miR-199a-5p Is Upregulated during Fibrogenic Response to Tissue Injury and Mediates TGFbeta-Induced Lung Fibroblast Activation by Targeting Caveolin-1

As miRNAs are associated with normal cellular processes, deregulation of miRNAs is thought to play a causative role in many complex diseases. Nevertheless, the precise contribution of miRNAs in fibrotic lung diseases, especially the idiopathic form (IPF), remains poorly understood. Given the poor response rate of IPF patients to current therapy, new insights into the pathogenic mechanisms controlling lung fibroblasts activation, the key cell type driving the fibrogenic process, are essential to develop new therapeutic strategies for this devastating disease. To identify miRNAs with potential roles in lung fibrogenesis, we performed a genome-wide assessment of miRNA expression in lungs from two different mouse strains known for their distinct susceptibility to develop lung fibrosis after bleomycin exposure. This led to the identification of miR-199a-5p as the best miRNA candidate associated with bleomycin response. Importantly, miR-199a-5p pulmonary expression was also significantly increased in IPF patients (94 IPF versus 83 controls). In particular, levels of miR-199a-5p were selectively increased in myofibroblasts from injured mouse lungs and fibroblastic foci, a histologic feature associated with IPF. Therefore, miR-199a-5p profibrotic effects were further investigated in cultured lung fibroblasts: miR-199a-5p expression was induced upon TGFβ exposure, and ectopic expression of miR-199a-5p was sufficient to promote the pathogenic activation of pulmonary fibroblasts including proliferation, migration, invasion, and differentiation into myofibroblasts. In addition, we demonstrated that miR-199a-5p is a key effector of TGFβ signaling in lung fibroblasts by regulating CAV1, a critical mediator of pulmonary fibrosis. Remarkably, aberrant expression of miR-199a-5p was also found in unilateral ureteral obstruction mouse model of kidney fibrosis, as well as in both bile duct ligation and CCl4-induced mouse models of liver fibrosis, suggesting that dysregulation of miR-199a-5p represents a general mechanism contributing to the fibrotic process. MiR-199a-5p thus behaves as a major regulator of tissue fibrosis with therapeutic potency to treat fibroproliferative diseases. © 2013 Lino Cardenas et al

The Airway Microbiota in Cystic Fibrosis: A Complex Fungal and Bacterial Community—Implications for Therapeutic Management

International audienceBackground Given the polymicrobial nature of pulmonary infections in patients with cystic fibrosis (CF), it is essential to enhance our knowledge on the composition of the microbial community to improve patient management. In this study, we developed a pyrosequencing approach to extensively explore the diversity and dynamics of fungal and prokaryotic populations in CF lower airways. Methodology and Principal Findings Fungi and bacteria diversity in eight sputum samples collected from four adult CF patients was investigated using conventional microbiological culturing and high-throughput pyrosequencing approach targeting the ITS2 locus and the 16S rDNA gene. The unveiled microbial community structure was compared to the clinical profile of the CF patients. Pyrosequencing confirmed recently reported bacterial diversity and observed complex fungal communities, in which more than 60% of the species or genera were not detected by cultures. Strikingly, the diversity and species richness of fungal and bacterial communities was significantly lower in patients with decreased lung function and poor clinical status. Values of Chao1 richness estimator were statistically correlated with values of the Shwachman-Kulczycki score, body mass index, forced vital capacity, and forced expiratory volume in 1 s (p = 0.046, 0.047, 0.004, and 0.001, respectively for fungal Chao1 indices, and p = 0.010, 0.047, 0.002, and 0.0003, respectively for bacterial Chao1 values). Phylogenetic analysis showed high molecular diversities at the sub-species level for the main fungal and bacterial taxa identified in the present study. Anaerobes were isolated with Pseudomonas aeruginosa, which was more likely to be observed in association with Candida albicans than with Aspergillus fumigatus

