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1.  Delay of airway epithelial wound repair in COPD is associated with airflow obstruction severity 
Respiratory Research  2014;15(1):151.
Airway epithelium integrity is essential to maintain its role of mechanical and functional barrier. Recurrent epithelial injuries require a complex mechanism of repair to restore its integrity. In chronic obstructive pulmonary disease (COPD), an abnormal airway epithelial repair may participate in airway remodeling. The objective was to determine if airway epithelial wound repair of airway epithelium is abnormal in COPD.
Patients scheduled for lung resection were prospectively recruited. Demographic, clinical data and pulmonary function tests results were recorded. Emphysema was visually scored and histological remodeling features were noted. Primary bronchial epithelial cells (BEC) were extracted and cultured for wound closure assay. We determined the mean speed of wound closure (MSWC) and cell proliferation index, matrix metalloprotease (MMP)-2, MMP-9 and cytokines levels in supernatants of BEC 18 hours after cell wounding. In a subset of patients, bronchiolar epithelial cells were also cultured for wound closure assay for MSWC analyze.
13 COPD and 7 non COPD patients were included. The severity of airflow obstruction and the severity of emphysema were associated with a lower MSWC in BEC (p = 0.01, 95% CI [0.15-0.80]; p = 0.04, 95% CI [−0.77;-0.03] respectively). Cell proliferation index was decreased in COPD patients (19 ± 6% in COPD vs 27 ± 3% in non COPD, p = 0.04). The severity of COPD was associated with a lower level of MMP-2 (7.8 ± 2 105 AU in COPD GOLD D vs 12.8 ± 0.13 105 AU in COPD GOLD A, p = 0.04) and a lower level of IL-4 (p = 0.03, 95% CI [0.09;0.87]). Moreover, higher levels of IL-4 and IL-2 were associated with a higher MSWC (p = 0.01, 95% CI [0.17;0.89] and p = 0.02, 95% CI [0.09;0.87] respectively). Clinical characteristics and smoking history were not associated with MSWC, cell proliferation index or MMP and cytokines levels. Finally, we showed an association of the MSWC of bronchial and corresponding bronchiolar epithelial cells obtained from the same patients (p = 0.02, 95% CI [0.12;0.89]).
Our results showed an abnormal bronchial epithelial wound closure process in severe COPD. Further studies are needed to elucidate the contribution and the regulation of this mechanism in the complex pathophysiology of COPD.
Electronic supplementary material
The online version of this article (doi:10.1186/s12931-014-0151-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4251925  PMID: 25427655
COPD; Airway epithelium; Bronchial cells; Bronchiolar cells; Wound repair; Cell proliferation
2.  Systematic Analysis of Blood Cell Transcriptome in End-Stage Chronic Respiratory Diseases 
PLoS ONE  2014;9(10):e109291.
End-stage chronic respiratory diseases (CRD) have systemic consequences, such as weight loss and susceptibility to infection. However the mechanisms of such dysfunctions are as yet poorly explained. We hypothesized that the genes putatively involved in these mechanisms would emerge from a systematic analysis of blood mRNA profiles from pre-transplant patients with cystic fibrosis (CF), pulmonary hypertension (PAH), and chronic obstructive pulmonary disease (COPD).
Whole blood was first collected from 13 patients with PAH, 23 patients with CF, and 28 Healthy Controls (HC). Microarray results were validated by quantitative PCR on a second and independent group (7PAH, 9CF, and 11HC). Twelve pre-transplant COPD patients were added to validate the common signature shared by patients with CRD for all causes. To further clarify a role for hypoxia in the candidate gene dysregulation, peripheral blood mononuclear cells from HC were analysed for their mRNA profile under hypoxia.
Unsupervised hierarchical clustering allowed the identification of 3 gene signatures related to CRD. One was common to CF and PAH, another specific to CF, and the final one was specific to PAH. With the common signature, we validated T-Cell Factor 7 (TCF-7) and Interleukin 7 Receptor (IL-7R), two genes related to T lymphocyte activation, as being under-expressed. We showed a strong impact of the hypoxia on modulation of TCF-7 and IL-7R expression in PBMCs from HC under hypoxia or PBMCs from CRD. In addition, we identified and validated genes upregulated in PAH or CF, including Lectin Galactoside-binding Soluble 3 and Toll Like Receptor 4, respectively.
