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Airway–liquid interface cultures of primary epithelial cells and of induced pluripotent stem-cell-derived airway epithelial cells (ALI and iALI, respectively) are physiologically relevant models for respiratory virus infection studies because they can mimic the in vivo human bronchial epithelium. Here, we investigated gene expression profiles in human airway cultures (ALI and iALI models), infected or not with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), using our own and publicly available bulk and single-cell transcriptome datasets. SARS-CoV-2 infection significantly increased the expression of interferon-stimulated genes (IFI44, IFIT1, IFIT3, IFI35, IRF9, MX1, OAS1, OAS3 and ISG15) and inflammatory genes (NFKBIA, CSF1, FOSL1, IL32 and CXCL10) by day 4 post-infection, indicating activation of the interferon and immune responses to the virus. Extracellular matrix genes (ITGB6, ITGB1 and GJA1) were also altered in infected cells. Single-cell RNA sequencing data revealed that SARS-CoV-2 infection damaged the respiratory epithelium, particularly mature ciliated cells. The expression of genes encoding intercellular communication and adhesion proteins was also deregulated, suggesting a mechanism to promote shedding of infected epithelial cells. These data demonstrate that ALI/iALI models help to explain the airway epithelium response to SARS-CoV-2 infection and are a key tool for developing COVID-19 treatments. [ABSTRACT FROM AUTHOR]

Epithelial cytokines are involved in the orchestration of T1/T2 inflammatory patterns. We question the persistence of this trait in air–liquid interface (ALI) epithelial cultures and whether this local orientation can be related to systemic patterns (e.g., blood eosinophil counts [BECs]). We investigated alarmin release related to high versus low T2 phenotypes associated with chronic airway diseases. ALIs were reconstituted from 32 control, 40 chronic obstructive pulmonary disease, and 20 asthmatic patients. Interleukin‐8 (IL‐8; a T1‐cytokine), IL‐25, IL‐33, and thymic stromal lymphopoietin (T2‐alarmins) concentrations were assessed in subnatants at steady state and used to explain blood neutrophil and eosinophil counts. IL‐25 and IL‐8 levels were highest in asthma ALI‐subnatants, whereas IL‐33 was sparsely detected. Thymic stromal lymphopoietin levels were similar among groups. All asthma cell cultures were T1‐high/T2‐high, while chronic obstructive pulmonary disease and controls tended to be mixed. BECs were independently explained by both disease and in‐culture T2‐alarmin levels, irrespective of the T2‐alarmin considered. The epithelial ALI‐T2 signature was more frequently high in patients with a BEC > 300/mm3. Despite removal from an in vivo environment for ≥2 months, ALIs release disease‐specific cytokine "cocktails" into their subnatants, suggesting continued persistence of alarmin orientation in differentiated cell line environments. [ABSTRACT FROM AUTHOR]

(1) Background: We have previously shown that sputum rheology can discriminate between patients with COPD and other muco-obstructive lung diseases, and that it is correlated with mucin content and sputum eosinophilia. We now hypothesize that it could be a more-accurate guide than clinical evaluation for the prescription of azithromycin to prevent exacerbations of COPD and to reduce exposure to antibiotics; (2) Methods: "COPD CaRhe" is a multicentric, randomized, controlled trial comparing outcomes in two parallel arms (36 vs. 36 patients). Patients will be recruited in the university hospitals of Montpellier, Bordeaux, and Toulouse, in France, and they should have a diagnosis of COPD with frequent exacerbations (≥3/year). Enrollment will occur during a routine visit to a respiratory department, and follow-up visits will occur every 3 months for a period of 1 year. At each visit, a 3-month prescription of azithromycin will be provided to those patients who obtain a score of <70 on the Cough and Sputum Assessment Questionnaire (CASA-Q) or a critical stress score of σc > 39 on a rheological assessment of sputum, depending upon their randomization group. The primary outcome will be the number of exacerbations of COPD; (3) Discussion: By using sputum rheology, the COPD CaRhe study may provide clinicians with an objective biomarker to guide the prescription of azithromycin while reducing the cumulative exposure to macrolides. [ABSTRACT FROM AUTHOR]

