Increasing NRF2-regulated antioxidants could be a new treatment direction

Tag : broccoli
According to the US National Heart, Lung and Blood Institute(NHLBI), COPD, an umbrella term for what used to be calledemphysema and chronic bronchitis, is the 4th leading cause of deathin the US, where there are 12 million people living with thedisease.

There is no effective therapy for COPD, and over time, patientsfind it increasingly difficult to breathe, as the airways getnarrower from inflammation caused by toxins. The World HealthOrganization (WHO) predicts that by 2030 COPD will be the thirdmajor cause of death in the world. Smoking is the leading cause ofCOPD.

Scientists already knew that a gene called NRF2 regulates a groupof antioxidants that appear to go down as the severity of COPD goesup in smokers, and that a substance found in broccoli, anisothiocynate called sulforaphane, increases the activity of thisgene. One of the researchers had also shown that disruption in theexpression of NRF2 in mice exposed to cigarette smoke triggeredearly onset of severe COPD.

For this study, the researchers looked at tissue samples from thelungs of smokers with and without COPD to see if there were anydifferences 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 smokerswith COPD had much lower levels of NRF2-dependent antioxidants,higher levels of oxidative stress markers and a significantdecrease in NRF2 protein. There was however no change in NRF2 mRNAlevels (showing that the gene was switched on and expressing theprotein, but this was later being degraded). Also, levels of KEAP1were the same for both groups, but the tissue from the smokersshowed a significant drop in DJ-1.

Principal investigator Dr Shyam Biswal, an associate professor inthe Bloomberg School's Department of Environmental Health Sciencesand Division of Pulmonary and Critical Care at the Johns HopkinsSchool of Medicine, explained:

"NRF2-dependent antioxidants and DJ-1 expression was negativelyassociated with severity of COPD."

Biswal suggested that increasing NRF2-regulated antioxidants couldbe a new treatment direction for reducing the oxidative damage ofCOPD.

So far, clinical trials have failed to show significant benefitfrom treating COPD with antioxidants, but this study shows it maybe possible to get better results by reducing the action of KEAP1,which inhibits NRF2.

In an accompanying editorial, Dr Peter Barnes, of the NationalHeart and Lung Institute in London, wrote:

"Increasing NRF2 may also restore important detoxifying enzymes tocounteract other effects of tobacco smoke."

"This has been achieved in vitro and in vivo by isothiocynatecompounds, such as sulforaphane, which occurs naturally in broccoliand [wasabi]."

Isothicyanates, like the ones found in broccoli, inhibit KEAP1 andthus stop it degrading NRF2, wrote Barnes, and sulforapane has beenshown to restore antioxidant gene expression in human epithelialtissue where DJ-1 has been reduced.

"Decline in NRF2-regulated Antioxidants in Chronic ObstructivePulmonary Disease Lungs Due to Loss of Its Positive Regulator, DJ-1."
Deepti Malhotra, Rajesh Thimmulappa, Ana Navas-Acien, AndrewSandford, 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

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Source: Journal abstract, American Thoracic Society, NHLBI, WHO.

Written by: Catharine Paddock, PhD
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