Enzyme Discovery Could Lead to a Potent New Therapy for Asthma

The activity of aldose reductase (AR), an enzyme critical to most allergen-provoked asthma attacks, can be significantly reduced by compounds originally developed for treating complications of diabetes.

Researchers at the University of Texas Medical Branch (UTMB; Galveston, USA) used primary human small airway epithelial cells (SAEC) to investigate the in vitro effects of AR inhibition on ragweed pollen extract (RWE)-induced cytotoxic and inflammatory signals. The results indicate that inhibition of AR prevents RWE -induced apoptotic cell death, as measured by markers such as inducible nitric oxide synthase (iNOS), cycloxygenase (COX)-2, prostaglandin (PG) E(2), interleukin (IL)-6, and IL-8. Additionally, mice that were sensitized with endotoxin-free RWE (in both the absence and presence of an AR inhibitor) showed that the inhibition of AR prevented airway inflammation and production of inflammatory cytokines, accumulation of eosinophils in airways and sub-epithelial regions, mucin production in the bronchoalveolar lavage fluid, and airway hyper-responsiveness. The study was published in the August 6, 2009, issue of the journal PLoS One.

"Oral administration of aldose reductase inhibitors works effectively in experimental animals,” said lead author Satish Srivastava, Ph.D., a professor in the departments of biochemistry and molecular biology and immunology at UTMB. "Our hypothesis performed exactly as expected, with the experiments showing that aldose reductase is an essential enzyme in the transduction pathways that cause the transcription of the cytokines and chemokines known to act in asthma pathogenesis. They attract eosinophils and cause inflammation and mucin production in the airway.”

"If these drugs work as well in humans as they do in animals you could administer them either orally or in a single puff from an inhaler and get long-lasting results,” added Professor Srivastava.

Aldose reductase is an enzyme in the carbohydrate metabolism that catalyzes one of the steps in the sorbitol (polyol) pathway that is responsible for fructose formation from glucose. AR activity increases as the glucose concentration rises in diabetes in those tissues that are not insulin sensitive. Since sorbitol does not diffuse through cell membranes easily, it then accumulates, causing osmotic damage, which eventually leads to retinopathy and neuropathy. Inhibitors of AR, such as epalrestat and ranirestat, have already gone through phase-III clinical studies for diabetic complications and have been found to be safe.

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