Biologic Phenotyping of the Human Small Airway Epithelial Response to Cigarette Smoking

BACKGROUND: The first changes associated with smoking are in the small airway epithelium (SAE). Given that smoking alters SAE gene expression, but only a fraction of smokers develop chronic obstructive pulmonary disease (COPD), we hypothesized that assessment of SAE genome-wide gene expression would permit biologic phenotyping of the smoking response, and that a subset of healthy smokers would have a "COPD-like" SAE transcriptome. METHODOLOGY/PRINCIPAL FINDINGS: SAE (10th-12th generation) was obtained via bronchoscopy of healthy nonsmokers, healthy smokers and COPD smokers and microarray analysis was used to identify differentially expressed genes. Individual responsiveness to smoking was quantified with an index representing the % of smoking-responsive genes abnormally expressed (I(SAE)), with healthy smokers grouped into "high" and "low" responders based on the proportion of smoking-responsive genes up- or down-regulated in each smoker. Smokers demonstrated significant variability in SAE transcriptome with I(SAE) ranging from 2.9 to 51.5%. While the SAE transcriptome of "low" responder healthy smokers differed from both "high" responders and smokers with COPD, the transcriptome of the "high" responder healthy smokers was indistinguishable from COPD smokers. CONCLUSION/SIGNIFICANCE: The SAE transcriptome can be used to classify clinically healthy smokers into subgroups with lesser and greater responses to cigarette smoking, even though these subgroups are indistinguishable by clinical criteria. This identifies a group of smokers with a "COPD-like" SAE transcriptome

How to promote, improve and test adherence to scientific evidence in clinical practice

BACKGROUND: Negative variation in the management of patients with the same clinical condition is frequent, and affects quality of care. Recent studies indicate that single interventions are not an effective solution. We aim to demonstrate that a multifaceted strategy can favor the introduction of research into practice, and to assess its long-term effects on a set of common medical conditions exhibiting significant negative variation at our institution. METHODS: The strategy, devised and agreed upon by a multidisciplinary group, was first applied to one relevant medical condition – cerebral ischemic stroke. To test its effectiveness a quasi-experimental study was conducted, comparing an intervention group with historical controls. After validation the strategy was extended to other pathologies, and its long-term effect measured using evidence-based quality indicators. Adherence to each indicator was determined prospectively on a six-month basis for a period of at least two consecutive years. Measures are expressed as proportions with 95% confidence intervals. RESULTS: Validation findings demonstrated that the strategy improved compliance with scientific evidence: the percentage of patients who received a CT scan within 24 hours of hospital presentation rose from 56% to 75%, (χ(2 )= 7.43 p < 0.01); admissions to selected wards increased from 45% to 64%, (χ(2 )= 7.81 p < 0.01); the number of physical medicine visits within 24 hours of the request grew from 59% to 91% (χ(2 )= 14,40 p < 0.001). Over a four-year period the program was gradually applied to 14 medical conditions. Except for 3 cases, compliance with the pathway, i.e. number of eligible patients for whom data on the care process is collected, was above the minimum requirement of 75%. Indicator adherence generally exhibited a positive trend, though variability was observed both among different conditions and between different semesters for the same pathology. CONCLUSION: According to our experience, incorporation of research into practice can be favored by systematically applying a shared, multifaceted strategy, involving multidisciplinary teams supported by central coordination. Institutions should device a tailor-made approach, should train personnel on implementation strategies, and create cultural acceptance of change. Just like for experimental trials, human and economic resources should be allocated within health care services to allow the achievement of this objective

Overexpression of extracellular superoxide dismutase reduces acute radiation induced lung toxicity

BACKGROUND: Acute RT-induced damage to the lung is characterized by inflammatory changes, which proceed to the development of fibrotic lesions in the late phase of injury. Ultimately, complete structural ablation will ensue, if the source of inflammatory / fibrogenic mediators and oxidative stress is not removed or attenuated. Therefore, the purpose of this study is to determine whether overexpression of extracellular superoxide dismutase (EC-SOD) in mice ameliorates acute radiation induced injury by inhibiting activation of TGFβ1 and downregulating the Smad 3 arm of its signal transduction pathway. METHODS: Whole thorax radiation (single dose, 15 Gy) was delivered to EC-SOD overexpressing transgenic (XRT-TG) and wild-type (XRT-WT) animals. Mice were sacrificed at 1 day, 1 week, 3, 6, 10 and 14 weeks. Breathing rates, right lung weights, total/differential leukocyte count, activated TGFβ1 and components of its signal transduction pathway (Smad 3 and p-Smad 2/3) were assessed to determine lung injury. RESULTS: Irradiated wild-type (XRT-WT) animals exhibited time dependent increase in breathing rates and right lung weights, whereas these parameters were significantly less increased (p < 0.05) at 3, 6, 10 and 14 weeks in irradiated transgenic (XRT-TG) mice. An inflammatory response characterized predominantly by macrophage infiltration was pronounced in XRT-WT mice. This acute inflammation was significantly attenuated (p < 0.05) in XRT-TG animals at 1, 3, 6 and 14 weeks. Expression of activated TGFβ1 and components of its signal transduction pathway were significantly reduced (p < 0.05) at later time-points in XRT-TG vs. XRT-WT. CONCLUSION: This study shows that overexpression of EC-SOD confers protection against RT-induced acute lung injury. EC-SOD appears to work, in part, via an attenuation of the macrophage response and also decreases TGFβ1 activation with a subsequent downregulation of the profibrotic TGFβ pathway

Early-Age-Related Changes in Proteostasis Augment Immunopathogenesis of Sepsis and Acute Lung Injury

adult) mechanisms that augment immunopathogenesis of sepsis and acute lung injury. model to standardize the efficacy of salubrinal (inhibitor of eIF2α de-phosphorylation) in controlling the accumulation of ubiquitinated proteins and the NFκB levels. Finally, we evaluated the therapeutic efficacy of salubrinal to correct proteostasis-imbalance in the adult mice based on its ability to control CLP induced IL-6 secretion or recruitment of pro-inflammatory cells.Our data demonstrate the critical role of early-age-related proteostasis-imbalance as a novel mechanism that augments the NFκB mediated inflammation in sepsis and ALI. Moreover, our data suggest the therapeutic efficacy of salubrinal in restraining NFκB mediated inflammation in the adult or older subjects

Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis.

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide. We performed a genetic association study in 15,256 cases and 47,936 controls, with replication of select top results (P < 5 × 10(-6)) in 9,498 cases and 9,748 controls. In the combined meta-analysis, we identified 22 loci associated at genome-wide significance, including 13 new associations with COPD. Nine of these 13 loci have been associated with lung function in general population samples, while 4 (EEFSEC, DSP, MTCL1, and SFTPD) are new. We noted two loci shared with pulmonary fibrosis (FAM13A and DSP) but that had opposite risk alleles for COPD. None of our loci overlapped with genome-wide associations for asthma, although one locus has been implicated in joint susceptibility to asthma and obesity. We also identified genetic correlation between COPD and asthma. Our findings highlight new loci associated with COPD, demonstrate the importance of specific loci associated with lung function to COPD, and identify potential regions of genetic overlap between COPD and other respiratory diseases

Erratum to: Scaling up strategies of the chronic respiratory disease programme of the European Innovation Partnership on Active and Healthy Ageing (Action Plan B3: Area 5).

[This corrects the article DOI: 10.1186/s13601-016-0116-9.]

Erratum to: Scaling up strategies of the chronic respiratory disease programme of the European Innovation Partnership on Active and Healthy Ageing (Action Plan B3: Area 5).

[This corrects the article DOI: 10.1186/s13601-016-0116-9.]

Differential Effects of p38, MAPK, PI3K or Rho Kinase Inhibitors on Bacterial Phagocytosis and Efferocytosis by Macrophages in COPD

Pulmonary inflammation and bacterial colonization are central to the pathogenesis of chronic obstructive pulmonary disease (COPD). Defects in macrophage phagocytosis of both bacteria and apoptotic cells contribute to the COPD phenotype. Small molecule inhibitors with anti-inflammatory activity against p38 mitogen activated protein kinases (MAPKs), phosphatidyl-inositol-3 kinase (PI3K) and Rho kinase (ROCK) are being investigated as novel therapeutics in COPD. Concerns exist, however, about off-target effects. We investigated the effect of p38 MAPK inhibitors (VX745 and SCIO469), specific inhibitors of PI3K α (NVS-P13K-2), δ (NVS-P13K-3) or γ (NVS-P13K-5) and a ROCK inhibitor PF4950834 on macrophage phagocytosis, early intracellular killing of bacteria and efferocytosis of apoptotic neutrophils. Alveolar macrophages (AM) obtained from broncho-alveolar lavage (BAL) or monocyte-derived macrophages (MDM) from COPD patients (GOLD stage II/III) enrolled from a well characterized clinical cohort (MRC COPD-MAP consortium) or from healthy ex-smoker controls were studied. Both COPD AM and MDM exhibited lower levels of bacterial phagocytosis (using Streptococcus pneumoniae and non-typeable Haemophilus influenzae) and efferocytosis than healthy controls. None of the inhibitors altered bacterial internalization or early intracellular bacterial killing in AM or MDM. Conversely PF4950834, but not other inhibitors, enhanced efferocytosis in COPD AM and MDM. These results suggest none of these inhibitors are likely to exacerbate phagocytosis-related defects in COPD, while confirming ROCK inhibitors can enhance efferocytosis in COPD