Background: Obesity is known to diminish lung volumes and worsen asthma. However, mechanistic understanding is lacking, especially as concerns small‐airway responsiveness. The objective of this study was therefore to compare small‐airway responsiveness, as represented by the change in expiratory:inspiratory mean lung density ratios (MLDe/i, as determined by computed tomography [CT]) throughout methacholine testing in obese versus non‐obese women with asthma. Methods: Thoracic CT was performed during methacholine bronchoconstriction challenges to produce standardized response curves (SRC: response parameter versus ln[1 + % PD20], where PD20 is the cumulative methacholine dose) for 31 asthma patients (n = 18 non‐obese and n = 13 obese patients). Mixed models evaluated obesity effects and interactions on SRCs while adjusting for age and bronchial morphology. Small airway responsiveness as represented by SRC slope was calculated for each third of the MLDe/i response and compared between groups. Results: Obesity‐associated effects observed during experimental bronchoconstriction included: (i) a significant baseline effect for forced expiratory volume in 1 second with lower values for the obese (73.11 ± 13.44) versus non‐obese (82.19 ± 8.78; p = 0.002) groups prior to methacholine testing and (ii) significantly higher responsiveness in small airways as estimated via differences in MLDe/i slopes (group×ln(1 + % PD20 interaction; p = 0.023). The latter were pinpointed to higher slopes in the obese group at the beginning 2/3 of SRCs (p = 0.004 and p = 0.021). Significant obesity effects (p = 0.035 and p = 0.008) indicating lower forced vital capacity and greater % change in MLDe/I (respectively) throughout methacholine testing, were also observed. Conclusion: In addition to baseline differences, small‐airway responsiveness (as represented by the change in MLDe/i) during methacholine challenge is greater in obese women with asthma as compared to the non‐obese. [ABSTRACT FROM AUTHOR]

Background: Chronic Obstructive Pulmonary Disease (COPD), a major cause of mortality and disability, is a complex disease with heterogeneous and ill-understood biological mechanisms. Human induced pluripotent stem cells (hiPSCs) are a promising tool to model human disease, including the impact of genetic susceptibility. Methods: We developed a simple and reliable method for reprogramming peripheral blood mononuclear cells into hiPSCs and to differentiate them into air–liquid interface bronchial epithelium within 45 days. Importantly, this method does not involve any cell sorting step. We reprogrammed blood cells from one healthy control and three patients with very severe COPD. Results: The mean cell purity at the definitive endoderm and ventral anterior foregut endoderm (vAFE) stages was >80%, assessed by quantifying C-X-C Motif Chemokine Receptor 4/SRY-Box Transcription Factor 17 (CXCR4/SOX17) and NK2 Homeobox 1 (NKX2.1) expression, respectively. vAFE cells from all four hiPSC lines differentiated into bronchial epithelium in air–liquid interface conditions, with large zones covered by beating ciliated, basal, goblets, club cells and neuroendocrine cells, as found in vivo. The hiPSC-derived airway epithelium (iALI) from patients with very severe COPD and from the healthy control were undistinguishable. Conclusions: iALI bronchial epithelium is ready for better understanding lung disease pathogenesis and accelerating drug discovery. [ABSTRACT FROM AUTHOR]

Thiazolidinediones (TZDs) are synthetic peroxisome proliferator-activated receptor-[gamma] (PPAR[gamma]) ligands that are widely used in type II diabetes treatment. In addition to their ability to improve glucose homeostasis, TZDs possess antiinflammatory properties and inhibit growth of many cells, particularly cancerous airway epithelial cells. However, the functional effects of PPAR[gamma] ligands on nonmalignant human bronchial epithelial cells have never been investigated. In the present study, we questioned whether PPAR[gamma] ligands may regulate proliferation of human bronchial epithelial cells, and we studied their potential molecular mechanisms. We found that synthetic PPAR[gamma] agonists, rosiglitazone (RGZ) and troglitazone (TGZ), induced proliferation of human bronchial epithelial cells, whereas the endogenous PPAR[gamma], ligand, 15-deoxy-[[DELTA].sup.12,14]-prostaglandin [J.sub.2] (15d-[PGJ.sub.2]), inhibited cell growth. RGZ and TGZ (10 [micro]M) induced a rapid and transient intracellular [Ca.sup.2+] mobilization from thapsigargin-sensitive intracellular stores, whereas 15d-[PGJ.sub.2] (5 [micro]M) did not induce any [Ca.sup.2+] signal. The PPAR[gamma] antagonist GW-9662 did not inhibit any biological responses, but it reversed the effect of 15d-[PGJ.sub.2] on cell growth. Using RT-PCR, we detected mRNA expression of the GPR40 receptor, a G proteincoupled receptor recently identified as a receptor for free fatty acids and TZDs, in human bronchial epithelial cells. Downregulation of GPR40 by small-interfering RNA led to a significant inhibition of TZD-induced [Ca.sup.2+] mobilization and proliferation. This study provides evidence for the proliferative effect of anti-diabetic drug TZDs in nonmalignant human bronchial epithelial cells through GPR40 receptor activation, involving an intracellular [Ca.sup.2+] signaling pathway. airway epithelium; glitazone; calcium; peroxisome proliferator-activated receptor-[gamma]; G protein receptor 40