Variabilitätsmodellierung in Software Produktlinien Drei Lösungsansätze im Fokus

INTRODUCTION: The aim of this study was to gain insight into the physiological changes occurring in subjects with cystic fibrosis (CF) after autogenic drainage (AD). Changes in respiratory system resistance (Rrs), reactance (Xrs), and spirometry were analyzed in adult CF subjects after a single AD physiotherapy session. METHODS: This prospective observational study was conducted during the annual check-up of adult CF subjects in stable condition. Spirometry and Rrs and Xrs measurements using the forced oscillations technique at 5, 11, and 19 hertz (Hz) were performed before and 30 min after a 20-min AD session. Control CF subjects were tested at baseline and 50 min without AD. Results are expressed as mean ± standard deviation or median [interquartile range]. RESULTS: Thirty subjects were included in the physiotherapy group (age 29 [25-34] years, forced expiratory volume in 1 s (FEV1) 40.3 [30.1-57.9]% predicted) and 11 in the control group (age 31 [28.5-36.5] years, FEV1 43.6 [31.1-51.9] % predicted). No significant changes in any parameter were observed in the control group. AD modestly but significantly increased the forced vital capacity (FVC) and FEV1 (p<0.001). Inspiratory resistance was also significantly improved by AD: Rrs5 from 5.74±2.39 to 5.24±2.17 cmH2O/L/s, p<0.05; Rrs11 from 4.83±1.98 to 4.32±1.7 cmH2O/L/s, p = 0.003; and Rrs19 from 4.18 [3.46-5.07] to 3.86 [2.76-4.98] cmH2O/L/s, p<0.001. In contrast, AD had no significant effects on frequency dependence of resistance (Rrs5-Rrs19) or expiratory resistance. Inspiratory Xrs5, but not ΔXrs5 (expiratory-inspiratory Xrs), was improved by AD (p<0.05). Moderate correlations were detected between the improvement in FEV1 and FVC and inspiratory resistance (r = 0.53, p = 0.005 and r = 0.44, p = 0.02, respectively). CONCLUSION: A single session of AD improved inspiratory airway resistance, except in the distal airways. The forced oscillations technique provides a new tool for understanding the pathophysiological effects of airway clearance physiotherapy in CF

Cardiorespiratory Response to Different Exercise Tests in Interstitial Lung Disease.

International audienceIntroduction: The 6-min stepper test (6MST) has been used as an alternative to the 6-min walk test (6MWT) to assess exercise tolerance in patients with interstitial lung disease (ILD). Recent data suggest that the tests may involve different energy pathways and cardiorespiratory responses. We thus aimed to compare the cardiorespiratory responses of ILD patients during the 6MWT and the 6MST.Methods: Thirty-one patients with ILD were randomized to perform both tests in the order 6MST → 6MWT (n = 16) or 6MWT → 6MST (n = 15). Gas exchange, HR, and pulse O2 saturation (SpO2) were measured continuously, and dyspnoea, leg discomfort, and blood lactate concentration were assessed before and immediately after each test.Results: Oxygen uptake (V˙O2) was lower (P = 0.002) and respiratory equivalent ratio for O2 (V˙E/V˙O2) and RER were higher (both P < 0.001) during the 6MST compared with the 6MWT. The 6MST was also associated with higher blood lactate concentrations (6MST, 4.16 ± 1.95 mmol·L; 6MWT, 2.84 ± 1.17 mmol·L; P = 0.01), higher leg discomfort scores (6MST 5 ± 3 points, 6MWT 3 ± 2 points; P < 0.001), and smaller decreases in SpO2 (6MST -5% ± 5%, 6MWT -9% ± 6%; P < 0.001).Conclusions: ILD patients exhibited greater ventilatory responses and lower arterial O2 desaturation during the 6MST compared with the 6MWT. The higher lactate concentrations and perceived muscle fatigue observed during the 6MST may indicate the presence of intertest differences in active muscle metabolism that could contribute to the distinct cardiorespiratory responses

The 1-minute sit-to-stand test to detect exercise-induced oxygen desaturation in patients with interstitial lung disease

