Astaxanthin Suppresses Cigarette Smoke-Induced Emphysema through Nrf2 Activation in Mice.

Oxidative stress plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). The activation of nuclear factor erythroid 2-related factor 2 (Nrf2) is a key cellular defense mechanism against oxidative stress. Recent studies have shown that astaxanthin protects against oxidative stress via Nrf2. In this study, we investigated the emphysema suppression effect of astaxanthin via Nrf2 in mice. Mice were divided into four groups: control, smoking, astaxanthin, and astaxanthin + smoking. The mice in the smoking and astaxanthin + smoking groups were exposed to cigarette smoke for 12 weeks, and the mice in the astaxanthin and astaxanthin + smoking groups were fed a diet containing astaxanthin. Significantly increased expression levels of Nrf2 and its target gene, heme oxygenase-1 (HO-1), were found in the lung homogenates of astaxanthin-fed mice. The number of inflammatory cells in the bronchoalveolar lavage fluid (BALF) was significantly decreased, and emphysema was significantly suppressed. In conclusion, astaxanthin protects against oxidative stress via Nrf2 and ameliorates cigarette smoke-induced emphysema. Therapy with astaxanthin directed toward activating the Nrf2 pathway has the potential to be a novel preventive and therapeutic strategy for COPD.

Atrial natriuretic peptide protects against bleomycin-induced pulmonary fibrosis via vascular endothelial cells in mice : ANP for pulmonary fibrosis.

BACKGROUND: Pulmonary fibrosis is a life-threatening disease characterized by progressive dyspnea and worsening pulmonary function. Atrial natriuretic peptide (ANP), a heart-derived secretory peptide used clinically in Japan for the treatment of acute heart failure, exerts a wide range of protective effects on various organs, including the heart, blood vessels, kidneys, and lungs. Its therapeutic properties are characterized by anti-inflammatory and anti-fibrotic activities mediated by the guanylyl cyclase-A (GC-A) receptor. We hypothesized that ANP would have anti-fibrotic and anti-inflammatory effects on bleomycin (BLM)-induced pulmonary fibrosis in mice. METHODS: Mice were divided into three groups: normal control, BLM with vehicle, and BLM with ANP. ANP (0.5 µg/kg/min via osmotic-pump, subcutaneously) or vehicle administration was started before BLM administration (1 mg/kg) and continued until the mice were sacrificed. At 7 or 21 days after BLM administration, fibrotic changes and infiltration of inflammatory cells in the lungs were assessed based on histological findings and analysis of bronchoalveolar lavage fluid. In addition, fibrosis and inflammation induced by BLM were evaluated in vascular endothelium-specific GC-A overexpressed mice. Finally, attenuation of transforming growth factor-ß (TGF-ß) signaling by ANP was studied using immortalized mouse endothelial cells stably expressing GC-A receptor. RESULTS: ANP significantly decreased lung fibrotic area and infiltration of inflammatory cells in lungs after BLM administration. Furthermore, similar effects of ANP were observed in vascular endothelium-specific GC-A overexpressed mice. In cultured mouse endothelial cells, ANP reduced phosphorylation of Smad2 after TGF-ß stimulation. CONCLUSIONS: ANP exerts protective effects on BLM-induced pulmonary fibrosis via vascular endothelial cells.

Handgrip strength measurement in patients with chronic obstructive pulmonary disease: Possible predictor of exercise capacity.

BACKGROUND: Impaired exercise capacity is one of the most important prognostic factors for patients with chronic obstructive pulmonary disease (COPD). The 6-min walk test (6MWT) is a widely used method for assessing exercise capacity in patients with COPD. However, the 6MWT requires considerable effort from patients. Therefore, a less physically demanding, but also noninvasive, method is warranted. The objective of this study was to determine the predictors of the 6MWT distance (6MWD) in patients with COPD. METHODS: This retrospective observational study enrolled 133 Japanese patients with COPD. All patients underwent the 6MWT, COPD assessment test (CAT), spirometry, respiratory muscle strength evaluation, body composition assessment, and handgrip strength (HGS) measurement. We examined the associations between the 6MWD and evaluated parameters. RESULTS: From single regression analysis, the 6MWD was significantly correlated with age, CAT score, several spirometric measurements (e.g., percentages of forced vital capacity, forced expiratory volume in 1 s, and carbon monoxide diffusing capacity of the lungs [%DLCO]), respiratory muscle strength parameters (e.g., percentages of maximal expiratory and inspiratory pressures), skeletal muscle mass index, and HGS. In multiple regression analysis, age, CAT score, %DLCO, and HGS were independent predictors of the 6MWD. The %DLCO and HGS were strongly correlated as predictors of the 6MWD (p < 0.001). CONCLUSIONS: We found that HGS was significantly correlated with the 6MWD compared with spirometric measurements or respiratory muscle strength parameters in Japanese patients with COPD, suggesting that HGS could be a simple and noninvasive predictor of the 6MWD in patients with COPD.

