[Lung transplantation in chronic obstructive lung diseases]

Lung transplantation (uni- or bilateral) is an accepted treatment option for patients with end-stage chronic obstructive pulmonary disease. Pulmonary function improves significantly and 5-year-actuarial survival is more than 70% at acceptable early mortality rates. Careful evaluation of risks and benefits in necessary because of the known donor-organ shortage and the risks of life-long immunosuppressive treatment. The bronchiolitis obliterans syndrome is still a nonsolved problem in the long-term course after LTx and it can influence late graft function and patient survival.

Cellular uptake and localization of inhaled gold nanoparticles in lungs of mice with chronic obstructive pulmonary disease

BACKGROUND: Inhalative nanocarriers for local or systemic therapy are promising. Gold nanoparticles (AuNP) have been widely considered as candidate material. Knowledge about their interaction with the lungs is required, foremost their uptake by surface macrophages and epithelial cells.Diseased lungs are of specific interest, since these are the main recipients of inhalation therapy. We, therefore, used Scnn1b-transgenic (Tg) mice as a model of chronic obstructive pulmonary disease (COPD) and compared uptake and localization of inhaled AuNP in surface macrophages and lung tissue to wild-type (Wt) mice. METHODS: Scnn1b-Tg and Wt mice inhaled a 21-nm AuNP aerosol for 2 h. Immediately (0 h) or 24 h thereafter, bronchoalveolar lavage (BAL) macrophages and whole lungs were prepared for stereological analysis of AuNP by electron microscopy. RESULTS: AuNP were mainly found as singlets or small agglomerates of <= 100 nm diameter, at the epithelial surface and within lung-surface structures. Macrophages contained also large AuNP agglomerates (> 100 nm). At 0 h after aerosol inhalation, 69.2+/-4.9% AuNP were luminal, i.e. attached to the epithelial surface and 24.0+/-5.9% in macrophages in Scnn1b-Tg mice. In Wt mice, 35.3+/-32.2% AuNP were on the epithelium and 58.3+/-41.4% in macrophages. The percentage of luminal AuNP decreased from 0 h to 24 h in both groups. At 24 h, 15.5+/-4.8% AuNP were luminal, 21.4+/-14.2% within epithelial cells and 63.0+/-18.9% in macrophages in Scnn1b-Tg mice. In Wt mice, 9.5+/-5.0% AuNP were luminal, 2.2+/-1.6% within epithelial cells and 82.8+/-0.2% in macrophages. BAL-macrophage analysis revealed enhanced AuNP uptake in Wt animals at 0 h and in Scnn1b-Tg mice at 24 h, confirming less efficient macrophage uptake and delayed clearance of AuNP in Scnn1b-Tg mice. CONCLUSIONS: Inhaled AuNP rapidly bound to the alveolar epithelium in both Wt and Scnn1b-Tg mice. Scnn1b-Tg mice showed less efficient AuNP uptake by surface macrophages and concomitant higher particle internalization by alveolar type I epithelial cells compared to Wt mice. This likely promotes AuNP depth translocation in Scnn1b-Tg mice, including enhanced epithelial targeting. These results suggest AuNP nanocarrier delivery as successful strategy for therapeutic targeting of alveolar epithelial cells and macrophages in COPD.

Position paper on the management of patients with obstructive sleep apnea and hypertension: joint recommendations by the European Society of Hypertension, by the European Respiratory Society and by the members of European COST (COoperation in Scientific and Technological research) ACTION B26 on obstructive sleep apnea

This article is aimed at addressing the current state of the art in epidemiology, pathophysiology, diagnostic procedures and treatment options for appropriate management of obstructive sleep apnea (OSA) in cardiovascular (particularly hypertensive) patients, as well as for the management of cardiovascular diseases (particularly arterial hypertension) in OSA patients. The present document is the result of the work done by a panel of experts participating in the European Union COST (COoperation in Scientific and Technological research) ACTION B26 on OSA, with the endorsement of the European Respiratory Society (ERS) and the European Society of Hypertension (ESH). These recommendations are particularly aimed at reminding cardiovascular experts to consider the occurrence of sleep-related breathing disorders in patients with high blood pressure. They are at the same time aimed at reminding respiration experts to consider the occurrence of hypertension in patients with respiratory problems at night.

