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Introduction Airway epithelial mitochondrial injury is an important pathogenesis of chronic obstructive pulmonary disease (COPD). Cyclophilin D (CypD) is a component of mitochondrial permeability transition pore and related to mitochondrial damage. However, the role of CypD in airway epithelial mitochondrial injury and COPD pathogenesis remains unclear. Methods CypD expression in human airway epithelium was determined by immunohistochemistry, and mitochondrial structure of airway epithelial cell was observed under the transmission electron microscopy. The expression of CypD signaling pathway in cigarette smoke extract (CSE)-treated airway epithelial cells was measured by real-time PCR and Western-blot. CSE-induced damage of airway epithelial cell and mitochondria was further studied. Results Immunohistochemistry and transmission electron microscopy analysis revealed that CypD expression in airway epithelium was significantly increased associated with notable airway epithelial mitochondrial structure damage in the patients with COPD. The mRNA and protein expression of CypD was significantly increased in concentration- and time-dependent manners when airway epithelial cells were treated with CSE. CypD siRNA pretreatment significantly suppressed the increases of CypD and Bax expression, and reduced the decline of Bcl-2 expression in 7.5% CSE-treated airway epithelial cells. Furthermore, CypD silencing significantly attenuated mitochondrial damage and cell apoptosis, and increased cell viability when airway epithelial cells were stimulated with 7.5% CSE. Conclusion These data suggest that CypD signaling pathway is involved in the pathogenesis of COPD and provide a potential therapeutic target for COPD., Author(s): Rui Zhang [sup.1], Hu Shan [sup.1], Yuer Li [sup.1], Yuefeng Ma [sup.2], Shiyuan Liu [sup.2], Xiaohuan Liu [sup.1], Xia Yang [sup.1], Jie Zhang [sup.1], Ming Zhang [sup.1] Author Affiliations: [...]

The serum level of the soluble Receptor for Advanced Glycation End-products (sRAGE) is a promising blood biomarker for the development, severity, and progression of chronic obstructive pulmonary disease (COPD). However, cigarette smoking causes a nearly instant drop in circulating sRAGE levels, strongly impacting on the variability in sRAGE levels. In the current study, we investigated the possible mechanism behind the sudden drop in sRAGE upon smoking. We showed that the number of activated neutrophils in blood significantly increases within two hours upon smoking three cigarettes within one hour. Furthermore, an increased expression of the leukocyte activation marker CD11b, which is a known ligand for RAGE, was observed upon smoking. Additionally, the in vitro activation of neutrophils increased their capacity to bind sRAGE. Together, these data indicate that smoking activates neutrophils in the circulation with concomitant upregulation of the RAGE ligand CD11b, leading to reduced levels of sRAGE in serum., Author(s): Valerie R. Wiersma [sup.1], Susan J. M. Hoonhorst [sup.2] [sup.3], Nick H. T. ten Hacken [sup.2], Maarten van den Berge [sup.2] [sup.3], Dirk-Jan Slebos [sup.2] [sup.3], Simon D. Pouwels [...]

Multidrug resistance associated protein-1 (MRP1) and Notch signaling are closely related and both play a critical role in chronic obstructive pulmonary disease (COPD) establishment and progression. The aim of our work was to test whether Notch1 is involved in allyl isothiocyanate (AITC) induced MRP1 expression. We used cigarette smoke extract (CSE) to simulate the smoking microenvironment in vitro. The results demonstrated that CSE led to apoptosis as well as reduced the expression of Notch1, Hes1, and MRP1, while AITC significantly reversed this downregulation. Transfected with Notch1 siRNA downregulated MRP1 expression and activity, aggravated the suppression effect by CSE, and abolished the AITC-induced Notch1, Hes1, and MRP1 expression. Validation of the correlation between Notch1 and MRP1 was implemented by gel-shift assays (electrophoretic mobility shift assay). The result revealed an interaction between a specific promoter region of MRP1 and the intracellular domain of Notch1. In conclusion, Notch1 signaling positively regulated MRP1 in 16HBE cells and AITC induced MRP1 expression and function may be attributed to Notch1 signaling. These findings show that Notch1 and MRP1 might have a potential protective effect in the COPD process and become a new therapeutic target for COPD or other lung diseases. It also provides a theoretical basis for the therapeutic effects of AITC. Key words: allyl isothiocyanate (AITC), chronic obstructive pulmonary disease (COPD), cigarette smoke extract (CSE), Notch1 signaling, multidrug resistance associated protein-1(MRP1). La proteine 1 associee a la multiresistance aux medicaments (ou MRP1 pour <>) et la voie de signalisation Notch sont intimement liees et jouent toutes deux un role essentiel dans la presentation et l'evolution de la maladie pulmonaire obstructive chronique (MPOC). Nos travaux avaient pour but d'evaluer si la proteine Notch1 joue un role dans l'expression de la MRP1 engendree par l'isothiocyanate d'allyle (ITCA). Nous avons simule un microenvironnement de tabagisme in vitro a l'aide d'extraits de fumee de cigarette (EFC). Les resultats ont montre que les EFC menaient a l'apoptose, ainsi qu'a une diminution de l'expression des proteines Notch1, Hes1 et MRP1, tandis que l'ITCA inversait cette regulation a la baisse de facon notable. La transfection avec du siRNA du gene Notch1 entrainait une regulation a la baisse de l'expression et de l'activite de la proteine MRP1, une aggravation de l'effet suppresseur des EFC, avec une inhibition complete de l'expression des proteines Notch1, Hes1 et MRP1 produites par l'ITCA. Nous avons valide la correlation entre les proteines Notch1 et MRP1 a l'aide de la technique de retard sur gel (ou EMSA pour <>). Les resultats ont revele la presence d'une interaction entre une region promotrice specifique du gene MRP1 et le domaine intracellulaire de la proteine Notch1. En conclusion, la signalisation par la proteine Notch1 entrainait une regulation avantageuse du gene MRP1 dans les cellules 16HBE, et l'expression ainsi que le fonctionnement de la proteine MRP1 produite par l'ITCA pourraient etre attribues a la signalisation par la proteine Notch1. Ces resultats montrent que les proteines Notch1 et MRP1 pourraient avoir un effet protecteur eventuel contre les processus de la MPOC et devenir une nouvelle cible therapeutique dans la MPOC ou d'autres maladies pulmonaires. Ils fournissent aussi une base theorique pour expliquer les effets therapeutiques de l'ITCA. [Traduit par la Redaction] Mots-cles: isothiocyanate d'allyle (ITCA), maladie pulmonaire obstructive chronique (MPOC), extraits de fumee de cigarette (EFC), signalisation Notch1, proteine 1 associee a la multiresistance aux medicaments (MRP1)., Introduction Chronic obstructive pulmonary disease (COPD) is one common and serious disease characterized by irreversible and progressive airflow obstruction, which is associated with abnormal chronic inflammatory responses in the airway [...]