Possible role of airway microvascular permeability on airway obstruction in patients with chronic obstructive pulmonary disease.

BACKGROUND: Airway microvascular system participates in the airway inflammation that is central to the pathophysiology of inflammatory lung disorders. OBJECTIVE: To examine the role of airway microvascular permeability on airway obstruction in patients with chronic obstructive pulmonary disease (COPD). METHODS: We measured the airway microvascular permeability index (AMPI) separately in the central or peripheral airways using a bronchoscopic microsampling technique in 9 non-smokers, 18 smokers without COPD (10 former smokers and 8 current smokers), and 26 smokers with COPD (12 former smokers and 14 current smokers). RESULTS: AMPI in the central airways was relatively low, and this index was comparable among the five groups. In contrast, AMPI in the peripheral airways was significantly higher in smokers with or without COPD compared with non-smokers. Moreover, AMPI in the peripheral airways was significantly higher in current smokers than in former smokers with COPD. Especially, AMPI in the peripheral airways, but not in the central airways, showed a significant correlation with the degree of airway obstruction in former or current smokers with COPD. However, AMPI in the peripheral airways was not correlated with the diffusing capacity of the lung in former or current smokers with COPD. CONCLUSION: Airway microvascular permeability in the peripheral airways is increased in patients with COPD, and is associated with the severity of airway obstruction. We may need to consider this characteristic feature as a target in any therapeutic strategy for the treatment of the disease. (237 words).

Isoflavone Aglycones Attenuate Cigarette Smoke-Induced Emphysema via Suppression of Neutrophilic Inflammation in a COPD Murine Model.

Chronic obstructive pulmonary disease (COPD), a lung disease caused by chronic exposure to cigarette smoke, increases the number of inflammatory cells such as macrophages and neutrophils and emphysema. Isoflavone is a polyphenolic compound that exists in soybeans. Daidzein and genistein, two types of isoflavones, have been reported to have anti-inflammatory effects in various organs. We hypothesized that the daidzein-rich soy isoflavone aglycones (DRIAs) attenuate cigarette smoke-induced emphysema in mice. Mice were divided into four groups: the (i) control group, (ii) isoflavone group, (iii) smoking group, and (iv) isoflavone + smoking group. The number of inflammatory cells in the bronchoalveolar lavage fluid (BALF) and the airspace enlargement using the mean linear intercept (MLI) were determined 12 weeks after smoking exposure. Expressions of neutrophilic inflammatory cytokines and chemokines were also examined. In the isoflavone + smoking group, the number of neutrophils in BALF and MLI was significantly less than that in the smoking group. Furthermore, the gene-expressions of TNF-α and CXCL2 (MIP-2) in the isoflavone + smoking group were significantly less than those in the smoking group. Supplementation of the COPD murine model with DRIAs significantly attenuates pathological changes of COPD via suppression of neutrophilic inflammation.

Exercise Ameliorates Emphysema Of Cigarette Smoke-Induced COPD In Mice Through The Exercise-Irisin-Nrf2 Axis.

Background: Oxidative stress is one of the important mechanisms underlying the pathogenesis of chronic obstructive pulmonary disease (COPD). Irisin is a type of myokine secreted from the muscle during exercise and acts against oxidative stress via nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor with antioxidant properties. Here, we examined the emphysema suppressive effects of the exercise-irisin-Nrf2 axis in mice. Methods: Mice were divided into three groups, namely, the control, smoking, and exercise + smoking groups. All mice from the smoking and exercise + smoking groups were exposed to cigarette smoke once a day. The mice from the exercise + smoking group were adapted to a treadmill once a day. To investigate the Nrf2 cascade, after 12 weeks, serum irisin concentration and Nrf2 and heme oxygenase-1 (HO-1) expression in the lung homogenate were determined. To evaluate cigarette smoke-induced COPD, the number of inflammatory cells in bronchoalveolar lavage fluid (BALF), mean linear intercept (MLI), and destructive index in the lung tissue were examined. Results: Serum irisin concentration and the expression levels of Nrf2 and HO-1 in the lung homogenate were significantly higher in mice from the exercise + smoking group than in those from the control and smoking groups. The proportion of neutrophils in the BALF was significantly lower in the exercise + smoking group than in the smoking group. The MLI and destructive index were also significantly smaller in mice from the exercise + smoking group than mice from the smoking group. Conclusion: Irisin secreted from the muscle during exercise may exert protective effects against oxidative stress via Nrf2 and HO-1, and ameliorate emphysema of cigarette smoke-induced COPD. The exercise-irisin-Nrf2 axis may serve as a novel target for COPD treatment.