Human pluripotent stem cells (hiPSC) represent a unique opportunity to model lung development and chronic bronchial diseases. We generated a hiPSC line from a highly characterized healthy heavy smoker male donor free from emphysema or tobacco related disease. Peripheral blood mononuclear cells (PBMCs) were reprogrammed using integration-free Sendai virus. The cell line had normal karyotype, expressed pluripotency hallmarks, and differentiated into the three primary germ layers. The reported UHOMi007-A iPSC line may be used as a control to model lung development, study human chronic bronchial diseases and drug testing. [ABSTRACT FROM AUTHOR]

Purpose: Asthma exacerbations are inflammatory events that rarely result in full hospitalization following an ER visit. Unfortunately, certain patients require prolonged support, including occasional external lung support through ECMO or ECCOR (with subsequent further exposure to other life‐threatening issues), and some die. In parallel, biologics are revolutionizing severe asthma management, mostly in T2 high patients. Methods: We extensively reviewed the current unmet needs surrounding ICU‐admitted asthma exacerbations, with a focus on currently available drugs and the underlying biological processes involved. We explored whether currently available T2‐targeting drugs can reasonably be seen as potential players not only for relapse prevention but also as candidate drugs for a faster resolution of such episodes. The patient's perspective was also sought. Results: About 30% of asthma exacerbations admitted to the ICU do not resolve within five days. Persistent severe airway obstruction despite massive doses of corticosteroids and maximal pharmacologically induced bronchodilation is the main cause of treatment failure. Previous ICU admission is the main risk factor for such episodes and may eventually be considered as a T2 surrogate marker. Fatal asthma cases are hallmarked by poorly steroid‐sensitive T2‐inflammation associated with severe mucus plugging. New, fast‐acting T2‐targeting biologics (already used for preventing asthma exacerbations) have the potential to circumvent steroid sensitivity pathways and decrease mucus plugging. This unmet need was confirmed by patients who reported highly negative, traumatizing experiences. Conclusions: There is room for improvement in the management of ICU‐admitted severe asthma episodes. Clinical trials assessing how biologics might improve ICU outcomes are direly needed. [ABSTRACT FROM AUTHOR]

Background: Distal airway metaplasia may precede honeycombing in progressive fibrosing interstitial lung disease (ILD). The SCGB1A1+ bronchiolar-specific club cell may play a role in this aberrant regenerative process. Objective: To assess the presence of club cells in the small airways of patients suffering from ILD. Methods: Small airways (internal diameter <2 mm) in lung samples [surgical lung biopsy (SLB) and/or transbronchial lung cryobiopsy (TBLC)] from 14 patients suffering from ILD and 10 controls were morphologically assessed and stained for SCGB1A1. SCGB1A1 was weighted by epithelial height as a marker of airway generation (SCGB1A1/EH). Correlations between clinical, functional, and high-resolution CT (HRCT) prognostic factors and histomorphometry were assessed. Results: Small airways from samples with ILD patterns were significantly less dense in terms of SCGB1A1+ cells [0.064 (0.020–0.172)] as compared to controls' sample's small airways [0.393 (0.082–0.698), p < 0.0001]. Usual interstitial pneumonia (UIP) patterns most frequently contained small airways with limited or absent SCGB1A1 expression (SCGB1A1/EH <0.025): UIP (18/33; 55%) as compared with non-UIP patterns (4/31; 13%) or controls (0/29; 0%): p < 0.0001. In addition, correlations with HRCT indicated a significant negative relationship between SCGB1A1 and bronchiectasis as a feature of bronchiolization (Rho −0.63, p < 0.001) and a positive relationship with both forced vital capacity (FVC) and Hounsfield unit (HU)-distribution pattern in kurtosis (Rho 0.38 and 0.50, respectively, both p < 0.001) as markers of fibrotic changes. Conclusion: Compared with controls, the small airways of patients with ILD more often lack SCGB1A1, especially so in UIP. Low densities of SCGB1A1-marked cells correlate with bronchiectasis and fibrotic changes. Further research investigating SCGB1A1 staining as a pathological feature of the bronchiolization process is merited. [ABSTRACT FROM AUTHOR]

