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Estrogens have well-documented effects on lung development and physiology. However, the classical estrogen receptor ␣ (ER␣) is undetectable in the lung, and this has left many unanswered questions about the mechanism of estrogen action in this organ. Here we show, both in vivo and in vitro, that ER␤ is abundantly expressed and biologically active in the lung. Comparisons of lungs from wild-type mice and mice with an inactivated ER␤ gene (ER␤ ؊/؊ ) revealed decreased numbers of alveoli in adult female ER␤ ؊/؊ mice and findings suggesting deficient alveolar formation as well as evidence of surfactant accumulation. Plateletderived growth factor A (PDGF-A) and granulocyte-macrophage colony-stimulating factor (GM-CSF), key regulators of alveolar formation and surfactant homeostasis, respectively, were decreased in lungs of adult female ER␤ ؊/؊ mice, and direct transcriptional regulation of these genes by ER␤ was demonstrated. This suggests that estrogens act via ER␤ in the lung to modify PDGF-A and GM-CSF expression. These results provide a potential molecular mechanism for the gender differences in alveolar structure observed in the adult lung and establish ER␤ as a previously unknown regulator of postnatal lung development and homeostasis.The vital function of the lung is to provide a gas-exchange surface to meet the organism's needs for oxygen uptake and carbon dioxide elimination. Several parameters in lung biology and pathology, both during development and in the adult, are sexually dimorphic. A role for estrogen in these dimorphisms was suggested in 1980 when Mendelson et al. (21) showed an estrogen-binding component in human fetal lung tissue. Lung maturation during fetal development is more rapid in female fetuses than in male fetuses, and the onset of surfactant synthesis occurs later in the male fetus. This difference appears to be mediated mainly by inhibitory effects of androgens, but stimulatory effects of estrogens have also been demonstrated (2). Postnatal sex differences in the rodent lung have been described by Massaro et al. (20). Adult females have a larger number of alveoli, smaller in size, than males, probably to allow for elevated oxygen consumption during pregnancy and lactation. This difference develops as animals reach sexual maturity and seems to be mediated mainly by estrogens (19). In the human population, women are more prone than men to developing chronic obstructive pulmonary disease (29) and incur a higher risk of developing lung cancer (13, 41), indicating that women are more susceptible to the deleterious effects of tobacco smoking. The reasons for these sex differences are unknown, but estrogens are likely to play a major role, since in animal models, there are estrogen-dependent gender differences in susceptibility towards tobacco-associated lung carcinogens (23), and furthermore, epidemiological studies suggest that hormone replacement therapy with estrogen is associated with a higher risk of lung cancer in postmenopausal women (1,39).Although previous data suggest that estrogen...

Scanning transmission electron microscopy (STEM) data with atomic resolution can contain a large amount of information about the structure of a crystalline material. Often, this information is hard to extract, due to the large number of atomic columns and large differences in intensity from sublattices consisting of different elements. In this work, we present a free and open source software tool for analysing both the position and shapes of atomic columns in STEM-images, using 2-D elliptical Gaussian distributions. The software is tested on variants of the perovskite oxide structure. By first fitting the most intense atomic columns and then subtracting them, information on all the projected sublattices can be obtained. From this, we can extract changes in the lattice parameters and shape of A-cation columns from annular dark field images of perovskite oxide heterostructures. Using annular bright field images, shifts in oxygen column positions are also quantified in the same heterostructure. The precision of determining the position of atomic columns is compared between STEM data acquired using standard acquisition, and STEM-images obtained as an image stack averaged after using non-rigid registration.

Bronchoalveolar lavage fluid exosomes from asthmatic and healthy individuals exhibit distinct phenotypes and functions. BALF exosomes from asthmatics might contribute to subclinical inflammation by increasing cytokine and LTC(4) generation in airway epithelium.

During recent years, the biological roles of CCAAT/enhancer binding proteins (C/EBPs) in the lung have started to be uncovered. C/EBPs form a family within the basic region-leucine zipper class of transcription factors. In the lung epithelium C/EBPalpha, -beta, and -delta are expressed. Lung-specific target genes for these transcription factors include the surfactant proteins A and D, the Clara cell secretory protein, and the P450 enzyme CYP2B1. As more information is gathered, a picture is emerging in which C/EBPalpha has a role in regulating proliferation as well as differentiation-dependent gene expression, whereas C/EBPbeta and -delta, in addition to a partly overlapping role in regulating expression of differentiation markers, also seem to be involved in responses to injury and hormones.

