Nitric oxide in health and disease of the respiratory system

During the past decade a plethora of studies have unravelled the multiple roles of nitric oxide (NO) in airway physiology and pathophysiology. In the respiratory tract, NO is produced by a wide variety of cell types and is generated via oxidation of l-arginine that is catalyzed by the enzyme NO synthase (NOS). NOS exists in three distinct isoforms: neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS). NO derived from the constitutive isoforms of NOS (nNOS and eNOS) and other NO-adduct molecules (nitrosothiols) have been shown to be modulators of bronchomotor tone. On the other hand, NO derived from iNOS seems to be a proinflammatory mediator with immunomodulatory effects. The concentration of this molecule in exhaled air is abnormal in activated states of different inflammatory airway diseases, and its monitoring is potentially a major advance in the management of, e.g., asthma. Finally, the production of NO under oxidative stress conditions secondarily generates strong oxidizing agents (reactive nitrogen species) that may modulate the development of chronic inflammatory airway diseases and/or amplify the inflammatory response. The fundamental mechanisms driving the altered NO bioactivity under pathological conditions still need to be fully clarified, because their regulation provides a novel target in the prevention and treatment of chronic inflammatory diseases of the airway

Therapeutic novelties of inhaled corticosteroids and bronchodilators in asthma

Orally inhaled agents are a key therapeutic class for treatment of asthma. Inhaled corticosteroids (ICS) are the most effective anti-inflammatory treatment for asthma thus representing the first-line therapy and bronchodilators complement the effects of ICSs. A significant body of evidence indicates that addition of a \u3b22-agonist to ICS therapy is more effective than increasing the dose of ICS monotherapy. In this paper, pharmacological features of available ICSs and bronchodilators will be reviewed with a focus on fluticasone propionate/formoterol fumarate combination which represents the one of the most powerful ICS acting together with the most rapid active LABA

Long-Term Adjustment of Stable Asthma Treatment with Fractional Exhaled Nitric Oxide and Sputum Eosinophils

Current approaches to control asthma do not involve direct assessment of airway inflammation. The aim of this study is to assess whether the therapeutic adjustments of steroid treatment according to a stepwise algorithm based on sputum Eosinophils (sEos) and fractioned exhaled Nitric Oxide (FeNO) were effective in maintaining the stability of a group of stable asthmatic patients during a twelvemonth follow-up. Fourteen asthmatic patients, treated for asthma according to a previously published protocol, were enrolled in the study. The patients underwent clinical evaluation, pulmonary function tests, measuring of airway hyperresponsiveness to methacholine, and determination of FeNO and sEos at visit 1. These procedures were repeated after 6 and 12 months (Visits 2 and 3, respectively). Symptoms score gradually improved during the study (p=0.008), no changes were observed in the frequency of clinical asthma exacerbations or in airway hyperresponsiveness to methacholine. At the end of the study both sEos and FeNO were significantly improved (p=0.011 and p=0.003, respectively) and at visit 3 the median steroid dose was reduced (p=0.039) in accordance with the improving of symptoms score, FeNO and sEos values. A direct relationship was observed between the difference of FeNO values and the difference of sEos registered between visits 1 and 2 (r 2 =609, p0.001) and between visits 2 and 3 (r 2 =646, p<0.001). In conclusion, long-term titration of asthma inhaled steroid treatment based on sEos and FeNO values was able to provide long-term clinical stability and improvement to the asthmatic patients studied, without significant increases in the steroid dose

MiR-142-3p is associated with aberrant WNT signaling during airway remodeling in asthma.

Asthma is characterized by &mdash;Asthma a chronic inflammation and remodeling of the airways. Although inflammation can be controlled, therapeutic options to revert remodeling do not exist. Thus, there is a large and unmet need to understand the underlying molecular mechanisms to develop novel therapies. We previously identified a pivotal role for miR-142-3p in regulating airway smooth muscle (ASM) precursor cell proliferation during lung development by fine-tuning the Wingless/Integrase I (WNT) signaling. Thus, we here aimed to investigate the relevance of this interaction in asthma. We performed quantitative RT-PCR and immune staining in a murine model for ovalbumin-induced allergic airway inflammation and in bronchial biopsies from patients with asthma and isolated primary fibroblasts thereof. miR-142-3p was increased in hyperproliferative regions of lung in murine and human asthma, whereas this microRNA (miRNA) was excluded from regions with differentiated ASM cells. Increases in miR-142-3p were associated with a decrease of its known target Adenomatous polyposis coli. Furthermore, we observed a differential expression of miR-142-3p in bronchial biopsies from patients with early or late onset severe asthma, which coincided with a differential WNT signature. Our data suggest that miR-142-3p is involved in regulating the balance between proliferation and differentiation of ASM cells in asthma, possibly via controlling WNT signaling. Thus, this miRNA might be an interesting target to prevent ASM hyperproliferation in asthma