The airway epithelium represents a fragile environmental interface potentially disturbed by cigarette smoke (CS), the major risk factor for developing chronic obstructive pulmonary disease (COPD). CS leads to bronchial epithelial damage on ciliated, goblet, and club cells, which could involve calcium (Ca2+) signaling. Ca2+ is a key messenger involved in virtually all fundamental physiological functions, including mucus and cytokine secretion, cilia beating, and epithelial repair. In this study, we analyzed Ca2+ signaling in air-liquid interface-reconstituted bronchial epithelium from control subjects and smokers (with and without COPD). We further aimed to determine how smoking impaired Ca2+ signaling. First, we showed that the endoplasmic reticulum (ER) depletion of Ca2+ stores was decreased in patients with COPD and that the Ca2+ influx was decreased in epithelial cells from smokers (regardless of COPD status). In addition, acute CS exposure led to a decrease in ER Ca2+ release, significant in smoker subjects, and to a decrease in Ca2+ influx only in control subjects. Furthermore, the differential expression of 55 genes involved in Ca2+ signaling highlighted that only ORAI3 expression was significantly altered in smokers (regardless of COPD status). Finally, we incubated epithelial cells with an ORAI antagonist (GSK- 7975A). GSK-7975A altered Ca2+ influx and ciliary beating, but not mucus and cytokine secretion or epithelial repair, in control subjects. Our data suggest that Ca2+ signaling is impaired in smoker epithelia (regardless of COPD status) and involves ORAI3.Moreover, ORAI3 is additionally involved in ciliary beating. [ABSTRACT FROM AUTHOR]

Summary: Background: Goblet cell hyperplasia (GCH) is a pathological finding classically reported across asthma severity levels and usually associated with smoking. Multiple biological mechanisms may contribute to excessive mucus production. Objective: We aimed to decipher the clinical meanings and biological pathways related to GCH in non‐smokers with asthma. Methods: Cough and sputum assessment questionnaire (CASA‐Q) responses at entry and 1 year later were compared to clinical and functional outcomes in 59 asthmatic patients. GCH was assessed through periodic‐acid shift (PAS) staining on endobronchial biopsies obtained at entry in a subset of 32 patients. Results: Periodic‐acid shift‐staining analysis revealed a double wave distribution discriminating patients with (>10% of the epithelial area) or without GCH. CASA‐Q scores were mostly driven by overall asthma severity (P < 0.0001). CASA‐Q scores remained stable at 1 year and were independently associated with BAL eosinophil content irrespective of the presence of GCH. GCH was unrelated to the presence of bronchiectasis at CT, GERD or chronic rhinosinusitis, but correlated well with neutrophilic inflammatory patterns observed upon BAL cellular analysis (P = 0.002 at multivariate analysis). BALF bacterial loads were unrelated to GCH or to CASA‐Q. Conclusions and Clinical Relevance: Goblet cell hyperplasia is disconnected from chronic cough and sputum when assessed by a specific questionnaire. GCH is related to neutrophilic asthma whereas symptoms are related to airway eosinophilia. The clinical counterpart of GCH is unlikely assessed by the CASA‐Q. [ABSTRACT FROM AUTHOR]

