Rationale: Basic science research suggests a causal role for endothelial dysfunction in chronic obstructive pulmonary disease (COPD). Clinical studies examining endothelial function are lacking, particularly early in the disease. Flow-mediated dilation (FMD) is a physiologic measure of endothelial reactivity to endogenous nitric oxide. Objectives: We hypothesized that lower FMD among former smokers would be associated with lower post-bronchodilator FEV 1 , higher percentage of emphysema using computed tomography (CT) and lower diffusing capacity. Methods: We measured FMD, pulmonary function, and CT percentage of emphysema in a random sample of 107 cotinine-confirmed former smokers in the ongoing EMCAP study. FMD was defined as percentage change in the brachial artery diameter with reactive hyperemia. Generalized additive models were used to adjust for potential confounders and assess linearity. Measurements and Main Results: Mean age of participants was 71 6 5 years, 46% were female, and pack-years averaged 48 6 26. Mean FMD was 3.8 6 3.1%; mean post-bronchodilator FEV 1 , 2.3 6 0.8 L; and mean CT percentage of emphysema, 26 6 10%. A 1 SD decrease in FMD was associated with a 132-ml (95% confidence interval, 16-248 ml; P 5 0.03) decrement in post-bronchodilator FEV 1 and a 2.6% (95% confidence interval, 0.5-4.7%; P 5 0.02) increase in CT percentage of emphysema in fully adjusted models. These associations were linear across the spectrum from normality to disease, independent of smoking history, and also significant among participants without COPD. Associations with diffusing capacity were consistent but nonsignificant (P 5 0.09). The FMD-FEV 1 association was entirely attributable to percentage of emphysema. Conclusions: Impaired endothelial function, as measured by FMD, was associated with lower FEV 1 and higher CT percentage of emphysema in former smokers early in COPD.Keywords: pulmonary disease, chronic obstructive; bronchitis, chronic; pulmonary emphysema; endothelial dysfunction Recent research on the pathogenesis of chronic obstructive pulmonary disease (COPD) suggests that perturbations in the vasculature and, specifically, endothelial health may occur early in COPD (1). Decreased expression of vascular endothelial growth factor (VEGF) causes endothelial apoptosis, epithelial apoptosis, and emphysema (2-4). The second messenger lipid ceramide mediates VEGF blockade-induced apoptosis in COPD and ceramide instillation acutely triggers apoptosis in pulmonary endothelial cells, causing emphysema in mice (5).Apoptotic endothelial cells are present in the lungs of smokers with COPD (6, 7), and there are significant morphologic differences in the endothelium of smokers with mild, moderate, and severe COPD compared with smokers without COPD (8). Furthermore, nitric oxide (NO)-mediated, endotheliumdependent relaxation provoked by adenosine diphosphate and acetylcholine is attenuated in the excised pulmonary arteries of patients with COPD compared with those of smoking and nonsmoking control subjects (9, 10). Publ...

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We previously reported that antiestrogen-liganded estrogen receptor b (ERb) transcriptionally activates the major detoxifying enzyme quinone reductase (QR) (NAD(P)H:-quinone oxidoreductase). Further studies on the functional role of ERb-mediated upregulation of antioxidative enzymes indicated protective effects against estrogeninduced oxidative DNA damage (ODD). We now report on in vivo and in vitro studies that show that ERbmediated upregulation of QR are involved in the protection against estrogen-induced mammary tumorigenesis. Using the August Copenhagen Irish (ACI) model of estrogen-induced carcinogenesis, we observed that increased ODD and decreased QR expression occur early in the process of estrogen-induced mammary tumorigenesis. Prevention of ACI mammary gland tumorigenesis by tamoxifen was accompanied by decreased ODD and increased QR levels. These correlative findings were supported by our findings that downregulation of QR levels led to increased levels of estrogen quinone metabolites and enhanced transformation potential of 17b-estradiol treated MCF10A non-tumorigenic breast epithelial cells. Concurrent expression of ERb and treatment with 4-hydroxytamoxifen decreased tumorigenic potential of these MCF10A cells. We conclude that upregulation of QR, through induction by tamoxifen, can inhibit estrogen-induced ODD and mammary cell tumorigenesis, representing a possible novel mechanism of tamoxifen prevention against breast cancer.