Extracorporeal Shock Waves Increase Markers of Cellular Proliferation in Bronchial Epithelium and in Primary Bronchial Fibroblasts of COPD Patients

Chronic obstructive pulmonary disease (COPD) is due to structural changes and narrowing of small airways and parenchymal destruction (loss of the alveolar attachment as a result of pulmonary emphysema), which all lead to airflow limitation. Extracorporeal shock waves (ESW) increase cell proliferation and differentiation of connective tissue fibroblasts. To date no studies are available on ESW treatment of human bronchial fibroblasts and epithelial cells from COPD and control subjects. We obtained primary bronchial fibroblasts from bronchial biopsies of 3 patients with mild/moderate COPD and 3 control smokers with normal lung function. 16HBE cells were also studied. Cells were treated with a piezoelectric shock wave generator at low energy (0.3 mJ/mm2, 500 pulses). After treatment, viability was evaluated and cells were recultured and followed up for 4, 24, 48, and 72 h. Cell growth (WST-1 test) was assessed, and proliferation markers were analyzed by qRT-PCR in cell lysates and by ELISA tests in cell supernatants and cell lysates. After ESW treatment, we observed a significant increase of cell proliferation in all cell types. C-Kit (CD117) mRNA was significantly increased in 16HBE cells at 4 h. Protein levels were significantly increased for c-Kit (CD117) at 4 h in 16HBE (p &lt; 0.0001) and at 24 h in COPD-fibroblasts (p = 0.037); for PCNA at 4 h in 16HBE (p = 0.046); for Thy1 (CD90) at 24 and 72 h in CS-fibroblasts (p = 0.031 and p = 0.041); for TGF\u3b21 at 72 h in CS-fibroblasts (p = 0.038); for procollagen-1 at 4 h in COPD-fibroblasts (p = 0.020); and for NF-B-p65 at 4 and 24 h in 16HBE (p = 0.015 and p = 0.0002). In the peripheral lung tissue of a representative COPD patient, alveolar type II epithelial cells (TTF-1+) coexpressing c-Kit (CD117) and PCNA were occasionally observed. These data show an increase of cell proliferation induced by a low dosage of extracorporeal shock waves in 16HBE cells and primary bronchial fibroblasts of COPD and control smoking subjects

EXHALED NITRIC OXIDE IS RELATED TO BRONCHIAL EOSINOPHILIA AND AIRWAY HYPERRESPONSIVENESS TO BRADYKININ IN ALLERGEN-INDUCED ASTHMA EXACERBATION

Pathogenesis and treatment of chronic pulmonary disease

Bradykinin-induced asthmatic fibroblast/myofibroblast activities via bradykinin B-2 receptor and different MAPK pathways

Pathogenesis and treatment of chronic pulmonary disease

A european respiratory society technical standard: Exhaled biomarkers in lung disease

Breath tests cover the fraction of nitric oxide in expired gas (FENO), volatile organic compounds (VOCs), variables in exhaled breath condensate (EBC) and other measurements. For EBC and for FENO, official recommendations for standardised procedures are more than 10 years old and there is none for exhaled VOCs and particles. The aim of this document is to provide technical standards and recommendations for sample collection and analytic approaches and to highlight future research priorities in the field. For EBC and FENO, new developments and advances in technology have been evaluated in the current document. This report is not intended to provide clinical guidance on disease diagnosis and management. Clinicians and researchers with expertise in exhaled biomarkers were invited to participate. Published studies regarding methodology of breath tests were selected, discussed and evaluated in a consensus-based manner by the Task Force members. Recommendations for standardisation of sampling, analysing and reporting of data and suggestions for research to cover gaps in the evidence have been created and summarised. Application of breath biomarker measurement in a standardised manner will provide comparable results, thereby facilitating the potential use of these biomarkers in clinical practice. Copyright ©ERS 201