Rationale: The diagnostic concordance between transbronchial lung cryobiopsy (TBLC)-versus surgical lung biopsy (SLB) as the current gold standard-in interstitial lung disease (ILD) cases requiring histology remains controversial. Objectives: To assess diagnostic concordance between TBLC and SLB sequentially performed in the same patients, the diagnostic yield of both techniques, and subsequent changes in multidisciplinary assessment (MDA) decisions. Methods: A two-center prospective study included patients with ILD with a nondefinite usual interstitial pneumonia pattern (on high-resolution computed tomography scan) confirmed at a first MDA. Patients underwent TBLC immediately followed by video-assisted thoracoscopy for SLB at the same anatomical locations. After open reading of both sample types by local pathologists and final diagnosis at a second MDA (MDA2), anonymized TBLC and SLB slides were blindly assessed by an external expert pathologist (T.V.C.). Kappa-concordance coefficients and percentage agreement were computed for: TBLC versus SLB, MDA2 versus TBLC, MDA2 versus SLB, and blinded pathology versus routine pathology. Measurements and Main Results: Twenty-one patients were included. The median TBLC biopsy size (longest axis) was 7 mm (interquartile range, 5-8 mm). SLB biopsy sizes averaged 46.1 ± 13.8 mm. Concordance coefficients and percentage agreement were: TBLC versus SLB: κ = 0.22 (95% confidence interval [CI], 0.01-0.44), percentage agreement = 38% (95% CI, 18-62%); MDA2 versus TBLC: κ = 0.31 (95% CI, 0.06-0.56), percentage agreement = 48% (95% CI, 26-70)%; MDA2 versus SLB: κ = 0.51 (95% CI, 0.27-0.75), percentage agreement = 62% (95% CI, 38-82%); two pneumothoraces (9.5%) were recorded during TBLC. TBLC would have led to a different treatment if SLB was not performed in 11 of 21 (52%) of cases. Conclusions: Pathological results from TBLC and SLB were poorly concordant in the assessment of ILD. SLBs were more frequently concordant with the final diagnosis retained at MDA. [ABSTRACT FROM AUTHOR]

Abstract Primary Ciliary Dyskinesia (PCD) is a rare heterogeneous genetic disorder affecting motile cilia structure and function leading to lung disease. We generated induced pluripotent stem cells (iPSCs) from dermal fibroblasts of a female PCD patient carrying disease-causing variants in the CCDC40 gene. Reprogramming was performed with the human OSKM transcription factors using the Sendai-virus delivery system. The resulting transgene free iPSCs had normal karyotype, expressed pluripotency markers, could differentiate into the three germ layers in vivo and retained the disease-causing CCDC40 mutations. This iPSC line could be useful to model PCD disease and test gene therapy strategies. Resource Table Unlabelled Table Unique stem cell line identifier UHOMi001-A Alternative name(s) of stem cell line iPCD02.30 Institution Institute for Regenerative Medicine & Biotherapy (IRMB), Montpellier, FRANCE Contact information of distributor John De Vos john.devos@inserm.fr Type of cell line iPSC Origin human Additional origin info Age: 34 Sex: Female Cell Source Dermal fibroblasts Clonality Clonal Method of reprogramming hOCT4, hSOX2, hC-MYC, hKLF4 (CytoTune™-iPS 2.0 Sendai Reprogramming Kit - Invitrogen, Thermo Fisher Scientific Inc.) Genetic Modification YES Type of Modification Spontaneous mutation Associated disease Primary Ciliary Dyskinesia Gene/locus Compound Heterozygous mutations the Coiled-Coil Domain Containing 40 Gene (CCDC40): c.1116_1117delCT (Exon 7) and c.3180 + 1G > A (Intron 19) Method of modification N/A Name of transgene or resistance N/A Inducible/constitutive system N/A Date archived/stock date 2018-02-12 Cell line repository/bank N/A Ethical approval The study was approved by the regional scientific ethical committee (CPP Sud Med IV) under the number ID-RCB: 2013-A00892–43/CILIPS, Promoter University Hospital Of Montpellier) and informed consent was obtained from the patient. [ABSTRACT FROM AUTHOR]

