Broccoli May Hold Key to Slowing COPD Progression

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Sulforaphane restored antioxidant gene expression in a humanbronchial epithelial cell line model of COPD, Shyam Biswal, Ph.D.,of Johns Hopkins University, and colleagues reported in the Sept.15 issue of the American Journal of Respiratory and Critical Care Medicine .
In their series of experiments, lungs of COPD patients showedmarkedly decreased levels of key anti-inflammatory antioxidants andthe protein that stabilizes these nuclear factor erythroid2-related factor 2 (NRF2)-dependent antioxidants againstdegradation.
Since both factors were linked to COPD severity, the findingssuggest that these compounds could be developed to halt COPD, theresearchers said.
Currently available glutathione-based antioxidants have provendisappointing against progression and exacerbations of COPD,commented Peter J. Barnes, D.M., of Imperial College London, in anaccompanying editorial.
Stronger antioxidants that consume the oxidative compounds thatcause damage are typically toxic, which makes restoring NRF2 levelsto normal by blocking the protein that degrades them a moreattractive approach, he said.
NRF2 is a transcription factor that regulates the antioxidantdefense system and plays an important role in lung diseases likeCOPD that involve oxidative stress and inflammation.
Effective reduction of oxidative stress should cut down oninflammation and reverse corticosteroid resistance for COPDpatients, he said. "Furthermore, increasing NRF2 may also restoreimportant detoxifying enzymes to counteract other effects oftobacco smoke."
For this reason, the researchers studied NRF2 and related proteinsin frozen peripheral lung tissue samples from tissue banks for 26patients without COPD, 18 with early stage COPD, and 21 with moreadvanced COPD.
The samples from COPD patients had depleted NRF2-dependentantioxidants with a 0.30- to 0.58-fold change in expression ofgenes for GCLM, HO1, and NQO1 compared with non-COPD patients (all P <0.0001).
Reduced expression of these targets of NRF2 was associated withdecreased lung function as measured by the ratio of expiratoryvolume to lung capacity (all P <0.001).
Gene expression of NRF2 appeared to be normal whereas NRF2 proteinlevels were decimated in advanced COPD compared with non-COPD lungs(ratio 0.04, P <0.0001), which suggested that this key factor in theantioxidant system was expressed but subsequently degraded.
The protein that degrades this protein -- KEAP1 -- was notexpressed more or found in greater quantities in COPD lung tissues.But the DJ-1 protein that stabilizes NRF2 by preventing degradationwas expressed less in patients with mild and more advanced COPDcompared with non-COPD lungs (relative fold change 0.71 and 0.43, P <0.0001).
Disruption of DJ-1 in mouse lungs and human lung epithelial cellsimpaired antioxidant induction in response to exposure to cigarettesmoke.
As expected from these findings, markers of oxidative stress wereelevated in the advanced COPD human lung tissue samples with 94%depletion of glutathione and 94% greater lipid peroxidation ( P =0.005 and P <0.0001, respectively, versus non-COPD).
But when the researchers treated the DJ-1-deficient mouse lungs andhuman lung epithelial cells with sulforaphane, which targets KEAP1,the NRF2-mediated antioxidant defenses were restored.
The compound restored increased induction of the NRF2-dependentantioxidants NQO1 and GCLM ( P <0.001) in response to cigarette smoke back to the level ofunaffected mouse lungs or control cells.
These findings support developing sulforaphane or otherpharmacologic activators of the NRF2 pathway as therapies forpatients with COPD, the researchers said.
However, they noted that caution would be warranted in using thisstrategy in COPD patients with lung cancer since activation of NRF2may provide a growth advantage to lung cancer cells.
"Nonetheless, controlled restoration of NRF2 antioxidant defensestogether with existing therapies, such as smoking cessation and useof anti-inflammatory agents, may greatly help in attenuating COPDprogression as well as in preventing disease exacerbations," theysaid.