A c c e p t e d m a n u s c r i p t AbstractThe aim of this pilot study was to explore the relative efficacy in terms of improvement in symptoms and lung function of combining fluticasone propionate/salmeterol combination (FSC) and tiotropium in patients with severe-to-very severe stable COPD. Ninety patients were randomized to receive 3 months of treatment in one of three treatment groups: (1) FSC 500/50 µg Diskus, 1 inhalation twice daily + placebo Handihaler 1 inhalation once-daily daily; (2) tiotropium 18 µg Handihaler, 1 inhalation once daily + placebo Diskus, 1 inhalation twice daily; (3) FSC 500/50 µg Diskus, 1 inhalation twice daily + tiotropium 18 µg Handihaler, 1 inhalation once-daily daily. Patients attended the clinic before and after 1 month, 2 months, and 3 months of treatment for evaluations of pulmonary function, and dyspnea, which was assessed using a visual analog scale (VAS). Also the supplemental salbutamol use was measured. Eighty-one patients completed the 3-month treatment period: 26 patients receiving FSC, 26 patients receiving tiotropium, and 29 patients receiving FSC + tiotropium. Patients were withdrawn for COPD exacerbation. Improvements in trough FEV 1 with all treatments medications were observed by the first month when trough FEV 1 had improved significantly above baseline by 74 mL (p < 0.05) in the tiotropium group, by 117 mL (p < 0.05) in the FSC group and by 115 mL (p < 0.05) in FSC + tiotropium group. At the end of the study, trough FEV1 had improved significantly above baseline by141 mL (p < 0.05) in the tiotropium group, by 140 mL (p < 0.05) in the FSC group and by 186 mL (p < 0.05) in FSC + tiotropium group. The difference between FSC and tiotropium appeared to decrease, that between FSC and FSC + tiotropium appeared to increase and that between tiotropium and FSC + tiotropium remained almost similar with study duration. Our results suggest that adding FSC and tiotropium may provide benefits in symptomatic patients with severe-to-very severe stable COPD.

Coughing is an important defensive reflex that occurs through the stimulation of a complex reflex arc. It accounts for a significant number of consultations both at the level of general practitioner and of respiratory specialists. In this review we first analyze the cough reflex under normal conditions; then we analyze the anatomy and the neuro-pathophysiology of the cough reflex arc. The aim of this review is to provide the anatomic and pathophysiologic elements of evaluation of the complex and multiple etiologies of cough.

Toll-like receptors (TLRs) and nucleotide-binding oligomerisation domain (NOD)-like receptors (NLRs) are two major forms of innate immune sensors but their role in the immunopathology of stable chronic obstructive pulmonary disease (COPD) is incompletely studied. Our objective here was to investigate TLR and NLR signalling pathways in the bronchial mucosa in stable COPD.Using immunohistochemistry, the expression levels of TLR2, TLR4, TLR9, NOD1, NOD2, CD14, myeloid differentiation primary response gene 88 (MyD88), Toll-interleukin-1 receptor domain-containing adaptor protein (TIRAP), and the interleukin-1 receptor-associated kinases phospho-IRAK1 and IRAK4 were measured in the bronchial mucosa of subjects with stable COPD of different severity (n=34), control smokers (n=12) and nonsmokers (n=12). The bronchial bacterial load of ,, and was measured by quantitative real-time PCR.TLR4 and NOD1 expression was increased in the bronchial mucosa of patients with severe/very severe stable COPD compared with control subjects. TLR4 bronchial epithelial expression correlated positively with CD4 and CD8 cells and airflow obstruction. NOD1 expression correlated with CD8 cells. The bronchial load of was directly correlated, but inversely correlated, with the degree of airflow obstruction. Bacterial load did not correlate with inflammatory cells.Bronchial epithelial overexpression of TLR4 and NOD1 in severe/very severe stable COPD, associated with increased bronchial inflammation and bacterial load, may play a role in the pathogenesis of COPD.

Coughing is an important defensive reflex that occurs through the stimulation of a complex reflex arc. It accounts for a significant number of consultations both at the level of general practitioner and of respiratory specialists. In this review we first analyze the cough reflex under normal conditions; then we analyze the anatomy and the neuro-pathophysiology of the cough reflex arc. The aim of this review is to provide the anatomic and pathophysiologic elements of evaluation of the complex and multiple etiologies of cough.