Background: A diagnosis of aspirin-intolerant asthma requires aspirin provocation in specialist clinics. Urinary leukotriene E 4 (LTE 4 ) is increased in aspirin-intolerant asthma. A study was undertaken to investigate new biomarkers of aspirin intolerance by comparing basal levels of cysteinyl-leukotrienes (CysLTs) and leukotriene B 4 (LTB 4 ) in saliva, sputum and ex vivo stimulated blood in subjects with aspirin-intolerant and aspirin-tolerant asthma. The effects of aspirin-and allergen-induced bronchoconstriction on leukotriene levels in saliva and ex vivo stimulated blood were also compared with the effects of the provocations on urinary mediators. Methods: Induced sputum, saliva, urine and blood were obtained at baseline from 21 subjects with asthma. At a separate visit, 11 subjects showed a positive response to lysine-aspirin inhalation and 10 were aspirin tolerant. Saliva, blood and urine were also collected on the provocation day. Analyses of CysLTs and LTB 4 and the prostaglandin D 2 metabolite 9a,11b-prostaglandin F 2 were performed and the fraction of exhaled nitric oxide was measured. Results: Subjects with aspirin-intolerant asthma had higher exhaled nitric oxide levels and higher baseline levels of CysLTs in saliva, sputum, blood ex vivo and urine than subjects with aspirin-tolerant asthma. There were no differences in LTB 4 levels between the groups. Levels of urinary LTE 4 and 9a,11b-prostaglandin F 2 increased after aspirin provocation whereas leukotriene levels in saliva and ex vivo stimulated blood did not increase. Conclusion: These findings support a global and specific increase in CysLT production in aspirin-intolerant asthma. Measurement of CysLTs in saliva has the potential to be a new and convenient non-invasive biomarker of aspirinintolerant asthma.

Clara cell secretory protein (CCSP) is a product of nonciliated cells of the conducting airway epithelium. The normal physiological function of CCSP is unknown. However, the ability of CCSP to bind small lipophilic molecules, such as steroid hormones and certain pollutants, has led to speculation that this protein may mediate the biological accumulation of potentially harmful polychlorinated biphenyl (PCB) metabolites within the lung. To investigate the contribution of CCSP in the in vivo accumulation of methylsulfonyl-PCB, a line of mice was established that were homozygous for a null allele of the CCSP gene. CCSP-deficient mice were healthy and fertile, with no gross physiological or pathological abnormalities Parenteral challenge with the PCB metabolite 4-methylsulfonyl-2,2',4',5,5'-pentachlorobiphenyl (MeSO2-PCB) demonstrated that CCSP-deficient mice no longer accumulate this class of pollutants within lung and kidney tissues. These data demonstrate that CCSP is the determinant for MeSO2-PCB accumulation within mice and support the notion that bioconcentration of MeSO2-PCB pollutants occurs at sites of CCSP localization, such as the respiratory and reproductive tracts of humans.

Chronic allergic asthma is characterized by Th2-polarized inflammation and leads to airway remodeling and fibrosis but the mechanisms involved are not clear. To determine whether epithelial-mesenchymal transition contributes to airway remodeling in asthma, we induced allergic airway inflammation in mice by intranasal administration of house dust mite (HDM) extract for up to 15 consecutive weeks. We report that respiratory exposure to HDM led to significant airway inflammation and thickening of the smooth muscle layer in the wall of the large airways. Transforming growth factor beta-1 (TGF-β1) levels increased in mouse airways while epithelial cells lost expression of E-cadherin and occludin and gained expression of the mesenchymal proteins vimentin, alpha-smooth muscle actin (α-SMA) and pro-collagen I. We also observed increased expression and nuclear translocation of Snail1, a transcriptional repressor of E-cadherin and a potent inducer of EMT, in the airway epithelial cells of HDM-exposed mice. Furthermore, fate-mapping studies revealed migration of airway epithelial cells into the sub-epithelial regions of the airway wall. These results show the contribution of EMT to airway remodeling in chronic asthma-like inflammation and suggest that Th2-polarized airway inflammation can trigger invasion of epithelial cells into the subepithelial regions of the airway wall where they contribute to fibrosis, demonstrating a previously unknown plasticity of the airway epithelium in allergic airway disease.