Bronchial inflammation and bacterial load in stable COPD is associated with TLR4 overexpression.

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.

Embolization of a Bronchial Artery Aneurysm in a Chronic Obstructive Pulmonary Disease (COPD) Patient with Non-Massive Hemoptysis.

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.

Glycogen synthase kinase-3ß modulation of glucocorticoid responsiveness in COPD.

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-3ß (GSK3ß) inactivation plays a key role in mediating signaling processes upon reactive oxygen species (ROS) exposure. We hypothesized that GSK3ß is involved in oxidative stress-induced glucocorticoid insensitivity in COPD. We studied levels of phospho-GSK3ß-Ser9, a marker of GSK3ß inactivation, in lung sections and cultured monocytes and bronchial epithelial cells of COPD patients, control smokers, and nonsmokers. We observed increased levels of phospho-GSK3ß-Ser9 in monocytes, alveolar macrophages, and bronchial epithelial cells from COPD patients and control smokers compared with nonsmokers. Pharmacological inactivation of GSK3ß 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 GSK3ß 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 GSK3ß inactivation. In conclusion, we demonstrate for the first time that ROS-induced glucocorticoid unresponsiveness in COPD is mediated through GSK3ß, acting as a ROS-sensitive hub.

Molecular links between COPD and lung cancer: new targets for drug discovery?

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.

Tiotropium and salmeterol/fluticasone combination do not cause oxygen desaturation in COPD.

It has been documented that tiotropium is less likely to induce oxygen desaturation in stable COPD patients compared to long-acting beta2-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 18 microg and salmeterol/fluticasone combination (SFC) 50/250 microg 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 360 min after inhalation of each treatment, and spirometry was performed at the same time points. As expected, both treatments significantly improved FEV1 (greatest changes were 0.20 L, 95% CI: 0.13-0.27 at 360 min after tiotropium; and 0.13 L, 95% CI: 0.06-0.19 at 180 min 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 15 min. Both drugs caused a small decrease in PaCO2 (greater changes: -1.9 (95% CI -3.2 to -0.6)mmHg, p=0.005 at 60 min after tiotropium; and -2.4 (95% CI: -3.5 to -1.3) mmHg, p=0.0002 at 180 min 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 intercourse and respiratory failure.

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.

Imbalance of serum cytokine network in sarcoid patients: index of sarcoidosis relapse?

BACKGROUND AND AIM OF THE WORK: The follow-up of sarcoidosis is usually performed by invasive tools such as thoracic biopsy, supported by Broncho-Alveolar Lavage (BAL), Gallium-scintigraphy and Gadolinium Magnetic Resonance Imaging (Gd-MRI) to evaluate the degree of disease. Its pathogenesis can be ascribed to an accumulation of cells due to the disregulation of the immune system which involves Th1/Th2 cells as well as the soluble factors they generate. We evaluated serum cytokine and membrane marker levels (cytokine network) in sarcoid patients in order to study the correlation with the disease activity, in particular with the occurrence of sarcoidosis relapses. PATIENTS AND METHODS: Seven sarcoid patients clinically stable without therapy, at different stages, were enrolled in our study. Cytokine and membrane marker serum values were measured monthly for 24 months, after a six-month period of run-in, by ELISA assay and MoAb indirect immunofluorescence, respectively. RESULTS: In some patients at the first and second stages of the disease we observed MCP-1 and inflammatory cytokine peaks and, moreover, MCP-1 values were increased before other cytokine values. After three subsequent increases of these parameters were observed, according to our personal experience, Gadolinium-MRI confirmed the presence of an increase of the lesion and therefore our hypothesis of sarcoidosis relapse. Only one patient at stage III showed constantly elevated values of fibro-angiogenic cytokines and membrane receptors of the TNF receptor family. CONCLUSIONS: Cytokine network monitoring could be a non-invasive means of following up the clinical course of sarcoidosis.

Recumbent deoxygenation in mild/moderate liver cirrhosis: the "clinodeoxia". The ortho-clino paradigm.

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").

Standards of suitability for the management of chronic obstructive respiratory diseases.

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.

Anatomy and neuro-pathophysiology of the cough reflex arc.

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.

A pilot study to assess the effects of combining fluticasone propionate/salmeterol and tiotropium on the airflow obstruction of patients with severe-to-very severe COPD.

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 500/50 microg Diskus, 1 inhalation twice daily+placebo Handihaler 1 inhalation once-daily daily; (2) tiotropium 18 microg Handihaler, 1 inhalation once daily+placebo Diskus, 1 inhalation twice daily; (3) FSC 500/50 microg Diskus, 1 inhalation twice daily+tiotropium 18 microg 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 FEV(1) had improved significantly above baseline by 141 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.

Mid- and long-term effects on pulmonary perfusion, anatomy and diaphragmatic motility in survivors of congenital diaphragmatic hernia.

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.