Introduction: COPD and lung cancer are leading causes of morbidity and mortality worldwide, and they share a common environmental risk factor in cigarette smoke exposure and a genetic predisposition represented by their incidence in only a fraction of smokers. This reflects the ability of cigarette smoke to induce an inflammatory response in the airways of susceptible smokers. Moreover, COPD could be a driving factor in lung cancer, by increasing oxidative stress and the resulting DNA damage and repression of the DNA repair mechanisms, chronic exposure to pro-inflammatory cytokines, repression of innate immunity and increased cellular proliferation.Areas covered: We have focused our review on the potential pathogenic molecular links between tobacco smoking-related COPD and lung cancer and the potential molecular targets for new drug development by understanding the common signaling pathways involved in COPD and lung cancer.Expert commentary: Research in this field is mostly limited to animal models or small clinical trials. Large clinical trials are needed but mostly combined models of COPD and lung cancer are necessary to investigate the processes caused by chronic inflammation, including genetic and epigenetic alteration, and the expression of inflammatory mediators that link COPD and lung cancer, to identify new molecular therapeutic targets.

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 Pseudomonas aeruginosa, Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pneumoniae 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 P. aeruginosa was directly correlated, but H. influenzae 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 P. aeruginosa bacterial load, may play a role in the pathogenesis of COPD.

BACKGROUND:Bronchial 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 REPORT:We 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.CONCLUSIONS:An 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.

Nella pratica clinica non esiste piu alcuna giustificazione per un nichilismo terapeutico in quanto oggi il trattamento personalizzato farmacologico e non farmacologico dei pazienti con broncopneumopatia cronica ostruttiva (BPCO) in fase stabile, in accordo con le attuali linee guida dell’Organizzazione Mondiale della Sanita (OMS) del Progetto Mondiale BPCO, e sicuramente in grado di diminuire i sintomi respiratori, migliorare la capacita e la tolleranza allo sforzo e la qualita di vita del paziente, di prevenire in parte le riacutizzazioni, anche gravi, della malattia e di diminuirne la mortalita. Tuttavia, gli unici due provvedimenti terapeutici dimostratisi finora sicuramente efficaci nel diminuire la mortalita nei pazienti con BPCO in fase stabile sono: 1) la completa sospensione del fumo di tabacco, e 2) l’ossigenoterapia domiciliare a lungo termine limitatamente ai pazienti con BPCO e grave insufficienza respiratoria cronica refrattaria ad un trattamento ottimale con farmaci broncodilatatori ed antinfiammatori. Al contrario il trattamento farmacologico personalizzato della BPCO in fase stabile attualmente disponibile rimane in gran parte puramente sintomatico e modifica solo in parte la storia naturale della malattia. Sono quindi indispensabili ulteriori studi di medicina traslazionale umana per chiarire la patogenesi della malattia ed ulteriori studi clinici controllati a lungo termine con nuove terapie farmacologiche usando come misure primarie di efficacia clinica il decorso clinico e la mortalita della BPCO. Per accelerare la ricerca in questo settore, sono necessari investimenti significativi, sia a livello pubblico che privato, con lo scopo ambizioso di rendere nell’imminente futuro, la BPCO, una malattia pienamente prevenibile e trattabile.

Citation for published version (APA): Ngkelo, A., Hoffmann, R. F., Durham, A. L., Marwick, J. A., Brandenburg, S. M., de Bruin, H. G., Jonker, M. R., Rossios, C., Tsitsiou, E., Caramori, G., Contoli, M., Casolari, P., Monaco, F., Ando, F., Speciale, G., Kilty, I., Chung, K. F., Papi, A., Lindsay, M. A., ... Heijink, I. H. (2015). Glycogen synthase kinase-3 beta modulation of glucocorticoid responsiveness in COPD. American Journal of Physiology Lung Cellular and Molecular Physiology, 309(10), L1112-L1123. https://doi.org/10.1152/ajplung.00077.2015