The aim of the present study was to evaluate the pulmonary sequelae and diaphragmatic motility in infant, adolescent and adult patients (pts) who had undergone the repair of a congenital diaphragmatic hernia. Thirty-one (81.5%) out of 38 survivors after left side CDH repair, without using a patch, were followed-up. They were subdivided in two groups. Group A (mid-term follow-up): 12 pts (39%) (5 males, 7 females) with a mean age of 4.5 years; Group B (long-term follow-up): 19 pts (61%) (9 males, 10 females) with a mean age of 21.0 years. All pts underwent physical examination, chest X-ray, diaphragmatic ultrasonographic (US) examination, pulmonary perfusion scintigraphy. Patients of the group B were also submitted to spirometry. All pts had a normal life-style and no one complained of respiratory symptoms. The chest X-ray revealed pathologic findings in 12 pts (39%). 8 pts (26%) showed chest wall alterations. The profile of the left diaphragmatic dome appeared irregular in 9 pts (29%). In all pts M-mode sonography disclosed a reduced diaphragmatic motility on the treated side. The mean pulmonary perfusion scintigraphy value on the affected side was 39.2+/-0.7%. The spirometric study showed normal values. We noted that the lung perfusion significantly and rapidly improved after CDH repair even the apparently hypoplastic and small lungs, the diaphragm maintained a good contractility during forced respiration.

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In chronic obstructive pulmonary disease (COPD), oxidative stress regulates the inflammatory response of bronchial epithelium and monocytes/macrophages through kinase modulation and has been linked to glucocorticoid unresponsiveness. Glycogen synthase-3β (GSK3β) inactivation plays a key role in mediating signaling processes upon reactive oxygen species (ROS) exposure. We hypothesized that GSK3β is involved in oxidative stress-induced glucocorticoid insensitivity in COPD. We studied levels of phospho-GSK3β-Ser9, a marker of GSK3β inactivation, in lung sections and cultured monocytes and bronchial epithelial cells of COPD patients, control smokers, and nonsmokers. We observed increased levels of phospho-GSK3β-Ser9 in monocytes, alveolar macrophages, and bronchial epithelial cells from COPD patients and control smokers compared with nonsmokers. Pharmacological inactivation of GSK3β did not affect CXCL8 or granulocyte-macrophage colony-stimulating factor (GM-CSF) expression but resulted in glucocorticoid insensitivity in vitro in both inflammatory and structural cells. Further mechanistic studies in monocyte and bronchial epithelial cell lines showed that GSK3β inactivation is a common effector of oxidative stress-induced activation of the MEK/ERK-1/2 and phosphatidylinositol 3-kinase/Akt signaling pathways leading to glucocorticoid unresponsiveness. In primary monocytes, the mechanism involved modulation of histone deacetylase 2 (HDAC2) activity in response to GSK3β inactivation. In conclusion, we demonstrate for the first time that ROS-induced glucocorticoid unresponsiveness in COPD is mediated through GSK3β, acting as a ROS-sensitive hub.

SummaryBackgroundBronchial artery aneurysm (BAA) is a rare condition with a reported prevalence of less than 1% of all selective bronchial arterial angiograms. Despite its low incidence, BAA represents a potential cause of hemoptysis.Case ReportWe describe the case of a 63-year-old man suffering from chronic obstructive pulmonary disease (COPD), who presented with non-massive hemoptysis.CT angiography revealed a single bronchial artery aneurysm of 9 mm in diameter, abutting the esophageal wall.Other CT findings included hypertrophy of the bronchial arteries along the mediastinal course, diffuse thickening of the walls of numerous bronchial branches and a “ground glass” opacity in the anterior segment of the right upper pulmonary lobe suggestive of alveolar hemorrhage.The final diagnosis was established based on selective angiography, which was followed by transcatheter arterial embolization (TAE) of the BAA and of the pathological bronchial circulation.Follow-up CT scans revealed a total exclusion of the aneurysm from the systemic circulation, resolution of the parenchymal “ground glass” opacity and absence of further episodes of hemoptysis over a period of two years.ConclusionsAn incidental finding of a bronchial artery aneurysm necessitates prompt treatment.CT angiography and TAE represent the methods of choice for an appropriate diagnosis and treatment, respectively.In case of a BAA associated with chronic inflammatory diseases, such as COPD, in patients with hemoptysis, TAE of the BAA and of the pathological bronchial circulation, in association with the treatment of the underlying disease, represents a valid approach that can improve the pulmonary status and prevent further episodes of hemoptysis.