKR1B1 mediates ROS induced inflammation in small airway epithelial cells. Our results indicate that AKR1B1 inhibitors may offer a novel therapeutic approach to treat inflammatory airway diseases such as asthma.

Original languageEnglish (US)
Pages (from-to)339-345
Number of pages7
JournalChemico-Biological Interactions
Volume191
Issue number1-3
DOIs
StatePublished - May 30 2011

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Keywords

  • Airway inflammation
  • Aldose reductase
  • Asthma
  • ROS
  • Ragweed pollen extract

ASJC Scopus subject areas

  • Toxicology

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