X Anta Ngkelo,* Roland F. Hoffmann,* Andrew L. Durham, John A. Marwick, Simone M. Brandenburg, Harold G. de Bruin, Marnix R. Jonker, Christos Rossios, Eleni Tsitsiou, Gaetano Caramori, Marco Contoli, Paolo Casolari, Francesco Monaco, Filippo Andò, Giuseppe Speciale, Iain Kilty, Kian F. Chung, Alberto Papi, Mark A. Lindsay, Nick H. T. ten Hacken, Maarten van den Berge, Wim Timens, Peter J. Barnes, Antoon J. van Oosterhout, X Ian M. Adcock,* Paul A. Kirkham,* and Irene H. Heijink* Airways Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom; University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, The Netherlands; Medical Research Council Centre for Inflammation Research, Queen’s Medical Research Institute, University of Edinburgh Medical School, Edinburgh, United Kingdom; Respiratory Research Group, Faculty of Medical and Human Sciences, University of Manchester, and National Institute for Health Research Translational Research Facility in Respiratory Medicine, University Hospital of South Manchester, Manchester, United Kingdom; Dipartimento di Scienze Mediche, Sezione di Medicina Interna e Cardiorespiratoria, Centro per lo Studio delle Malattie Infiammatorie Croniche delle Vie Aeree e Patologie Fumo Correlate dell’Apparato Respiratorio (formerly termed Centro di Ricerca su Asma e BPCO), Università di Ferrara, Ferrara, Italy; Thoracic Surgery Unit, Cardiovascular and Thoracic Department, University of Messina, Messina, Italy; Pneumology Unit, Cardiovascular and Thoracic Department, University of Messina, Italy; Department of Human Pathology “Gaetano Barresi,” University of Messina, Messina, Italy; Pfizer, Inflammation and Remodeling Research Unit, Cambridge, Massachusetts; Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, United Kingdom; University of Groningen, University Medical Center Groningen, Department of Pulmonology, Groningen, The Netherlands; andUniversity of Groningen, University Medical Center Groningen, Groningen, Groningen Research Institute for Asthma Research Institute, Groningen, The Netherlands

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.

BACKGROUND:Chronic Obstructive Pulmonary Disease (COPD) ranks third as cause of mortality and disability-adjusted life years (DALY) worldwide and also in Italy it imposes a huge health, social and economic load. Early symptoms of COPD are often disregarded by patients and physicians, spirometry is underutilized, and the diagnosis is delayed till the disease has reached a distinct severity level. Despite the availability of various guidelines, the behavior of health workers involved in the management of COPD is still rather unlike. These considerations are the reason why in October 2013 AIMAR (Interdisciplinary Scientific Association for Research in Lung Disease) devised and organized a "Third Consensus Conference", aimed at pointing out the standards of suitability for COPD management. In this context three important topics of discussion were identified: early and more widespread diagnosis, management of acute and subacute phases, long-term assistance to chronic patients.METHODS:The procedure recommended by the Italian Health Superior Institute (ISS) for Consensus Conferences organization was applied. The Conference was structured in three sessions, each dealing with one of the above mentioned topics and including a short update of the subject-matter and presentation, discussion and voting of some statements with a choice ranging from total agreement to total disagreement or no knowledge. The results of voting were eventually recorded in the document, reviewed by an independent jury, that forms the substance of this paper.RESULTS:The essential role of spirometry, the need for distinguish between different COPD phenotypes, and the obligatoriness to base on the blood gas analysis findings the long-term oxygen therapy, were largely agreed, as well as the need for interventions aimed at decreasing the rate of acute exacerbations. More specific topics like the use of noninvasive ventilation, recognizing the factors affecting outcome and mortality, the choice of pharmacological and non pharmacological treatments in COPD patients led to lively discussing, but they did not always reach the total agreement, probably because of insufficient familiarity with these problems and of diversities in organization and instruments availability. The chronic respiratory assistance was treated with particular regard to smoking cessation, whose implementation is still insufficient. Many doubts rose due to uncertainty, lack of ability and standardization of procedures, insufficient institutional support, and difficulties to realize a network for assistance to chronic patients.CONCLUSIONS:The results of this Third Consensus Conference revealed some certainties and many doubts and diversities of view also on topics whose importance is well demonstrated in scientific literature. Thus, there is still a long distance to cover before reaching a suitable standardization of COPD management and such situation urges the need for improving not only the health professional's operativeness but also the organizational support by competent institutions. In this context some initiatives organized by AIMAR in cooperation with other respiratory scientific societies and patients' associations are going on.

