Potential Discovery of New Asthma Therapy
Istvan Boldogh, Ph.D. and Satish Srivastava, Ph.D.
University of Texas Medical Branch
NIEHS Grant P30ES006676
Clinical investigators at the NIEHS-funded Center at the University of Texas Medical Branch in Galveston discovered that a single enzyme is critical in most allergen-induced asthma attacks. The activity of the enzyme, aldose reductase, can be significantly reduced by drugs which have already undergone clinical trials for diabetes complications. These discoveries open a pathway for human clinical investigations to determine their effectiveness in treating asthma.
In a wide variety of diseases including cancer, atherosclerosis, asthma, diabetes, etc. exposure to high levels of reactive species leads to the release of a barrage of inflammatory signaling proteins. These proteins stimulate more immune system cells to enter the affected tissue causing the release of even more reactive oxygen species, producing a cycle of ever-increasing inflammation.
Aldose reductase plays a pivotal role in the activation of inflammatory processes. In previous studies, the research team found that when aldose reductase is blocked, the inflammation does not develop. Knowing that asthma is a chronic disease of inflammation, they postulated that aldose reductase inhibition would have beneficial effects in preventing asthma exacerbations.
Experiments were carried out in cultures of human airway epithelial cells. Some cells were treated with an aldose reductase inhibitor. After exposure to ragweed pollen, the untreated cells responded in the same way airway cells respond during an asthma attack, with increased rates of apoptosis, activation of key inflammatory transcription factors, and the generation of a host of molecules associated with inflammation. Cells treated with the enzyme inhibitor had a much milder inflammatory response to the ragweed pollen. Similar studies were also carried out in live mice with similar results. Mice given an aldose reductase inhibitor had a dramatically reduced inflammatory response after exposure to ragweed pollen.
The research team plans to conduct clinical trials to determine whether aldose reductase inhibitors will be beneficial in treating human asthma.
Citation: Yadav UC, Ramana KV, Aguilera-Aguirre L, Boldogh I, Boulares HA, Srivastava SK. Inhibition of aldose reductase prevents experimental allergic airway inflammation in mice. PLoS One. 2009 Aug 6;4(8):e6535.
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