A potent new treatment for asthma seems to waiting in the wings after a research team, including an Indian origin boffin, has made major breakthroughs.
Researchers at the University of Texas Medical Branch at Galveston found that a single enzyme is apparently critical to most allergen-provoked asthma attacks - and that activity of the enzyme, known as aldose reductase, can be significantly reduced by compounds that have already undergone clinical trials as treatments for complications of diabetes.
Advertisement"Oral administration of aldose reductase inhibitors works effectively in experimental animals. 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," said UTMB professor Satish Srivastava, senior author of a study.
Srivastava and his colleagues focused on aldose reductase inhibition as a possible asthma therapy after establishing an essential role for the enzyme in other diseases also characterized by inflammation.
Srivastava said: "We found that if you block aldose reductase, you block the inflammation. Now, asthma, a chronic disease of inflammation is augmented by reactive oxygen species. So we thought, why not find out if aldose reductase inhibition also has an effect on asthma?"
In an initial series of in vitro experiments, the researchers applied ragweed pollen extract (ragweed pollen is notorious for provoking the allergic reactions that lead to allergies and asthmatic airway inflammation) to cultures of human airway epithelial cells -the cells that line the network of air passages within the lungs. Some of the cultures had been pretreated with an aldose reductase inhibitor, while others had not.
The untreated cells responded in much the same way airway cells do in an asthma attack, with an increased rate of apoptosis (cell suicide), a jump in the levels of reactive oxygen species, the activation of key "transcription factors" that kick-start the production of inflammatory proteins and the large-scale generation of a whole host of molecules associated with inflammation.
On contrary, cells treated with aldose reductase inhibitors had a much lower rate of apoptosis, reduced levels of reactive oxygen species, far smaller increases in critical transcription factors and substantially lower increases in inflammatory signaling molecules.
Srivastava next investigated whether aldose reductase inhibitors could reduce the asthma-like symptoms of mice exposed to ragweed extract, a well-established clinical model mimicking the allergic airway inflammation that commonly leads to asthma in humans.
When untreated mice inhaled ragweed extract, their lungs suffered an influx of eosinophils (inflammation-inducing white blood cells), a jump in inflammatory signaling molecules, a buildup of mucin (a protein component of mucus) and an increase in airway hyper-reactivity (the tendency of air passages to suddenly constrict under stress).
However, mice fed a dose of aldose reductase inhibitor before inhaling ragweed extract showed dramatically reduced levels of these components of the asthmatic response.
"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," Srivastava said
Srivastava said that the next step will be clinical trials to determine whether aldose reductase inhibitors can relieve asthma in humans.
The study appears in the Aug. 6 issue of the journal PLoS One.
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