NOX enzymes: potential target for the treatment of acute lung injury

Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS), is characterized by acute inflammation, disruption of the alveolar-capillary barrier, and in the organizing stage by alveolar pneumocytes hyperplasia and extensive lung fibrosis. The cellular and molecular mechanisms leading to the development of ALI/ARDS are not completely understood, but there is evidence that reactive oxygen species (ROS) generated by inflammatory cells as well as epithelial and endothelial cells are responsible for inflammatory response, lung damage, and abnormal repair. Among all ROS-producing enzymes, the members of NADPH oxidases (NOXs), which are widely expressed in different lung cell types, have been shown to participate in cellular processes involved in the maintenance of lung integrity. It is not surprising that change in NOXs' expression and function is involved in the development of ALI/ARDS. In this context, the use of NOX inhibitors could be a possible therapeutic perspective in the management of this syndrome. In this article, we summarize the current knowledge concerning some cellular aspects of NOXs localization and function in the lungs, consider their contribution in the development of ALI/ARDS and discuss the place of NOX inhibitors as potential therapeutical targe

Bird breeder's disease: a rare diagnosis in young children

Bird breeder's lung disease is the most common form of hypersensitivity pneumonitis and is a rare entity in young children. We report three cases of children under 7 years of age in whom this diagnosis was confirmed early in the course of the disease. Three children aged 4.4 to 6.5 years presented with dry cough lasting for more than 1 month, dyspnoea, variable loss of appetite, weight loss, fatigue, fever and mild signs of respiratory distress. Chest X-ray films and CT scans showed a bilateral micronodular infiltrate. All three patients had strongly suggestive bronchoalveolar lavage fluid findings with lymphocytosis; two had elevated cell counts and decreased CD4/CD8 ratios. Lung biopsy confirmed the diagnosis in all children. Contact with allergens was identified in all children: two had spent holidays close to a farm in the previous month and one was living next to a pigeon house. In all children, avian precipitins were positive. The symptoms rapidly resolved after allergen avoidance and treatment with oral prednisone. Corticoid treatment was given between 11 and 15 weeks. One child relapsed and required long-term low-dose corticotherapy for 1 year. Lung function tests were normal in all three patients, 3.9 to 5.7 years after diagnosis. Conclusion:Bird breeder's lung disease is a rare entity but should be considered in young children presenting long lasting cough. While rapid allergen exclusion and start of treatment can avoid the evolution into irreversible lung fibrosis, clinical and biological evolution should be monitored carefully even after stopping corticoid treatment because of the possibility of relaps

Chest physiotherapy using passive expiratory techniques does not reduce bronchiolitis severity: a randomised controlled trial

Chest physiotherapy (CP) using passive expiratory manoeuvres is widely used in Western Europe for the treatment of bronchiolitis, despite lacking evidence for its efficacy. We undertook an open randomised trial to evaluate the effectiveness of CP in infants hospitalised for bronchiolitis by comparing the time to clinical stability, the daily improvement of a severity score and the occurrence of complications between patients with and without CP. Children <1year admitted for bronchiolitis in a tertiary hospital during two consecutive respiratory syncytial virus seasons were randomised to group 1 with CP (prolonged slow expiratory technique, slow accelerated expiratory flow, rarely induced cough) or group 2 without CP. All children received standard care (rhinopharyngeal suctioning, minimal handling, oxygen for saturation ≥92%, fractionated meals). Ninety-nine eligible children (mean age, 3.9months), 50 in group 1 and 49 in group 2, with similar baseline variables and clinical severity at admission. Time to clinical stability, assessed as primary outcome, was similar for both groups (2.9 ± 2.1 vs. 3.2 ± 2.8days, P = 0.45). The rate of improvement of a clinical and respiratory score, defined as secondary outcome, only showed a slightly faster improvement of the respiratory score in the intervention group when including stethoacoustic properties (P = 0.044). Complications were rare but occurred more frequently, although not significantly (P = 0.21), in the control arm. In conclusion, this study shows the absence of effectiveness of CP using passive expiratory techniques in infants hospitalised for bronchiolitis. It seems justified to recommend against the routine use of CP in these patient

Erratum to: Chest physiotherapy using passive expiratory techniques does not reduce bronchiolitis severity: a randomised controlled trial

Chest physiotherapy (CP) using passive expiratory manoeuvres is widely used in Western Europe for the treatment of bronchiolitis, despite lacking evidence for its efficacy. We undertook an open randomised trial to evaluate the effectiveness of CP in infants hospitalised for bronchiolitis by comparing the time to clinical stability, the daily improvement of a severity score and the occurrence of complications between patients with and without CP. Children <1year admitted for bronchiolitis in a tertiary hospital during two consecutive respiratory syncytial virus seasons were randomised to group 1 with CP (prolonged slow expiratory technique, slow accelerated expiratory flow, rarely induced cough) or group 2 without CP. All children received standard care (rhinopharyngeal suctioning, minimal handling, oxygen for saturation ≥92%, fractionated meals). Ninety-nine eligible children (mean age, 3.9months), 50 in group 1 and 49 in group 2, with similar baseline variables and clinical severity at admission. Time to clinical stability, assessed as primary outcome, was similar for both groups (2.9 ± 2.1 vs. 3.2 ± 2.8days, P = 0.45). The rate of improvement of a clinical and respiratory score, defined as secondary outcome, only showed a slightly faster improvement of the respiratory score in the intervention group when including stethoacoustic properties (P = 0.044). Complications were rare but occurred more frequently, although not significantly (P = 0.21), in the control arm. In conclusion, this study shows the absence of effectiveness of CP using passive expiratory techniques in infants hospitalised for bronchiolitis. It seems justified to recommend against the routine use of CP in these patient

