The 2-phase study began with vitro experiments with human airway epithelial cells and concluded with experiments conducted with mice. In both phases, when a ragweed extract was introduced no allergic inflammation occurred at the cellular level in cells treated with aldose reductase inhibitors.

According to a public release by the University that conducted the study, "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."

UTMB professor Satish Srivastava, senior author of the paper and his colleagues in the study had speculated that since aldose reductase inhibitors had been shown to stop inflammation in colon cancer, atherosclerosis, sepsis, uveitis and other inflammatory diseases, it might have the same effect on asthma.

"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."

Srivastava sees the clinical human trials as the next step

News link: EurekAlert