In 2014, Brazil had the world's fourth largest prison population, with more than half a million prisoners in 1,424 facilities (1). Prison conditions include overcrowding, frequent prisoner movement, poor ventilation, [...]

Background: Fetal exposure to maternal smoking during pregnancy is associated with the development of noncommunicable diseases in the offspring. Maternal smoking may induce such long-term effects through persistent changes in the DNA methylome, which therefore hold the potential to be used as a biomarker of this early life exposure. With declining costs for measuring DNA methylation, we aimed to develop a DNA methylation score that can be used on adolescent DNA methylation data and thereby generate a score for in utero cigarette smoke exposure. Methods: We used machine learning methods to create a score reflecting exposure to maternal smoking during pregnancy. This score is based on peripheral blood measurements of DNA methylation (Illumina's Infinium HumanMethylation450K BeadChip). The score was developed and tested in the Raine Study with data from 995 white 17-y-old participants using 10-fold cross-validation. The score was further tested and validated in independent data from the Northern Finland Birth Cohort 1986 (NFBC1986) (16-y-olds) and 1966 (NFBC1966) (31-y-olds). Further, three previously proposed DNA methylation scores were applied for comparison. The final score was developed with 204 CpGs using elastic net regression. Results: Sensitivity and specificity values for the best performing previously developed classifier ('Reese Score') were 88% and 72% for Raine, 87% and 61% for NFBC1986 and 72% and 70% for NFBC1966, respectively; corresponding figures using the elastic net regression approach were 91% and 76% (Raine), 87% and 75% (NFBC1986), and 72% and 78% for NFBC1966. Conclusion: We have developed a DNA methylation score for exposure to maternal smoking during pregnancy, outperforming the three previously developed scores. One possible application of the current score could be for model adjustment purposes or to assess its association with distal health outcomes where part of the effect can be attributed to maternal smoking. Further, it may provide a biomarker for fetal exposure to maternal smoking. https://doi.org/10.1289/EHP6076, Introduction Fetal exposure to maternal smoking during pregnancy increases the risk that the offspring will develop noncommunicable diseases (NCDs) (Agrawal et al. 2010; Bhattacharya et al. 2014; DiFranza et al. [...]

Anti-glomerular basement membrane (anti-GBM) disease, which is extremely uncommon in children, is characterized by rapidly progressive glomerulonephritis (RPGN) and autoantibodies against GBM collagen. Pulmonary hemorrhage is the third component in Goodpasture Syndrome. Cigarette smoking and exposure to hydrocarbons have been linked to anti-GBM disease in adults, but such an association has not been established in children. We reviewed renal biopsy and autopsy specimens over 25 years from a major tertiary care U.S. children's hospital, diagnosing anti-GBM by clinical RPGN, crescentic glomerulonephritis, and linear immunofluorescence (IF) immunoglobulin G staining in patients under 18 years of age. We identified four patients, with and without pulmonary manifestations. The sole autopsy case showed diagnostic IF despite undetectable serum anti-GBM antibodies and positive testing for serum anti-neutrophil cytoplasmic antibodies (ANCA). Three patients have survived 1-18 years following diagnosis, one of whom is recovering renal function. One adolescent had a history of smoking cigarettes and one had a probable hydrocarbon exposure. Anti-GBM disease is unusual in children, and the relationship to inhaled agents is incompletely understood. Serum anti-GBM antibodies are typically present, but cases with undetectable levels can occur. Some patients are anti GBM and ANCA positive, with a small subset ANCApositive, anti-GBM-negative. Ours is the first such described pediatric case. Keywords Anti-glomerular basement membrane disease * Pediatric * Goodpasture syndrome * Rapidly progressive glomerulonephritis * Anti-GBM. Cigarette smoking * Hydrocarbon exposure * Etiology, Introduction Anti-glomerular basement membrane (anti-GBM) disease is characterized by glomerulonephritis and the formation of autoantibodies against the α3 chain of type IV collagen [α3 (IV) NC1 domain] in the GBM [...]