Public Release:  Key component of debilitating lung disease identified

Johns Hopkins University Bloomberg School of Public Health

For the first time, researchers have demonstrated a close correlation between the decline in a key component of the lung's antioxidant defense system and the progression of chronic obstructive pulmonary disease (COPD) in humans. COPD is a degenerative condition that decreases the flow of air through the lungs as the lung's air sacs are damaged. A study of lung tissue samples from COPD patients by scientists at the Johns Hopkins Bloomberg School of Public Health found that expression of the regulating gene NRF2 was significantly decreased in smokers with advanced COPD compared to smokers without COPD. The study is published in the September 15, 2008, edition of the American Journal of Respiratory and Critical Care Medicine.

The study team was led by Shyam Biswal, PhD, an associate professor in the Bloomberg School's Department of Environmental Health Sciences and the Division of Pulmonary and Critical Care Medicine at the Johns Hopkins School of Medicine. According to Biswal, NRF2 (nuclear factor erythroid-derived 2-related factor 2) works as a "master gene" to turn on numerous antioxidant and pollutant-detoxifying genes to protect the lungs from environmental pollutants, such as cigarette smoke. Biswal previously identified that disruption of NRF2 expression in mice caused early onset and severe emphysema, which is a major component of COPD in human. However, the status of this critical pathway in humans with COPD was unclear.

"This work clearly demonstrates that decline in our antioxidant system is involved in progression of COPD, which could also be the case for other environmental diseases," said Biswal. "There is no treatment of COPD, but NRF2 could be a novel target for the development of new drug therapies."

Rubin Tuder, MD, a co-author of the study now with the faculty of the University of Colorado, added, "As we learn how the protective actions of NRF2 are decreased in the course of a lifetime of exposure to cigarette smoke, it opens new venues for the development of novel drugs fitted for individual patients in specific stages of the disease."

The research was supported by the National Institutes of Health through an investigator- initiated grant, as well as the Specialized Center for Clinically Oriented Research (SCCOR) at the Johns Hopkins School of Medicine. Lung specimens were provided by the Lung Tissue Research Consortium, which is supported by the National Heart, Lung and Blood Institute.

"COPD affects more than 16 million Americans and is the fourth highest cause of death in the United States," said Robert Wise, MD, professor at the Johns Hopkins School of Medicine and director of the Hopkins SCCOR initiative. "It is the only disease among the top 10 causes of death with a rising mortality rate in the United States. It is predicted to be the third largest cause of death by 2020 and has already reached worldwide epidemic proportions."

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Additional authors of "Decline in NRF Regulated Antioxidants in COPD Lungs Due to Loss of Its Positive Regulator DJ-1" include Deepti Malhotra, MS; Rajesh Thimmulappa, PhD; Ana Navas-Acien, MD, PhD; Andrew Sandford, PhD; Mark Elliott, PhD; Anju Singh, PhD; Linan Chen, PhD; Xiaoxi Zhuang, PhD; James Hogg, MD; and Peter Pare, MD.

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