Recommendations for the management of patients with obstructive sleep apnoea and hypertension

This article is aimed at addressing the current state-of-the-art in epidemiology, pathophysiology, diagnostic procedures and treatment options for appropriate management of obstructive sleep apnoea (OSA) in cardiovascular (in particular hypertensive) patients, as well as for the management of cardiovascular diseases (in particular arterial hypertension) in OSA patients. The present document is the result of work performed by a panel of experts participating in the European Union COST (Cooperation in Scientific and Technological research) Action B26 on OSA, with the endorsement of the European Respiratory Society and the European Society of Hypertension. In particular, these recommendations are aimed at reminding cardiovascular experts to consider the occurrence of sleep-related breathing disorders in patients with high blood pressure. They are also aimed at reminding respiration experts to consider the occurrence of hypertension in patients with respiratory problems at night.

Oxidative stress in lungs of mice infected with influenza A virus

As oxidative stress has been implicated in the pathogenesis of certain viral diseases we determined antioxidant and prooxidant parameters in lungs and bronchoalveolar lavage fluid (BALF) of mice infected with a lethal dose of influenza A/PR8/34 virus. Viral infection was characterized by massive infiltration of leukocytes, mainly polymorphonuclear leukocytes, into the alveolar space. The total number of BALF cells increased up to 8-fold (day 3 post-infection) and these cells appeared activated as judged by their increased rates of superoxide anion radical (O2-.) generation upon stimulation. Maximal rates of radical generation by BALF cells during the early stages of infection were 15- or 70-fold higher than those of cells from control animals when expressed per cell or total BALF cells, respectively. At the terminal stages of infection the total capacity of BALF cells to release O2-. declined to approximately 35-fold the control values. Infection also resulted in increased in vivo formation of hydrogen peroxide (H2O2) within the lungs at a time that coincided with the maximal capacity of BALF cells to release O2-.. Whereas pulmonary activities of glutathione peroxidase and reductase remained unaltered, levels of ascorbate in the cell-free BALF decreased significantly during the early stages of the infection and then returned to normal levels and above, late in infection. The oxidation state of the dehydroascorbic acid/ascorbate couple increased concomitantly with the decrease in ascorbate concentrations early in infection and remained elevated throughout the infection. As assessed by the prevention of peroxyl radical-induced loss of phycoerythrin fluorescence, the total antioxidant capacity present in lung tissue homogenate from terminally ill animals was not diminished when compared to that prepared from lungs of control mice. We conclude that although early stages of influenza infection are associated with the presence of oxidative stress in the lung tissue and alveolar fluid lining the epithelial cells, this stress does not appear to overwhelm local antioxidant defenses. The results therefore do not support a direct causative role of oxidative tissue damage in the pathogenesis of influenza virus infection.

[Effects of tobacco use on general health: relevant information for dentistry (I)--part 1: pulmonary diseases and other malignancies]

This fifth part of a series of publications from the Swiss task force named "Smoking--Intervention in the private dental office" on the topic "tobacco use and dental medicine" focuses on the effects of tobacco use on general health. A significant increase of tobacco use associated morbidity and mortality for many cardiovascular and pulmonary diseases has been well documented in the literature. In this review, the epidemiologic background as well as the pathophysiological fundamentals for tobacco-mediated pulmonary diseases is presented, focusing especially on chronic obstructive pulmonary disease (COPD) and lung cancer. In addition, a causal relationship between nicotine abuse and an increased carcinoma incidence for other malignancies but lung cancer will be discussed. Regarding the evidence in the present literature, it is undisputable that smoking is the most preventable cause for COPD and lung cancer.

Copy number variation of the Beta-defensin genes in europeans: no supporting evidence for association with lung function, chronic obstructive pulmonary disease or asthma

