Chronic obstructive pulmonary disease (COPD) is caused by the prolonged inhalation of toxic gases, primarily cigarette smoke. Cigarette smoke contains many harmful substances, such as oxidants. It has been hypothesized that the etiology of COPD stems from an oxidant-antioxidant imbalance and a protease–antiprotease imbalance.

Oxidative stress is an important factor in COPD pathogenesis. Therefore, antioxidant treatment has recently attracted attention in COPD research. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that regulates antioxidant capacity. Nrf2 translocates to the cell’s nucleus and binds to the antioxidant response element (ARE) in response to oxidative stress.

Subsequently, Nrf2 initiates the transcription of antioxidant genes and the expression of corresponding proteins. The activation of the Nrf2–ARE signaling pathway is a primary mechanism in the defense against oxidative stress. In addition, the overexpression of Nrf2 was reported to protect against cigarette smoke-induced cell apoptosis. These reports suggest that Nrf2 activation protects against the oxidative stress seen in cigarette smoke-induced emphysema.

Astaxanthin has potent antioxidant activity, which is greater than that of other carotenoids and vitamin E. In addition, several studies have reported that astaxanthin activates the Nrf2–ARE signaling pathway as the mechanism for exerting its antioxidant effects.

In our study, astaxanthin increased Nrf2 and HO-1 expression in lung tissue and suppressed cigarette smoke-induced emphysema in mice. Our results indicate that the ingestion of astaxanthin stops cigarette smoke-induced inflammatory cell infiltration in the bronchoalveolar lavage fluid (BALF) and emphysema by activating the Nrf2–ARE signaling pathway in the lungs in a murine model of COPD.

Cigarette smoke is the primary cause of COPD and contains many oxidants. An insufficient antioxidant capacity is related to COPD pathogenesis. An excess of oxidants has been reported to induce emphysema through epithelial cell apoptosis. In recent decades, oxidative stress has been recognized as a key factor responsible for the pathogenesis of COPD.

Previously, it was reported that N-acetylcysteine significantly suppressed cigarette smoke extract-induced apoptosis of airway epithelial cells. This result suggests that antioxidants such as N-acetylcysteine may suppress cigarette smoke-induced apoptosis and emphysema in models of COPD. Epidemiologic evidence also supports the potential beneficial effects of an antioxidant-rich diet on pulmonary function and COPD risk. Antioxidant therapy or supplemental treatment with an external antioxidant to neutralize excess oxidants may have great therapeutic potential in COPD.

Nrf2 is a transcription factor involved in the regulation of various antioxidants. In response to oxidative stress, Nrf2 translocates to the nucleus and binds the ARE of target genes involved in an antioxidant response. Subsequently, Nrf2 initiates the transcription and expression of antioxidant proteins. Then, antioxidant proteins induced by Nrf2, such as HO-1, protect against oxidative stress. Nrf2 is expressed in various organs, including the lung. Nrf2-deficient mice show the reduced activity of antioxidant enzymes, are susceptible to cigarette smoke and develop severe lung emphysema.

Moreover, increased Nrf2 activation was shown to attenuate the oxidative stress of cigarette smoke and protect cells from apoptosis induced by oxidative stress. We previously showed that Nrf2 expression was significantly reduced in the airway epithelial cells of COPD patients. In addition, other studies indicate the relationship between Nrf2 polymorphisms and airflow limitations in smokers.

Astaxanthin has attracted attention due to its strong antioxidant properties, and many reports have focused on its antioxidant activity. Astaxanthin has been shown to protect various cells from oxidative stress in vitro and the brain, eyes, salivary glands, skeletal muscle, liver, kidney, and lungs from oxidative stress in vivo. These results indicate that astaxanthin is distributed throughout the body and has systemic effects.

Moreover, previous studies have reported that astaxanthin enhances Nrf2 expression in various organs, including the lungs. Additionally, some studies have investigated the pathway of Nrf2 activation by astaxanthin. Astaxanthin facilitates the dissociation and nuclear translocation of Nrf2 through activation of the PI3K/Akt and ERK signaling pathways.

In our study, Nrf2 expression in the lungs was slightly higher in the smoking group than in the control group; however, no significant difference was observed. Cigarette smoke-induced oxidants were potentially stronger than the protective effect of the antioxidants in the smoking group, which may have caused emphysema. In contrast, Nrf2 expression was significantly increased in the astaxanthin + smoking group compared to the smoking group. Therefore, the antioxidants may have exerted stronger effects than the cigarette smoke-induced oxidants and suppressed the development of emphysema in the astaxanthin + smoking group.

We showed that astaxanthin inhibited cigarette smoke-induced inflammatory cell infiltration in bronchoalveolar lavage fluid (BALF). Although Nrf2 suppresses inflammation as a secondary consequence of its antioxidant effect, astaxanthin has also been reported to suppress inflammation directly. The suppression of inflammatory cell infiltration in BALF may also be related to this property of astaxanthin.

Oxidative stress caused by cigarette smoke has persisted long after smoking cessation. Prolonged oxidative stress is a primary factor in enhancing both airway and systemic inflammation in COPD patients. It is known to play an important role in the development of COPD and its comorbidities. Therefore, it may be possible to suppress persistent oxidative stress and inflammation by ingesting astaxanthin even after smoking cessation; it may also be possible to treat COPD and its comorbidities with a single therapeutic agent. Ingestion of astaxanthin has been proven safe, it is widely used in beauty products, and mass production methods have been established. Therefore, astaxanthin may serve as a therapeutic agent or a supplement for COPD shortly.

This study has some limitations. First, the concentrations of astaxanthin in the blood of mice were not determined, and bioavailability is unknown. Second, the concentration of astaxanthin (0.02% w/w) in the diet was taken from a previous study. In addition, 50 mg/kg of astaxanthin was reported to be effective in mice. Therefore, we decided to use the diet to contain 0.02% (w/w) astaxanthin. However, the optimal effective concentration of astaxanthin is unknown. Further research is needed to clarify these points.