CD4+CD25−mTGFβ+ T cells induced by nasal application of ovalbumin transfer tolerance in a therapeutic model of asthma

Background: Intranasal administration of high amount of allergen was shown to induce tolerance and to reverse the allergic phenotype. However, mechanisms of tolerance induction via the mucosal route are still unclear. Objectives: To characterize the therapeutic effects of intranasal application of ovalbumin (OVA) in a mouse model of bronchial inflammation as well as the cellular and molecular mechanisms leading to protection upon re-exposure to allergen. Methods: After induction of bronchial inflammation, mice were treated intranasally with OVA and re-exposed to OVA aerosols 10 days later. Bronchoalveolar lavage fluid (BALF), T cell proliferation and cytokine secretion were examined. The respective role of CD4+CD25+ and CD4+CD25− T cells in the induction of tolerance was analysed. Results: Intranasal treatment with OVA drastically reduced inflammatory cell recruitment into BALF and bronchial hyperresponsiveness upon re-exposure to allergen. Both OVA- specific-proliferation of T cells, Th1 and Th2 cytokine production from lung and bronchial lymph nodes were inhibited. Transfer of CD4+CD25− T cells, which strongly expressed membrane-bound transforming growth factor β (mTGFβ), from tolerized mice protected asthmatic recipient mice from subsequent aerosol challenges. The presence of CD4+CD25+(Foxp3+) T cells during the process of tolerization was indispensable to CD4+CD25− T cells to acquire regulatory properties. Whereas the presence of IL-10 appeared dispensable in this model, the suppression of CD4+CD25−mTGFβ+ T cells in transfer experiments significantly impaired the down-regulation of airways inflammation. Conclusion: Nasal application of OVA in established asthma led to the induction of CD4+CD25−mTGFβ+ T cells with regulatory properties, able to confer protection upon allergen re-exposur

Airspace Diameter Map-A Quantitative Measurement of All Pulmonary Airspaces to Characterize Structural Lung Diseases.

(1) Background: Stereological estimations significantly contributed to our understanding of lung anatomy and physiology. Taking stereology fully 3-dimensional facilitates the estimation of novel parameters. (2) Methods: We developed a protocol for the analysis of all airspaces of an entire lung. It includes (i) high-resolution synchrotron radiation-based X-ray tomographic microscopy, (ii) image segmentation using the free machine-learning tool Ilastik and ImageJ, and (iii) calculation of the airspace diameter distribution using a diameter map function. To evaluate the new pipeline, lungs from adult mice with cystic fibrosis (CF)-like lung disease (βENaC-transgenic mice) or mice with elastase-induced emphysema were compared to healthy controls. (3) Results: We were able to show the distribution of airspace diameters throughout the entire lung, as well as separately for the conducting airways and the gas exchange area. In the pathobiological context, we observed an irregular widening of parenchymal airspaces in mice with CF-like lung disease and elastase-induced emphysema. Comparable results were obtained when analyzing lungs imaged with μCT, sugges-ting that our pipeline is applicable to different kinds of imaging modalities. (4) Conclusions: We conclude that the airspace diameter map is well suited for a detailed analysis of unevenly distri-buted structural alterations in chronic muco-obstructive lung diseases such as cystic fibrosis and COPD

Safely Discharging Infants with Bronchiolitis from an Emergency Department: A Five Step Guide for Pediatricians.

Recent publications have established the pulse oxygen saturation (SpO2) threshold of 90% for the hospitalization and discharge of infant patients with bronchiolitis. However, there is no clear recommendation regarding the Emergency Department (ED) observation period necessary before allowing safe home discharge for patients with SpO2 above 90%-92%. Our primary aims were to evaluate the risk factors associated with delayed desaturation in infants with SpO2 ≥ 92% on arrival at the ED as well as the ED observation period necessary before allowing safe home discharge. A secondary aim was to identify the risk factors for ED readmission. Of 581 episodes of bronchiolitis in patients 6KPa) were risk factors for delayed desaturation with OR varying from 1.7 to 7.5. In patients < 3 months old, mean desaturation occured later than in older patients [6.0 hours (IQR 3.0-14.0) vs. 3.0 hours (IQR 2.0-6.0), P = 0.0018]. In 95% of patients with a delayed desaturation this decrease occurred within 25 hours for patients < 3 months old and within 11 hours for patients ≥ 3 months old. In patients < 3 months old with respiratory rates above the normal range for their age the desaturation occurred earlier than in patients < 3 months with normal respiratory rates [4.4 hours (IQR 3.0-11.7) vs. 14.6 hours (IQR 7.6-22.2), P = 0.037]. Based on the present study's results, we propose a five step guide for pediatricians on discharging children with bronchiolitis from the ED. By using the threshold of an 11 hour ED observation period for patients ≥ 3 months old and a 25 hour period for patients < 3 months old we are able to detect 95% of the patients with bronchiolitis who are at risk of delayed desaturation

Correction: Safely Discharging Infants with Bronchiolitis from an Emergency Department: A Five Step Guide for Pediatricians.

[This corrects the article DOI: 10.1371/journal.pone.0163217.]