BACKGROUND:While the effects of postural change on arterial oxygenation have been well documented in normal subjects, and attributed to the relationship of closing volume (CV) to the tidal volume, in liver cirrhosis such postural changes have been evaluated mainly in a rare, peculiar clinical end-stage condition which is characterized by increased dyspnea shifting from supine to upright position ("platypnea"). The latter is associated with worsening of PaO2 ("orthodeoxia"). We evaluated the effects of postural changes on arterial oxygenation in patients affected by mild/moderate liver cirrhosis. METHODS:We performed pulmonary function tests and arterial blood gas evaluation in sitting and supine positions in 22 patients with mild/moderate liver cirrhosis, biopsy-proved, and 22 matched non-smokers control subjects. RESULTS:Recumbency elicited a decrease of PaO2 (Δ(sup-sit)PaO2) in 19 out of 22 controls and in all but one cirrhotics. The magnitude of this postural change was significantly (p = 0.04) greater in cirrhotics (9.6 ± 5.3%) compared to controls (6.7 ± 3.7%). In the subset of cirrhotics younger than 60 yrs and with PaO2 greater than 80 mmHg in sitting position, the Δ(sup-sit)PaO2 in recumbency further increased to 12 ± 5.8%, significantly (p = 0.014) greater than in same subgroup of controls (7.1 ± 3.8%). CONCLUSIONS:In mild/moderate liver cirrhosis the postural variations in PaO2 follow the normal trends, but are of greater magnitude probably as a consequence of hypoventilated units of lung for postural and disease-linked tidal airway closure, resulting in more pronounced recumbent hypoxemia ("clinodeoxia").

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.

It has been documented that tiotropium is less likely to induce oxygen desaturation in stable COPD patients compared to long-acting β2-agonists (LABAs) and combined administration of a LABA and an inhaled corticosteroid (ICS) reduces the potential for acute effects of LABA on blood-gas tensions. In this study, we have compared the acute effects of tiotropium 18μg and salmeterol/fluticasone combination (SFC) 50/250μg on arterial blood gases in 20 patients with stable COPD. Each subject was studied on 2 days, separated from one another by at least 4 days. Blood specimens were taken just before the inhalation and at 15, 30, 60, 180 and 360min after inhalation of each treatment, and spirometry was performed at the same time points. As expected, both treatments significantly improved FEV1 (greatest changes were 0.20L, 95% CI: 0.13–0.27 at 360min after tiotropium; and 0.13L, 95% CI: 0.06–0.19 at 180min after SFC). The greatest mean changes from baseline in PaO2 were −1.7 (95% CI: −4.0 to 0.6)mmHg, p=0.134, after tiotropium; −0.8 (95% CI: −2.2 to 0.6)mmHg, after SFC. Both changes were observed after 15min. Both drugs caused a small decrease in PaCO2 (greater changes: −1.9 (95% CI −3.2 to −0.6)mmHg, p=0.005 at 60min after tiotropium; and −2.4 (95% CI: −3.5 to −1.3) mmHg, p=0.0002 at 180min after SFC). These results indicate that both tiotropium and SFC are able to induce a significant long-last bronchodilation without affecting arterial blood gases. Moreover, they confirm that the impact of tiotropium on PaO2 is small and without clinical significance and the addition of a LABA to an ICS can reduce the potentially dangerous acute effect of the LABA on blood gases.