Primary ciliary dyskinesia (PCD) is a rare and heterogeneous genetic disorder that affects the structure and function of motile cilia. In the airway epithelium, impaired ciliary motion results in reduced or absent mucociliary clearance that leads to the appearance of chronic airway infection, sinusitis, and bronchiectasis. Currently, there is no effective treatment for PCD, and research is limited by the lack of convenient models to study this disease and investigate innovative therapies. Furthermore, the high heterogeneity of PCD genotypes is likely to hinder the development of a single therapy for all patients. The generation of patient-derived, induced pluripotent stem cells, and their differentiation into airway epithelium, as well as genome editing technologies, could represent major tools for in vitro PCD modeling and for developing personalized therapies. Here, we review PCD pathogenesis and then discuss how human induced pluripotent stem cells could be used to model this disease for the development of innovative, patient-specific biotherapies. [ABSTRACT FROM AUTHOR]

Background: Bronchial epithelium plays a key role in orchestrating innate and adaptive immunity. The fate of ex vivo airway epithelial cultures growing at the air liquid interface (ALI) derived from human endobronchial biopsies or brushings is not easy to predict. Calibrating and differentiating these cells is a long and expensive process requiring rigorous expertise. Pinpointing factors associated with ALI culture success would help researchers gain further insight into epithelial progenitor behavior.Methods: A successful ALI culture was defined as one in which a pseudostratified epithelium has formed after 28 days in the presence of all differentiated epithelial cell types. A 4-year prospective bi-center study was conducted with adult subjects enrolled in different approved research protocols.Results: 463 consecutive endobronchial biopsies were obtained from normal healthy volunteers, healthy smokers, asthmatic patients and smokers with COPD. All demographic variables, the different fiber optic centers and culture operators, numbers of endo-bronchial biopsies and the presence of ciliated cells were carefully recorded. Univariate and multivariate models were developed. A stepwise procedure was used to select the final logistic regression model. ALI culture success was independently associated with the presence of living ciliated cells within the initial biopsy (OR = 2.18 [1.50-3.16], p < 0.001).Conclusion: This finding highlights the properties of the cells derived from the epithelium dedifferentiation process. The preferential selection of samples with ciliated beating cells would probably save time and money. It is still unknown whether successful ALI culture is related to indicators of general cell viability or a purported stem cell state specifically associated with ciliated beating cells. [ABSTRACT FROM AUTHOR]

Background: To examine trends in mortality, costs and in-hospital management and outcomes of severe COPD exacerbations admitted in France. Methods: Patients hospitalized from 2007 to 2012 with COPD exacerbation as the primary diagnosis were identified from the exhaustive French medico-administrative hospitalizations database records. Four groups of severe COPD exacerbations were defined: hospitalisation in a general ward (GW) without acute respiratory failure (ARF), GW with ARF, ICU without invasive mechanical ventilation (MV), and ICU with MV. Results: A 15.48 % increase in admissions from 113 276 in 2007 to 133 497 in 2012 was recorded. Age (+9. 9 months), gender (−2.5 % of male) and length of stay (−0.29 day) slightly changed while the number of ICU admissions increased markedly (+41.78 %). In-hospital mortality rates increased (+8.06 %, p < .001) and followed seasonal variations peaking in winter. Total hospitalizations costs increased from 602 to 678 millions euros (+12. 6 %). Pneumonia-related mortality increased (+37.2 %). A progressive replacement of chest X-ray by CT scan was observed (−41.3 % vs +31.7 %) while fewer spirometries (−13.7 %) and bronchoscopies (−22.6 %) were performed. Conclusion: The incidence of severe COPD exacerbations and the proportion of ICU-managed patients are still increasing in France. Rising total costs and mortality rates especially related to pneumonia advocate for rethinking COPD management plans. [ABSTRACT FROM AUTHOR]