Systematic analysis of blood cell transcriptome in CRD patients identified common and specific signatures relevant to the systemic pathologies. TCF-7 and IL-7R were downregulated whatever the cause of CRD and this could play a role in the higher susceptibility to infection of these patients.
PMCID: PMC4203719  PMID: 25329529
3.  Successful treatment of a life-threatening air leakage, complicating severe abdominal sepsis, with a one-way endobronchial valve 
A 41-year-old woman had a jeopardizing air leak from an alveolar-pleural and transdiaphragmatic fistula with pulmonary cavitation, secondary to a severe postoperative abdominal sepsis. Her condition dramatically improved by introduction, in the lower bronchus, of a one-way endobronchial valve, leading to immediate cessation of air leakage and removal of extracorporeal membrane oxygenation, and thus avoiding a lower left lobectomy with myoplasty. Furthermore, removal of the valve nine weeks later led to near-complete recovery of the left lower lobe.
PMCID: PMC3445361  PMID: 22761125
ARDS; Airway; Endobronchial valve; Alveolar fistula; Endoscopy
4.  Impact of Geocoding Methods on Associations between Long-term Exposure to Urban Air Pollution and Lung Function 
Environmental Health Perspectives  2013;121(9):1054-1060.
Background: Errors in address geocodes may affect estimates of the effects of air pollution on health.
Objective: We investigated the impact of four geocoding techniques on the association between urban air pollution estimated with a fine-scale (10 m × 10 m) dispersion model and lung function in adults.
Methods: We measured forced expiratory volume in 1 sec (FEV1) and forced vital capacity (FVC) in 354 adult residents of Grenoble, France, who were participants in two well-characterized studies, the Epidemiological Study on the Genetics and Environment on Asthma (EGEA) and the European Community Respiratory Health Survey (ECRHS). Home addresses were geocoded using individual building matching as the reference approach and three spatial interpolation approaches. We used a dispersion model to estimate mean PM10 and nitrogen dioxide concentrations at each participant’s address during the 12 months preceding their lung function measurements. Associations between exposures and lung function parameters were adjusted for individual confounders and same-day exposure to air pollutants. The geocoding techniques were compared with regard to geographical distances between coordinates, exposure estimates, and associations between the estimated exposures and health effects.
Results: Median distances between coordinates estimated using the building matching and the three interpolation techniques were 26.4, 27.9, and 35.6 m. Compared with exposure estimates based on building matching, PM10 concentrations based on the three interpolation techniques tended to be overestimated. When building matching was used to estimate exposures, a one-interquartile range increase in PM10 (3.0 μg/m3) was associated with a 3.72-point decrease in FVC% predicted (95% CI: –0.56, –6.88) and a 3.86-point decrease in FEV1% predicted (95% CI: –0.14, –3.24). The magnitude of associations decreased when other geocoding approaches were used [e.g., for FVC% predicted –2.81 (95% CI: –0.26, –5.35) using NavTEQ, or 2.08 (95% CI –4.63, 0.47, p = 0.11) using Google Maps].
Conclusions: Our findings suggest that the choice of geocoding technique may influence estimated health effects when air pollution exposures are estimated using a fine-scale exposure model.
Citation: Jacquemin B, Lepeule J, Boudier A, Arnould C, Benmerad M, Chappaz C, Ferran J, Kauffmann F, Morelli X, Pin I, Pison C, Rios I, Temam S, Künzli N, Slama R, Siroux V. 2013. Impact of geocoding methods on associations between long-term exposure to urban air pollution and lung function. Environ Health Perspect 121:1054–1060;
PMCID: PMC3764075  PMID: 23823697
5.  Air pollution and asthma control in the Epidemiological study on the Genetics and Environment of Asthma 
The associations between exposure to air pollution and asthma control are not well known. The objective is to assess the association between long term exposure to NO2, O3 and PM10 and asthma control in the EGEA2 study (2003–2007).
Modeled outdoor NO2, O3 and PM10 estimates were linked to each residential address using the 4-km grid air pollutant surface developed by the French Institute of Environment for 2004. Asthma control was assessed in 481 subjects with current asthma using a multidimensional approach following the 2006–2009 GINA guidelines. Multinomial and ordinal logistic regressions were conducted adjusted on sex, age, BMI, education, smoking and use of inhaled corticosteroids. The association between air pollution and the three domains of asthma control (symptoms, exacerbations and lung function) was assessed. Odds Ratios (ORs) are reported per Inter Quartile Range (IQR).
