The DsbA-L gene is associated with respiratory function of the elderly via its adiponectin multimeric or antioxidant properties

Abstract

Oxidative stress and inflammation play a key role in the age-related decline in the respiratory function. Adipokine in relation to the metabolic and inflammatory systems is attracting growing interest in the field of respiratory dysfunction. The present clinical and experimental studies investigated the role of the disulfide bond-forming oxidoreductase Alike protein (DsbA-L) gene, which has antioxidant and adiponectin multimeric (i.e. activation) properties, on the respiratory function of the elderly. We performed a retrospective longitudinal genotype-phenotype relationship analysis of 318 Japanese relatively elderly participants (mean age ± standard deviation: 67.0 ± 5.8 years) during a health screening program and an in vitro DsbA-L knock-down evaluation using 16HBE14o-cells, a commonly evaluated human airway epithelial cell line. The DsbA-L rs1917760 polymorphism was associated with a reduction in the ratio of forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) and %FEV1 and with the elevation of the prevalence of FEV1/FVC < 70%. We also confirmed that the polymorphism was associated with a decreased respiratory function in relation to a decrease in the ratio of high-molecular-weight adiponectin/total adiponectin (as a marker of adiponectin multimerization) and an increase in the oxidized human serum albumin (as an oxidative stress marker). Furthermore, we clarified that DsbA-L knock-down induced oxidative stress and up-regulated the mucus production in human airway epithelial cells. These findings suggest that the DsbA-L gene may play a role in protecting the respiratory function of the elderly, possibly via increased systemic adiponectin functions secreted from adipocytes or through systemic and/or local pulmonary antioxidant properties. Airway inflammation and an impaired lung function are common in elderly populations, leading to decreased quality of life and increase in morbidity and mortality 1-3. Although exposures to cigarette smoke and other environmental pollutants (e.g. biomass fuel exposure and air pollution) are major risk factors for the development and progression of respiratory dysfunction 4,5 , previous evidence has shown that age-related changes in the respiratory functions are also key factors for respiratory dysfunction 1-3. Aging causes the loss of lung elasticity, decreased respiratory muscles, and a decreased surface area for alveolar gas exchange, leading to an impaired respiratory function 1-3. Furthermore, local and/or systemic oxidative stress as well as inflammation play substantial roles in the age-related decline in the respiratory function 1,2. However, these changes in respiratory pathological features

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