Lung function measures are heritable, predict mortality and are relevant in diagnosis of chronic obstructive pulmonary disease (COPD). COPD and asthma are diseases of the airways with major public health impacts and each have a heritable component. Genome-wide association studies of SNPs have revealed novel genetic associations with both diseases but only account for a small proportion of the heritability. Complex copy number variation may account for some of the missing heritability. A well-characterised genomic region of complex copy number variation contains beta-defensin genes (DEFB103, DEFB104 and DEFB4), which have a role in the innate immune response. Previous studies have implicated these and related genes as being associated with asthma or COPD. We hypothesised that copy number variation of these genes may play a role in lung function in the general population and in COPD and asthma risk. We undertook copy number typing of this locus in 1149 adult and 689 children using a paralogue ratio test and investigated association with COPD, asthma and lung function. Replication of findings was assessed in a larger independent sample of COPD cases and smoking controls. We found evidence for an association of beta-defensin copy number with COPD in the adult cohort (OR = 1.4, 95%CI:1.02-1.92, P = 0.039) but this finding, and findings from a previous study, were not replicated in a larger follow-up sample(OR = 0.89, 95%CI:0.72-1.07, P = 0.217). No robust evidence of association with asthma in children was observed. We found no evidence for association between beta-defensin copy number and lung function in the general populations. Our findings suggest that previous reports of association of beta-defensin copy number with COPD should be viewed with caution. Suboptimal measurement of copy number can lead to spurious associations. Further beta-defensin copy number measurement in larger sample sizes of COPD cases and children with asthma are needed.

Statement on smoking cessation in COPD and other pulmonary diseases and in smokers with comorbidities who find it difficult to quit.

Chronic obstructive pulmonary disease (COPD), lung cancer, asthma and pulmonary tuberculosis are common pulmonary diseases that are caused or worsened by tobacco smoking. Growing observational evidence suggests that symptoms and prognosis of these conditions improve upon smoking cessation. Despite increasing numbers of (small) randomised controlled trials suggesting intensive smoking cessation treatments work in people with pulmonary diseases many patients are not given specific advice on the benefits or referred for intensive cessation treatments and, therefore, continue smoking. This is a qualitative review regarding smoking cessation in patients with COPD and other pulmonary disorders, written by a group of European Respiratory Society experts. We describe the epidemiological links between smoking and pulmonary disorders, the evidence for benefits of stopping smoking, how best to assess tobacco dependence and what interventions currently work best to help pulmonary patients quit. Finally, we describe characteristics and management of any "hardcore" smoker who finds it difficult to quit with standard approaches.

Microbiota Promotes Chronic Pulmonary Inflammation by Enhancing IL-17A and Autoantibodies

RATIONALE Changes in the pulmonary microbiota are associated with progressive respiratory diseases including chronic obstructive pulmonary disease. Whether there is a causal relationship between these changes and disease progression remains unknown. OBJECTIVE To investigate the link between an altered microbiota and disease, we utilized a model of chronic lung inflammation in specific pathogen free (SPF) mice and mice depleted of microbiota by antibiotic treatment or devoid of a microbiota (axenic). METHODS Mice were challenged with LPS/elastase intranasally over 4 weeks, resulting in a chronically inflamed and damaged lung. The ensuing cellular infiltration, histological damage and decline in lung function were quantified. MEASUREMENTS AND MAIN RESULTS Similar to human disease, the composition of the pulmonary microbiota was altered in disease animals. We found that the microbiota richness and diversity were decreased in LPS/Elastase-treated mice, with an increased representation of the genera Pseudomonas, Lactobacillus and a reduction in Prevotella. Moreover, the microbiota was implicated in disease development as mice depleted of microbiota exhibited an improvement in lung function, reduction in airway inflammation, decrease in lymphoid neogenesis and auto-reactive antibody responses. The absence of microbial cues also markedly decreased the production of IL-17A, whilst intranasal transfer of fluid enriched with the pulmonary microbiota isolated from diseased mice enhanced IL-17A production in the lungs of antibiotic treated or axenic recipients. Finally, in mice harboring a microbiota, neutralizing IL-17A dampened inflammation and restored lung function. CONCLUSIONS Collectively, our data indicate that host-microbial cross-talk promotes inflammation and could underlie the chronicity of inflammatory lung diseases.

In vitro detection of cytotoxic T and NK cells in peripheral blood of patients with various drug-induced skin diseases