Median concentrations (μg.m−3) were 32(IQR 25–38) for NO2 (n=465), 46(41–52) for O3 and 21(18–21) for PM10 (n=481). In total, 44%, 29% and 27% had controlled, partly-controlled and uncontrolled asthma. The ordinal ORs for O3 and PM10 with asthma control were 1.69(95%CI 1.22–2.34) and 1.35(95%CI 1.13–1.64) respectively. When including both pollutants in the same model, both associations persisted. Associations were not modified by sex, smoking status, use of inhaled corticosteroids, atopy, season of examination or BMI. Both pollutants were associated with each of the three main domains of control.
The results suggest that long-term exposure to PM10 and O3 is associated with uncontrolled asthma in adults, defined by symptoms, exacerbations and lung function. Abstract Word count: 250 Key words: air pollution, asthma, asthma control
PMCID: PMC3943770  PMID: 21690606
Adult; Air Pollutants; adverse effects; analysis; Asthma; epidemiology; etiology; genetics; Case-Control Studies; Cross-Sectional Studies; Environmental Exposure; adverse effects; analysis; Environmental Monitoring; Follow-Up Studies; France; epidemiology; Hospitalization; statistics & numerical data; Humans; Logistic Models; Lung; physiopathology; Nitrous Acid; adverse effects; analysis; Ozone; adverse effects; analysis; Residence Characteristics; Respiratory Tract Diseases; complications; epidemiology; genetics; Seasons; Severity of Illness Index; air pollution; asthma; asthma control
6.  Systems medicine and integrated care to combat chronic noncommunicable diseases 
Genome Medicine  2011;3(7):43.
We propose an innovative, integrated, cost-effective health system to combat major non-communicable diseases (NCDs), including cardiovascular, chronic respiratory, metabolic, rheumatologic and neurologic disorders and cancers, which together are the predominant health problem of the 21st century. This proposed holistic strategy involves comprehensive patient-centered integrated care and multi-scale, multi-modal and multi-level systems approaches to tackle NCDs as a common group of diseases. Rather than studying each disease individually, it will take into account their intertwined gene-environment, socio-economic interactions and co-morbidities that lead to individual-specific complex phenotypes. It will implement a road map for predictive, preventive, personalized and participatory (P4) medicine based on a robust and extensive knowledge management infrastructure that contains individual patient information. It will be supported by strategic partnerships involving all stakeholders, including general practitioners associated with patient-centered care. This systems medicine strategy, which will take a holistic approach to disease, is designed to allow the results to be used globally, taking into account the needs and specificities of local economies and health systems.
PMCID: PMC3221551  PMID: 21745417
7.  Impact of nutritional status on body functioning in chronic obstructive pulmonary disease and how to intervene 
Purpose of review
Chronic obstructive pulmonary disease (COPD) is the fifth cause of mortality in the world. This article reviews diet as a risk or protective factor for COPD, mechanisms of malnutrition, undernutrition consequences on body functioning and how to modulate nutritional status of COPD patients.
Recent findings
Different dietary factors (dietary pattern, foods, nutrients) have been associated with COPD and the course of the disease. Mechanical disadvantage, energy imbalance, disuse muscle atrophy, hypoxemia, systemic inflammation and oxidative stress have been reported to cause systemic consequences such as cachexia and compromise whole body functioning. Nutritional intervention makes it possible to modify the natural course of the disease provide that it is included in respiratory rehabilitation combining bronchodilators optimization, infection control, exercise and in some patients correction of hypogonadism.
Diet, as a modifiable risk factor, appears more as an option to prevent and modify the course of COPD. Reduction of mechanical disadvantage, physical training and anabolic agents should be used conjointly with oral nutrition supplements to overcome undernutrition and might change the prognosis of the disease in some cases. Major research challenges address the role of systemic inflammation and the best interventions for control it besides smoking cessation.
PMCID: PMC2736295  PMID: 18542004
Cachexia; physiopathology; prevention & control; therapy; Diet; Humans; Inflammation; physiopathology; prevention & control; therapy; Inflammation Mediators; metabolism; Nutritional Status; Nutritional Support; methods; Oxidative Stress; Pulmonary Disease, Chronic Obstructive; etiology; physiopathology; prevention & control; therapy; Risk Factors; Nutrition disorders; COPD; inflammation; pulmonary rehabilitation; enteral feeding; oral nutrition supplement; anabolic agents; diet

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