Researchers Discover Gene that Determines Asthma Susceptibility by Regulating Inflammation

Findings offer therapeutic potential for human asthma treatment

Disruption of a single gene, Nrf2, plays a critical role in determining the susceptibility to asthma. A research team led by Shyam Biswal, PhD, at the Johns Hopkins Bloomberg School of Public Health found the absence of Nrf2 exacerbated allergen-mediated asthma in mice models. The study’s findings, published in the July 4, 2005, edition of the Journal of Experimental Medicine, may hold therapeutic potential for the treatment of human asthma.

Asthma is a complex inflammatory disease of the airway characterized by airway inflammation and hyperreactivity. The incidence of asthma has doubled in the past two decades in the United States, affecting 20 million Americans. Controlling inflammation is a focus of asthma therapy. Inflammation occurs when certain cells migrate into the airways. These “inflammatory” cells release reactive oxygen species (ROS), causing the airway lining to swell and restrict. ROS is thought to cause lung tissue damage as well. ROS levels are normally offset by antioxidants in non-asthmatics. Recently, researchers have been hunting for novel genes that regulate inflammation with the hope of developing them as targets for the next generation of asthma drugs.

Suspecting that a defect in antioxidant response exacerbates asthma severity, the team of researchers began looking into the genetic factors that might contribute to this deficiency. In 2002, Biswal’s lab discovered Nrf2 acts as a master regulator of the majority of antioxidant pathways and detoxifying enzymes for environmental pollutants. This led researchers to consider the role of Nrf2 in lung inflammatory diseases caused by exposure to allergens. They found that the absence of the Nrf2 gene increased migration of inflammatory cells into the airways and caused an enhanced asthmatic response in mice. “Nrf2 is critical for proper response to allergens in lungs and maintenance of a balance between ROS production. Antioxidant capability regulated by Nrf2 may be a major determinant of susceptibility to allergen-mediated asthma,” says Biswal. “Nrf2 regulated pathways seem to intervene inflammation at several points.”

The findings provide a better understanding of the human body’s defense mechanisms to stress, which may hold clues to better control the inflammation process and improve control over asthma and its symptoms. Study coauthor Tirumalai Rangasamy, PhD said that the next step for researchers will be to look for molecular mechanism of regulation of asthmatic inflammation by Nrf2 and determine if there are alterations in the response of Nrf2 gene in asthma-prone humans. Future studies will determine the therapeutic potential of targeting Nrf2 for treatment of asthma.

Shyam Biswal, PhD

“Disruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice” was written by Tirumalai Rangasamy, Jia Guo, Wayne A. Mitzner, Jessica Roman, Anju Singh, Allison D. Fryer, Masayuki Yamamoto, Thomas W. Kensler, Rubin M. Tuder, Steve N. Georas and Shyam Biswal.

The study was supported by grants from the National Institutes of Health, the National Institute of Environmental Health Sciences, the Maryland Cigarette Restitution Fund, the Flight Attendant Research Institute and the Thomas and Carol McCann Innovative Research Fund for Asthma and Respiratory Disease.

Contact for the Department of Environmental Health Sciences: Brian Fitzek (443) 287-2905 or bfitzek@jhsph.edu.