BACKGROUND: Cytotoxic cells are involved in most forms of drug-induced skin diseases. Till now, no in vitro test addressed this aspect of drug-allergic responses. Our report evaluates whether drug-induced cytotoxic cells can be detected in peripheral blood of nonacute patients with different forms of drug hypersensitivity, and also whether in vitro detection of these cells could be helpful in drug-allergy diagnosis. METHODS: GranzymeB enzyme-linked immunosorbent spot-forming (ELISPOT) and cell surface expression of the degranulation marker CD107a were evaluated on peripheral blood mononuclear cells from 12 drug-allergic patients in remission state and 16 drug-exposed healthy controls. RESULTS: In 10/12 allergic patients culprit but not irrelevant drug elicited granzymeB release after 48-72 h stimulation. It was clearly positive in patients with high proliferative response to the drug, measured in lymphocyte transformation tests. In patients, who showed moderate or low proliferation and low drug-response in granzymeB ELISPOT, overnight preincubation with interleukin (IL)-7/IL-15 enhanced drug-specific granzymeB release and allowed to clearly identify the offending agent. CD107a staining was positive on CD4+/CD3+, CD8+/CD3+ T cells as well as CD56+/CD3- natural killer cells. None of the drug-exposed healthy donors reacted to the tested drugs and allergic patients reacted only to the offending, but not to tolerated drugs. CONCLUSION: GranzymeB ELISPOT is a highly specific in vitro method to detect drug-reacting cytotoxic cells in peripheral blood of drug-allergic patients even several years after disease manifestation. Together with IL-7/IL-15 preincubation, it may be helpful in indentifying the offending drug even in some patients with weak proliferative drug-response.

Drug hypersensitivity reactions involving skin

Immune reactions to drugs can cause a variety of diseases involving the skin, liver, kidney, lungs, and other organs. Beside immediate, IgE-mediated reactions of varying degrees (urticaria to anaphylactic shock), many drug hypersensitivity reactions appear delayed, namely hours to days after starting drug treatment, showing a variety of clinical manifestations from solely skin involvement to fulminant systemic diseases which may be fatal. Immunohistochemical and functional studies of drug-specific T cells in patients with delayed reactions confirmed a predominant role for T cells in the onset and maintenance of immune-mediated delayed drug hypersensitivity reactions (type IV reactions). In these reactions, drug-specific CD4+ and CD8+ T cells are stimulated by drugs through their T cell receptors (TCR). Drugs can stimulate T cells in two ways: they can act as haptens and bind covalently to larger protein structures (hapten-carrier model), inducing a specific immune response. In addition, they may accidentally bind in a labile, noncovalent way to a particular TCR of the whole TCR repertoire and possibly also major histocompatibility complex (MHC)-molecules - similar to their pharmacologic action. This seems to be sufficient to reactivate certain, probably in vivo preactivated T cells, if an additional interaction of the drug-stimulated TCR with MHC molecules occurs. The mechanism was named pharmacological interaction of a drug with (immune) receptor and thus termed the p-i concept. This new concept may explain the frequent skin symptoms in drug hypersensitivity to oral or parenteral drugs. Furthermore, the various clinical manifestations of T cell-mediated drug hypersensitivity may be explained by distinct T cell functions leading to different clinical phenotypes. These data allowed a subclassification of the delayed hypersensitivity reactions (type IV) into T cell reactions which, by releasing certain cytokines and chemokines, preferentially activate and recruit monocytes (type IVa), eosinophils (type IVb), or neutrophils (type IVd).

[Swiss registry for TNF-alpha blockers in children and adolescents with rheumatological diseases]

We created a registry to evaluate long term outcome, efficacy and adverse events for children treated wit TNF-alpha inhibitors in Switzerland. 106 patients (68 female/38 male) were included. 61 patients were treated with Etanercept (Enbrel) and 45 with Infliximab (Remicade). Concomitant treatment at baseline included corticosteroids in 26% and Methotrexate in 75% of the patients. Subjective disease activity three months after initiation of TNF-alpha was better in 81%, worse in 4% and stable in 15% of the patients. In total 24 adverse events in 21 patients were reported. Treatment with TNF-alpha inhibitors seems to be safe and effective for children and adolescents with rheumatologic diseases.

The CFTR frameshift mutation 3905insT and its effect at transcript and protein level

Cystic fibrosis (CF) is one of the most common genetic diseases in the Caucasian population and is characterized by chronic obstructive pulmonary disease, exocrine pancreatic insufficiency, and elevation of sodium and chloride concentrations in the sweat and infertility in men. The disease is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, which encodes a protein that functions as chloride channel at the apical membrane of different epithelia. Owing to the high genotypic and phenotypic disease heterogeneity, effects and consequences of the majority of the CFTR mutations have not yet been studied. Recently, the frameshift mutation 3905insT was identified as the second most frequent mutation in the Swiss population and found to be associated with a severe phenotype. The frameshift mutation produces a premature termination codon (PTC) in exon 20, and transcripts bearing this PTC are potential targets for degradation through nonsense-mediated mRNA decay (NMD) and/or for exon skipping through nonsense-associated alternative splicing (NAS). