Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Discovery may lead to powerful new therapy for asthma

14.08.2009
Human clinical trials next for compounds that block key enzyme

University of Texas Medical Branch at Galveston researchers have 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.

The discovery, made in experiments conducted with mice and in human cell cultures, opens the way to human tests of a powerful new treatment for asthma, which today afflicts more than 20 million Americans. Such a development would provide a badly needed alternative to current asthma therapy, which primarily depends on hard-to-calibrate inhaled doses of corticosteroids and bronchodilators, which have a number of side effects.

"Oral administration of aldose reductase inhibitors works effectively in experimental animals," said UTMB professor Satish Srivastava, senior author of a paper on the discovery appearing in the Aug. 6 issue of the journal PLoS One. "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."

Srivastava and his colleagues (postdoctoral fellows Umesh Yadav and Leopoldo Aguilera-Aguirre, associate professor Kota Venkata Ramana, professor Istvan Boldogh and LSU Health Sciences Center assistant professor Hamid Boulares) 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. In disorders such as colon cancer, atherosclerosis, sepsis and uveitis, the Srivastava team has found, cells are hit by a sudden overload of reactive oxygen species (varieties of oxygen and oxygen compounds that are especially eager to react with other molecules). The result is a chain of biochemical reactions that leads the cells' genetic machinery to crank out a barrage of inflammatory signaling proteins. These summon immune system cells and generate even more reactive oxygen species, producing a vicious cycle of ever-increasing inflammation.

Aldose reductase plays an essential part in the activation of the cellular machinery that produces inflammatory proteins in these diseases, the Srivastava group discovered. "We found that if you block aldose reductase, you block the inflammation," Srivastava said. "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. Cells treated with aldose reductase inhibitors, by contrast, 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.

In collaboration with Boldogh, 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). Mice fed a dose of aldose reductase inhibitor before inhaling ragweed extract, however, 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," Srivastava said. "They attract eosinophils and cause inflammation and mucin production in the airway."

The next step, Srivastava said, will be clinical trials to determine whether aldose reductase inhibitors can relieve asthma in humans. The researcher expressed optimism about their potential outcome of the trials, as well as gratitude to the UTMB National Institute of Environmental Health Sciences Center and the sole supporter of his asthma work, the American Asthma Foundation, which last year awarded him a three-year $750,000 research grant.

"Really, a lot of the credit for this belongs to the AAF," Srivastava said. "Our primary interest is in cancer and the secondary complications of diabetes, but we were attracted to asthma pathogenesis because the AAF invited me to apply for a grant. I think they're going to be happy with the results."

Jim Kelly | EurekAlert!
Further information:
http://www.utmb.edu

More articles from Health and Medicine:

nachricht Second cause of hidden hearing loss identified
20.02.2017 | Michigan Medicine - University of Michigan

nachricht Prospect for more effective treatment of nerve pain
20.02.2017 | Universität Zürich

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

Impacts of mass coral die-off on Indian Ocean reefs revealed

21.02.2017 | Earth Sciences

Novel breast tomosynthesis technique reduces screening recall rate

21.02.2017 | Medical Engineering

Use your Voice – and Smart Homes will “LISTEN”

21.02.2017 | Trade Fair News

VideoLinks
B2B-VideoLinks
More VideoLinks >>>