International audienceBACKGROUND: Although the 6-min walk test (6MWT) is the gold standard for assessing exercise-induced impairment of gas exchange, it cannot easily be performed in a clinical office environment. The aim of this study was to compare the 1-min sit-to-stand test (1STST) with the 6MWT for the ability to assess exercise-induced oxygen desaturation in patients with interstitial lung diseases (ILDs).METHODS: A total of 107 patients were enrolled and classified into three groups: sarcoidosis, fibrotic idiopathic interstitial pneumonia (f-IIP), and other forms of ILD. The 6MWT and 1STST were performed on the same day, and pulmonary function tests, pulse oxygen saturation (SpO2), and dyspnea and fatigue (modified Borg scale) were assessed. SpO2 desaturation was evaluated by intraclass correlation coefficient (ICC), Bland-Altman analysis, and kappa (κ) coefficient in the whole population and the patient subgroups.RESULTS: The SpO2 nadir during the 1STST and 6MWT showed good consistency [mean ± standard deviation: 92.5% ± 5% and 90% ± 7%, respectively; ICC 0.77, 95% confidence interval (CI) 0.71-0.83] and correlated strongly ( r = 0.9, p < 0.0001). The frequency of patients with oxygen desaturation ⩾4% was also consistent for the two exercise tests ( κ = 0.68, 95% CI 0.54-0.82). The number of repetitions in the 1STST correlated with the 6MWT distance ( r = 0.5, p < 0.0001), but the dyspnea scores were higher during the 1STST than the 6MWT ( p < 0.0001). These findings did not differ for the three patient subgroups.CONCLUSION: The 1STST can measure exercise-induced desaturation in ILD patients and could be used as an alternative test to the 6MWT in office practice

Cardiorespiratory adaptation during 6-Minute Walk Test in fibrotic idiopathic interstitial pneumonia patients who did or did not respond to pulmonary rehabilitation

International audienceBackground: Pulmonary rehabilitation (PR) improves performance in the 6-min walk test (6MWT) in a subset of patients with fibrotic idiopathic interstitial pneumonia (f-IIP); however, a large proportion of patients does not respond to PR.Aim: To investigate the effects of a PR program on cardiorespiratory responses during a 6MWT and to identify the characteristics of patients who do not show improved performance after PR.Design: An observational study.Setting: Patients were recruited from the Competence Centre for Rare Pulmonary Diseases at Lille University Hospital, France and completed an 8-week home-based PR program.Population: A total of 19 patients with f-IIP; 12 with idiopathic pulmonary fibrosis (IPF) and 7 with fibrotic non-specific interstitial pneumonia.Methods: Patients underwent spirometry and completed a 6MWT before and after an 8-week PR program. Gas exchange, heart rate, and pulse O2 saturation were measured continuously during the 6MWT. Quality of life, dyspnea, and anxiety/depression were assessed using the Short-Form 36 (SF-36), the baseline/transition dyspnea index (BDI/TDI), and the Hospital Anxiety and Depression Scale (HADS) questionnaires.Results: Patients who did and did not improve the distance walked in the 6MWT by at least 30 m after PR were classified as responders (N.=9) and non-responders (N.=10), respectively. O2 uptake, ventilation rate, and distance covered during the 6MWT were significantly improved only in the responder group (P<0.05). Changes in SF-36, BDI/TDI, and HADS scores did not differ significantly between responders and non-responders. The non-responder group contained significantly more patients with IPF (P<0.05) and experienced greater arterial oxygen desaturation during the 6MWT compared with the responder group.Conclusions: Failure to improve performance in the 6MWT after PR was associated with a diagnosis of IPF, non-improvement in gas exchange, and greater arterial oxygen desaturation.Clinical rehabilitation impact: Most f-IIP patients who did not respond to PR were diagnosed with IPF and displayed greater hypoxemia during exercise. Clinical practitioners should seek to determine why patients fail to improve exercise performance after PR and propose an alternative exercise regimen to these patients

Real-life feasibility and effectiveness of home-based pulmonary rehabilitation in chronic obstructive pulmonary disease requiring medical equipment

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