Several investigators have suggested that certain hydroxylated metabolites of 17 -estradiol (E 2 ) are the proximate carcinogens that induce mammary carcinomas in estrogensensitive rodent models. The studies reported here were designed to examine the carcinogenic potential of different levels of E 2 and the effects of genotoxic metabolites of E 2 in an in vivo model sensitive to E 2 -induced mammary cancer. The potential induction of mammary tumors was determined in female ACI rats subcutaneously implanted with cholesterol pellets containing E 2 (1, 2, or 3 mg), or 2-hydroxyestradiol (2-OH E 2 ), 4-hydroxyestradiol (4-OH E 2 ), 16 -hydroxyestradiol (16 -OH E 2 ), or 4-hydoxyestrone (4-OH E 1 ) (equimolar to 2 mg E 2 ). Treatment with 1, 2, or 3 mg E 2 resulted in the first appearance of a mammary tumor between 12 and 17 weeks, and a 50% incidence of mammary tumors was observed at 36, 19, and 18 weeks respectively. The final cumulative mammary tumor incidence in rats treated with 1, 2, or 3 mg E 2 for 36 weeks was 50%, 73%, and 100% respectively. Treatment of rats with pellets containing 2-OH E 2 , 4-OH E 2 , 16 -OH E 2 , or 4-OH E 1 did not induce any detectable mammary tumors. The serum levels of E 2 in rats treated with a 1 or 3 mg E 2 pellet for 12 weeks was increased 2-to 6-fold above control values (30 pg/ml). Treatment of rats with E 2 enhanced the hepatic microsomal metabolism of E 2 to E 1 , but did not influence the 2-or 4-hydroxylation of E 2 . In summary, we observed a dosedependent induction of mammary tumors in female ACI rats treated continuously with E 2 ; however, under these conditions 2-OH E 2 , 4-OH E 2 , 16 -OH E 2 , and 4-OH E 1 were inactive in inducing mammary tumors.

IntroductionThe aetiology of acute exacerbations of chronic obstructive pulmonary disease (COPD) remains incompletely understood and strategies for treatment and prevention have not altered significantly for many years. Improved understanding of the role of respiratory pathogens in acute exacerbations of COPD (AECOPD) is required and the use of molecular microbiological techniques may lead to insights into host–pathogen interactions and the development of more targeted therapeutic approaches.Methods and analysesAcute Exacerbation and Respiratory InfectionS in COPD (AERIS) is a longitudinal epidemiological study to assess how changes in the COPD airway microbiome contribute to the incidence and severity of AECOPD. Patients with COPD aged 40–85 are followed monthly for 2 years, and reviewed within 72 h of onset of symptoms of AECOPD. Exacerbations are detected using daily electronic diary cards. Blood, sputum, nasopharyngeal and urine samples are collected at prespecified timepoints. Molecular diagnostic and typing techniques are used to describe the dynamics of airway infection during AECOPD and stable disease, and associations with clinical outcome. This study aims to refine the case definition of AECOPD to reflect the possible microbiological aetiology. AERIS will assess the impact of AECOPD on health-related quality of life and healthcare resource utilisation, and the possible interactions between nutritional status, infection and immune responses.Ethics and disseminationAERIS is conducted in accordance with the Declaration of Helsinki and Good Clinical Practice, and has been approved by the institutional ethics and review board. All participants must provide written informed consent. The results obtained will be disseminated at international medical conferences and in peer-reviewed publications.DiscussionFew other studies have addressed the complexity of the microbiological and systemic components of COPD or employed real-time electronic tracking of symptoms to identify AECOPD and potential aetiological triggers.ResultsResults of AERIS will increase our understanding of the contribution of pathogens to AECOPD, potentially leading to new targeted therapeutic and preventative interventions.Trial registration numberClinicalTrials.gov NCT01360398.