Research ArticleLung Disease

Targeting Nrf2 Signaling Improves Bacterial Clearance by Alveolar Macrophages in Patients with COPD and in a Mouse Model

Science Translational Medicine  13 Apr 2011:
Vol. 3, Issue 78, pp. 78ra32
DOI: 10.1126/scitranslmed.3002042

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Cleansing Breath

With every breath we take, the outside air assaults the lungs. Along with life-sustaining oxygen come dust, dirt, and microbes. A well-functioning lung cleanses itself with broom-like cilia that sweep out debris and with a robust innate immune defense system driven by macrophages that subdue infectious invaders. But constant exposure to cigarette smoke or pollution can interfere with this self-cleaning system and cause the lung ailment COPD (chronic obstructive pulmonary disease). This common disease is characterized by two conditions that cause shortness of breath, wheezing, chronic cough, and tightness in the chest: emphysema—which is associated with progressive destruction of lung tissue—and bronchitis—an inflammation of the airway passages (bronchi). Understanding the mechanistic details of how irritants in the air disable the lung’s defenses can help uncover possible drug targets. Now, Harvey and colleagues have fingered a cigarette smoke–triggered change in a signaling pathway that regulates defense against oxidative stress, which may impair lung macrophage function. In both COPD patients and a mouse model of COPD, a phytochemical found in broccoli can activate this pathway and improve the ability of lung macrophages to sequester and inactivate the bacteria that often causes exacerbations of COPD.

Although the mechanism is unclear, lung macrophages from patients with COPD are defective in taking up (phagocytosing) bacteria for eventual destruction. This aberration gives rise to both the persistent presence of bacteria, which promotes inflammation, and frequent bacterial infections often caused by Haemophilus influenzae and Pseudomonas aeruginosa; these conditions aggravate COPD symptoms, and there are no therapies that prevent these bacterially induced exacerbations. It has been suggested that macrophage defects in COPD result from oxidative stress. Studies in mice subjected to secondhand smoke reveal a role for the transcription factor Nrf2 (nuclear erythroid–related factor 2) in protection from emphysema and in the severity of COPD. In response to oxidative stress, Nrf2 moves into the cell’s nucleus, binds to antioxidant response elements in DNA, and activates genes that encode antioxidant proteins. The authors hypothesized that enhancing the synthesis of Nrf2-inducing antioxidants in lung macrophages from COPD patients would reduce oxidative stress and thus restore the cells’ ability to internalize and obliterate bacteria. To this end, Harvey et al. treated these cells with an Nrf2-stimulating phytochemical, sulforaphane, and showed that the macrophages were able to recognize and internalize H. influenzae and P. aeruginosa. The authors then treated mice that had been sucking in smoke for 6 months with the same chemical, which cooled inflammation and enhanced macrophage-driven bacterial clearance in the lungs of wild-type mice but not in Nrf2-deficient mice. Molecular analyses of Nrf-regulated genes revealed that the restorative effects on macrophages required direct transcriptional activation of the gene that encodes MARCO, a scavenger of molecules that cause oxidative stress. These findings suggest that by boosting macrophage function, therapies that regulate Nrf2 or its targets can protect the lungs of COPD patients from serial assaults.