Impaired airway homeostasis in chronic obstructive pulmonary disease (COPD) could be partly related to club cell secretory protein (CCSP) deficiency. We hypothesize that CCSP G38A polymorphism is involved and aim to examine the influence of the CCSP G38A polymorphism on CCSP transcription levels and its regulatory mechanisms. CCSP genotype and CCSP levels in serum and sputum were assessed in 66 subjects with stable COPD included in a 1-yr observational study. Forty-nine of them had an exacerbation. In an in vitro study, the impact on the CCSP promoter of 38G wild-type or 38A variant was assessed. BEAS-2B cells were transfected by either the 38G or 38A construct, in the presence/absence of cigarette smoke extract (CSE) or lipopolysaccharides (LPS). Cotransfections with modulating transcription factors, p53 and Nkx2.1, identified by in silico analysis by using ConSite and TFSEARCH were conducted. A allele carrier COPD patients had lower serum and sputum CCSP levels, especially among active smokers, and a decreased body mass index, airflow obstruction, dyspnea, and exercise capacity (BODE) score. In vitro, baseline CCSP transcription levels were similar between the wild and variant constructs. CSE decreased more profoundly the CCSP transcription level of 38A transfected cells. The opposite effect was observed with p53 cotransfection. LPS stimulation induced CCSP repression in 38A promoter transfected cells. Cotransfection with Nkx2.1 significantly activated the CCSP promoters irrespective of the polymorphism. Circulating CCSP levels are associated with smoking and the CCSP G38A polymorphism. CSE, LPS, and the Nkx2.1 and p53 transcription factors modulated the CCSP promoter efficiency. The 38A polymorphism exaggerated the CCSP repression in response to p53 and CSE. [ABSTRACT FROM AUTHOR]

Background Respiratory viral infections lead to bronchial inflammation in patients with cystic fibrosis, especially during pulmonary exacerbations. The aim of this study was to determine the impact of viral-associated pulmonary exacerbations in children with cystic fibrosis and failure to improve forced expiratory volume in 1 s ( FEV1) after an appropriate treatment. Methods We lead a pilot study from January 2009 until March 2013. Children with a diagnosis of cystic fibrosis were longitudinally evaluated three times: at baseline (Visit 1), at the diagnosis of pulmonary exacerbation (Visit 2), and after exacerbation treatment (Visit 3). Nasal and bronchial samples were analyzed at each visit with multiplex viral respiratory PCR panel (qualitative detection of 16 viruses). Pulmonary function tests were recorded at each visit, in order to highlight a possible failure to improve them after treatment. Lack of improvement was defined by an increase in FEV1 less than 5% between Visit 2 and Visit 3. Results Eighteen children were analyzed in the study. 10 patients failed to improve by more than 5% their FEV1 between Visit 2 and Visit 3. Rhinovirus infection at Visit 2 or Visit 3 was the only risk factor significantly associated with such a failure ( OR, 12; 95% CI, 1·3-111·3), P = 0·03. Conclusions Rhinovirus infection seems to play a role in the FEV1 recovery after pulmonary exacerbation treatment in children with cystic fibrosis. Such an association needs to be confirmed by a large-scale study because this finding may have important implications for pulmonary exacerbation management. [ABSTRACT FROM AUTHOR]

Objectives:to understand epidemiological trends in severe COPD exacerbations through analyzes of hospitalizations and deaths during three consecutive years in a French administrative region area.Methods:Medico-administrative records of hospitalizations for COPD exacerbations were sorted from 2010 to 2012 using selected International Classification of Diseases (ICD10) codes. Four groups of hospitalization for COPD severe exacerbations were elicited leading to hospitalizations (general ward without respiratory failure, general ward with acute respiratory distress, ICU without mechanical ventilation, ICU with mechanical ventilation).Results:Data extraction identified 5007, 4986 and 5359 admissions related to 4136, 4155 and 4460 patients in 2010, 2011 and 2012, respectively. Marked seasonal variations were observed. Duration of stay (median (IQR), 7 (7) vs 9 (8) vs 10 (9) vs 14 (16) days,P< .001), death rates (3.6% vs 14.2% vs 14.4% vs 21.2%,P< .01), number of co-morbid conditions (median (IQR), 2 (2) vs 2 (2) vs 4 (5) vs 4 (4.5),P< .01), type of institution (64.9% in public institution vs 79.9% vs 87.8% vs 76.6%,P< .01) were significantly associated with the hospitalization group and more than 8% of admissions led to death (3% to 24%). Age, type of institution and past hospitalizations were independent risk factors for deaths. Readmissions were infrequent but mainly related to the worsening of the co-morbid conditions.Conclusion:COPD severe exacerbations are frequent and lead to an important numbers of deaths related to the severity of acute respiratory failure and the number of co-morbid conditions. [ABSTRACT FROM PUBLISHER]