US researchers found that a compound that occurs naturally in broccoli increases the activity of a gene that can protect the lungs against oxidative damage by chronic obstructive pulmonary disease (COPD), a major smoking-related disease. The study could point the way to new therapies that slow the progress of COPD, for which there is currently no effective treatment.
The study is published in the second September issue of the American Journal of Respiratory and Critical Care Medicine and was conducted by researchers from the Johns Hopkins School of Medicine in Baltimore, Maryland.
According to the US National Heart, Lung and Blood Institute (NHLBI), COPD, an umbrella term for what used to be called emphysema and chronic bronchitis, is the 4th leading cause of death in the US, where there are 12 million people living with the disease.
There is no effective therapy for COPD, and over time, patients find it increasingly difficult to breathe, as the airways get narrower from inflammation caused by toxins. The World Health Organization (WHO) predicts that by 2030 COPD will be the third major cause of death in the world. Smoking is the leading cause of COPD.
Scientists already knew that a gene called NRF2 regulates a group of antioxidants that appear to go down as the severity of COPD goes up in smokers, and that a substance found in broccoli, an isothiocynate called sulforaphane, increases the activity of this gene. One of the researchers had also shown that disruption in the expression of NRF2 in mice exposed to cigarette smoke triggered early onset of severe COPD.
For this study, the researchers looked at tissue samples from the lungs of smokers with and without COPD to see if there were any differences in NRF2 expression and the proteins that regulate it, such as KEAP1, which inhibits it, and DJ-1, which stabilizes it.
Compared to the lungs of smokers without COPD, the lungs of smokers with COPD had much lower levels of NRF2-dependent antioxidants, higher levels of oxidative stress markers and a significant decrease in NRF2 protein. There was however no change in NRF2 mRNA levels (showing that the gene was switched on and expressing the protein, but this was later being degraded). Also, levels of KEAP1 were the same for both groups, but the tissue from the smokers showed a significant drop in DJ-1.
Principal investigator Dr Shyam Biswal, an associate professor in the Bloomberg School’s Department of Environmental Health Sciences and Division of Pulmonary and Critical Care at the Johns Hopkins School of Medicine, explained:
“NRF2-dependent antioxidants and DJ-1 expression was negatively associated with severity of COPD.”
Biswal suggested that increasing NRF2-regulated antioxidants could be a new treatment direction for reducing the oxidative damage of COPD.
So far, clinical trials have failed to show significant benefit from treating COPD with antioxidants, but this study shows it may be possible to get better results by reducing the action of KEAP1, which inhibits NRF2.
In an accompanying editorial, Dr Peter Barnes, of the National Heart and Lung Institute in London, wrote:
“Increasing NRF2 may also restore important detoxifying enzymes to counteract other effects of tobacco smoke.”
“This has been achieved in vitro and in vivo by isothiocynate compounds, such as sulforaphane, which occurs naturally in broccoli and [wasabi].”
Isothicyanates, like the ones found in broccoli, inhibit KEAP1 and thus stop it degrading NRF2, wrote Barnes, and sulforapane has been shown to restore antioxidant gene expression in human epithelial tissue where DJ-1 has been reduced.
“Decline in NRF2-regulated Antioxidants in Chronic Obstructive Pulmonary Disease Lungs Due to Loss of Its Positive Regulator, DJ- 1.”
Deepti Malhotra, Rajesh Thimmulappa, Ana Navas-Acien, Andrew Sandford, Mark Elliott, Anju Singh, Linan Chen, Xiaoxi Zhuang, James Hogg, Peter Pare, Rubin M. Tuder, and Shyam .
Am. J. Respir. Crit. Care Med. 178: 592-604.
First published online as doi:10.1164/rccm.200803-380OC
Source: Journal abstract, American Thoracic Society, NHLBI, WHO.
Written by: Catharine Paddock, PhD