Sexual activity is an important component of quality of life in patients suffering from chronic illnesses. To our knowledge, the effects of sexual activity on gas exchange in patients with respiratory failure have not been yet studied. To such an extent, we evaluated the oxygen saturation (SaO2), by a pulse oxymeter, during three different sexual performances in a 63-yr-old patient affected by chronic obstructive pulmonary disease (COPD) on long-term oxygen therapy (LTOT). The sexual performances were divided in four periods: basal, sex, 10 min after sex and relax. In each performance during sex, we observed a significant increase of either heart rate (HR) or SaO2, with the highest value of the latter achieved within the 10 min of the post-sex period. SaO2 returned to basal value (pre-sex) by the end of the relax period. We conclude that the observed improvement of SaO2 during sexual activity might be due to a better ventilation/perfusion ratio (V/Q) obtained for either an increase of ventilation (hyperventilation) and perfusion (tachycardia), without significant muscle expenditure.

Based on work by Miller and Hyatt, several parameters derived from the flow-volume loop are considered useful in the diagnosis of upper airway obstruction (UAO). However, since the normal values available have been derived from small. groups of individuals, the values obtained by different authors are often very dissimilar. For these reasons, we studied 72 normal males (aged 20-82 years) and 55 normal females (aged 15-79 years) in order to obtain more precise normal values, and tested 17 patients with known extrathoracic UAO against our normal values and the values in the literature. We found that FIF50 is sex and age dependent, necessitating different predicted formulae for males and females, and its value in our population was much higher than the 100 L/min previously considered as normal for both sexes. Normal 95% confidence limits for the other tests were as follows: 1.3 (mean value: 0.819 +/- 0.288 SD) for FEF50/FIF50 (< 1 previously); 9.5 (mean value: 6.918 +/- 1.59 SD) for FEV1.0/PEF (< 10 previously); 1.8 (mean value: 1.404 +/- 0.287 SD) for FEV1.0/FEV0.5 (< 1.5 previously). FIF50 was abnormal in 82.3% of 17 patients with UAO and was always abnormal when the other tests were abnormal. We conclude that the values reported here, different from those of previous standards, should be a more accurate reflection of normality. UAO can be best suspected when FIF50 is abnormal with other tests adding little to the suspicion of UAO.

The postural changes that occur in respiratory function have been well studied in normal subjects, but in pathological conditions they have been described in only a few cases of chronic liver disease: going from supine position to an erect one produced dyspnea ("platypnea") and a worsening of the basal arterial oxygen tension ("orthodeoxia"). Our study was undertaken to investigate the incidence of orthodeoxia and platypnea and the mechanisms of hypoxemia in unselected patients. We studied 18 consecutive biopsy-proven liver cirrhosis patients, at[ lifelong non smokers, none of whom complained of platypnea. We evaluated arterial blood gases, pulmonary ventilation and right-to-left shunt in sitting and recumbent positions in each patient. in sitting position arterial oxygen tension (Pao) ranged between 57.8 and 93.7 mmHg and hypoxemia was found in 6/18 patients (33%). All but one patient showed a decrease in Pa-O2 when lying down. In most patients the decrease was higher than predicted, and a high percentage of patients showed hypoxemia (14/18 patients: 78%). We propose the term "clinodeoxia", as the reverse of "orthodeoxia", to describe the accentuated arterial oxygen desaturation in clinostatism. The change of posture provoked age-retated variations of ventilation and right-to-left shunt, the postural trends of which differed significantly according to the patient's age. Ptatypnea and orthodeoxia have also been described in patients without liver diseases but sharing a severe standing hypoxemia. We conclude that platypnea and orthodeoxia can probably be found only in patients with severe hypoxemia, and, when present, are not markers of chronic liver disease, but simply of severe arterial hypoxemia.

The 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 500/50μg Diskus, 1 inhalation twice daily+placebo Handihaler 1 inhalation once-daily daily; (2) tiotropium 18μg Handihaler, 1 inhalation once daily+placebo Diskus, 1 inhalation twice daily; (3) FSC 500/50μg Diskus, 1 inhalation twice daily+tiotropium 18μg 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 FEV1 with all treatments medications were observed by the first month when trough FEV1 had improved significantly above baseline by 74mL (p<0.05) in the tiotropium group, by 117mL (p<0.05) in the FSC group and by 115mL (p<0.05) in FSC+tiotropium group. At the end of the study, trough FEV1 had improved significantly above baseline by141mL (p<0.05) in the tiotropium group, by 140mL (p<0.05) in the FSC group and by 186mL (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.

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.