Lung Fibroblasts from Patients with Idiopathic Pulmonary Fibrosis Exhibit Genome-Wide Differences in DNA Methylation Compared to Fibroblasts from Nonfibrotic Lung.

PLoS One. 2014;9(9):e107055

Authors: Huang SK, Scruggs AM, McEachin RC, White ES, Peters-Golden M

Abstract
Excessive fibroproliferation is a central hallmark of idiopathic pulmonary fibrosis (IPF), a chronic, progressive disorder that results in impaired gas exchange and respiratory failure. Fibroblasts are the key effector cells in IPF, and aberrant expression of multiple genes contributes to their excessive fibroproliferative phenotype. DNA methylation changes are critical to the development of many diseases, but the DNA methylome of IPF fibroblasts has never been characterized. Here, we utilized the HumanMethylation 27 array, which assays the DNA methylation level of 27,568 CpG sites across the genome, to compare the DNA methylation patterns of IPF fibroblasts (n = 6) with those of nonfibrotic patient controls (n = 3) and commercially available normal lung fibroblast cell lines (n = 3). We found that multiple CpG sites across the genome are differentially methylated (as defined by P value less than 0.05 and fold change greater than 2) in IPF fibroblasts compared to fibroblasts from nonfibrotic controls. These methylation differences occurred both in genes recognized to be important in fibroproliferation and extracellular matrix generation, as well as in genes not previously recognized to participate in those processes (including organ morphogenesis and potassium ion channels). We used bisulfite sequencing to independently verify DNA methylation differences in 3 genes (CDKN2B, CARD10, and MGMT); these methylation changes corresponded with differences in gene expression at the mRNA and protein level. These differences in DNA methylation were stable throughout multiple cell passages. DNA methylation differences may thus help to explain a proportion of the differences in gene expression previously observed in studies of IPF fibroblasts. Moreover, significant variability in DNA methylation was observed among individual IPF cell lines, suggesting that differences in DNA methylation may contribute to fibroblast heterogeneity among patients with IPF. These results demonstrate that IPF fibroblasts exhibit global differences in DNA methylation that may contribute to the excessive fibroproliferation associated with this disease.

PMID: 25215577 [PubMed - as supplied by publisher]

Related Articles

Bacterial contamination of different components of the waterpipe.

Int J Tuberc Lung Dis. 2014 Aug;18(8):988-91

Authors: Safizadeh H, Moradi M, Rad MR, Nakhaee N

Abstract
SETTING: Waterpipe smoking is an emerging topic in tobacco research that may have unrecognised health hazards.
OBJECTIVE: To determine whether waterpipes are a source of bacterial contamination.
METHODS: A total of 15 restaurants and waterpipe cafés were randomly selected from the list of locations serving waterpipe tobacco in Kerman city, Iran. Different parts of the waterpipe devices were sampled, including the disposable mouthpiece, the mouthpiece of the hose and the water in the bowl of the waterpipe. The samples were smeared onto bacterial culture media, including eosin methylene blue, blood agar and MacConkey agar growth media, and incubated at 37°C. After 24-48 h, they were examined for colony growth.
RESULTS: Of 285 samples from different parts of the waterpipes, 236 (82.8%) showed positive cultures; the rate of contamination ranged from 69% in the fixed mouthpiece to 96% in bowl water. Coagulase-negative staphylococci (32.9%), Streptococcus spp (26.9%), Neisseria spp (13.7%) and Escherichia coli (9.4%) were the most frequent contaminants.
CONCLUSION: Waterpipes are frequently contaminated with microorganisms. This study revealed potential microbial hazards in waterpipes that may contribute to respiratory tract colonisation.

PMID: 25199017 [PubMed - in process]

Clinical value of echocardiographic Doppler-derived right ventricular dp/dt in patients with pulmonary arterial hypertension.

Eur Heart J Cardiovasc Imaging. 2014 Sep 8;

Authors: Ameloot K, Palmers PJ, Vande Bruaene A, Gerits A, Budts W, Voigt JU, Delcroix M

Abstract
AIMS: Right ventricular (RV) dp/dt is the instantaneous rate of RV pressure rise during early systole and is a surrogate marker of RV contractility. The main objective of this study was to evaluate the ability of echocardiographic Doppler obtained RV dp/dt to predict long-term survival in patients with pulmonary arterial hypertension (PAH) and chronic thrombo-embolic pulmonary hypertension (CTEPH).
METHODS AND RESULTS: Seventy-eight consecutive newly diagnosed untreated patients (64 ± 15 years, 71% female, 57% PAH, 43% inoperable CTEPH) were included in the study. At baseline, patients were assessed clinically [New York Heart Association (NYHA) and 6 minutes walking distance (6MWD)], by transthoracic cardiac ultrasound and by right heart catherization. RV dp/dt was assessed using spectral Doppler recordings from the tricuspid regurgitation signal at a sweep speed of 200 mm/s by measuring the time interval in which the regurgitant velocity increased from 0.5 to 2 m/s. During a mean follow-up period of 3.5 ± 1.7 years, 31 patients died and 3 received a lung transplant [study endpoint reached in 34/78 (44%) patients]. The optimal RV dp/dt cut-off was determined by receiver operating characteristic analysis at 3 years to be 410 mmHg/s (specificity 84%, positive-predictive value 55%, and negative-predictive value 83%). In univariate analysis, RV dp/dt <410 mmHg/s (hazard ratio 2.67, 95% CI 1.30-5.47, P = 0.007), tricuspid annulus plane systolic excursion (TAPSE) <15 mm, NYHA, 6MWD, and right atrial pressure were predictors of mortality. In a multivariate model with TAPSE, RV dp/dt remained an independent predictor of mortality (P = 0.01).
CONCLUSION: A reduced baseline RV dp/dt is a clear indicator of poor outcome independent of TAPSE in patients with PAH/CTEPH.

PMID: 25201651 [PubMed - as supplied by publisher]

Related Articles

Chronic Thromboembolic Pulmonary Hypertension: Do not Miss the Chance for an Early Diagnosis.

Am J Case Rep. 2014;15:378-81

Authors: Bagalas V, Paspala A, Sourla E, Akritidou S, Tsolakidou K, Boutou A, Pitsis AA, Manika K, Kioumis IP, Stanopoulos I, Pitsiou G

Abstract
Background Chronic thromboembolic pulmonary hypertension most often results from obstruction of the pulmonary vascular bed by nonresolving thromboemboli. Misdiagnosis of the disease is common because patients often present with subtle or nonspecific symptoms. Furthermore, some features in chest imaging may mimic parenchymal lung disease. The most clinically important mimic in high-resolution chest tomography is air trapping, which can be seen in a variety of small airway diseases. Case Report We present the case of a 45-year-old woman with a long history of dyspnea and exercise intolerance, misdiagnosed with allergic alveolitis. The diagnosis of CTEPH was finally established with computed tomography (CT) angiography and hemodynamics. Conclusions Chronic thromboembolism is under-diagnosed and also frequently misdiagnosed in clinical practice. The present report aims to increase the awareness of clinicians towards an accurate diagnosis of the disease, which is necessary for the early referral of CTEPH patients for operability.

PMID: 25203436 [PubMed - in process]