Editors' ChoiceCOPD/Emphysema

Rtp801: Caught Redd Handed

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Science Translational Medicine  07 Jul 2010:
Vol. 2, Issue 39, pp. 39ec106
DOI: 10.1126/scitranslmed.3001429

Cough. Cough. Cough. Cough. Cough. For everyone, a bout of hacking brings annoyance and fatigue. But in patients with chronic obstructive pulmonary disease (COPD), the cough is persistent, courtesy of chronic bronchitis—a permanent inflammation of the lung airways. Worse, the cough comes with a second debilitating condition, emphysema, in which the alveoli—tiny sacs in the lung where oxygen exchange occurs—are destroyed or enlarged and the airways are obstructed, leaving the patient breathless. Smoking is the primary cause of this disease, which progresses with the years of puffing. The lung damage is often irreversible, and thus far the disease remains incurable. Now, Yoshida et al. demonstrate the DNA-damage response protein Rtp801/Redd1 is an essential mediator of cigarette smoke–induced lung injury.

The authors analyzed normal and emphysema-afflicted lung tissue from lung transplant and lung resection patients and showed that the Rtp801/Redd1 protein and its encoding mRNA were increased in the airways of patients with emphysema. Similarly, Rtp801/Redd1 mRNA and protein amounts were augmented in mice exposed to cigarette smoke. This increase in expression of Rtp801/Redd1 was blocked by antioxidants, suggesting that cigarette smoke–induced oxidative stress played a role in Rtp801/Redd1 overexpression. Elevated concentrations of Rtp801/Redd1 in the lungs of mice were accompanied by enhanced inflammation, oxidative stress, and alveolar cell death, thus reproducing the cigarette smoke–induced lung phenotype observed in humans with emphysema. The Rtp801/Redd1–induced inflammation was dependent on the stress-response transcription factor NF-κB. Mice in which the rtp801 gene was knocked out were protected from the acute effects of cigarette smoke and did not develop emphysema even after 6 months of cigarette smoke exposure. These studies warrant further investigation of Rtp801/Redd1 as a target for the treatment of emphysema. Small interfering RNAs that inhibit Rtp801/Redd1 expression are already being tested in clinical trials for the treatment of diseases of the eye, such as age-related macular degeneration and diabetic macular edema, both of which involve oxidative stress and inflammation.

T. Yoshida et al., Rtp801, a suppressor of mTOR signaling, is an essential mediator of cigarette smoke–induced pulmonary injury and emphysema. Nat. Med. 16, 767–774 (2010). [Abstract]

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