Estrogen deficiency promotes cigarette smoke-induced changes in the extracellular matrix in the lungs of aging female mice.

Female smokers have a faster decline in lung function with increasing age and overall develop a greater loss of lung function than male smokers. This raises the question of whether estrogen status in women affects susceptibility to cigarette smoke (CS)-induced lung disease. Mouse models suggest that female mice are more susceptible than males to CS-induced lung disease. Moreover, young CS-exposed female mice develop emphysema earlier than male mice. The purpose of this study was to characterize the relationship of estrogen status on the pattern and severity of CS-induced lung disease. In this study, 15-month-old female C57BL/6J mice were ovariectomized and administered either placebo (pla) or 17ß-estradiol (E2, 0.025 mg) 2 weeks after ovariectomy. They were further divided into those that were exposed to CS and no-smoke controls (NSC). Mice were exposed to CS in stainless steel inhalation chambers 3 hours a day, 5 days a week for 6 months, and sacrificed after 24 weeks of CS exposure. Blood and urine were collected at sacrifice to measure estrogen and cotinine levels, a metabolite of nicotine. Uterine weight was recorded as an indicator of estrogen status. Results showed that CS in the absence of E2 induced a decrease in hydroxyproline content, macrophage number, and respiratory chain complex-1 protein. CS without E2 also resulted in an increase in matrix metalloproteinase-2 activity and apoptosis and a change in the ratio of estrogen receptor subtype. These findings were abrogated with administration of E2, suggesting that estrogen deficiency increases susceptibility to CS-induced lung disease.

17ß-estradiol replacement reverses age-related lung disease in estrogen-deficient C57BL/6J mice.

The role that estrogens play in the aging lung is poorly understood. Remodeling of the aging lung with thickening of the alveolar walls and reduction in the number of peripheral airways is well recognized. The present study was designed to address whether estrogen deficiency would affect age-associated changes in the lungs of female C57BL/6J mice. Lungs isolated from old mice (24 months old, estrogen-deficient) demonstrated decreased lung volume and decreased alveolar surface area. There was no difference in alveolar number in the lungs of old and young mice (6 months old, estrogen-replete). Estrogen replacement restored lung volume, alveolar surface area, and alveolar wall thickness to that of a young mouse. Estrogen receptor-α (ERα) protein expression increased without a change in ERß protein expression in the lung tissue isolated from old mice. In the lungs of old mice, the number of apoptotic cells was increased as well as the activation of matrix metalloproteinase-2 and ERK. Young mice had the highest serum 17ß-estradiol levels that decreased with age. Our data suggest that in the aging female mouse lung, estrogen deficiency and an increase of ERα expression lead to the development of an emphysematous phenotype. Estrogen replacement partially prevents these age-associated changes in the lung architecture by restoration of interalveolar septa. Understanding the role of estrogens in the remodeling of the lung during aging may facilitate interventions and therapies for aging-related lung disease in women.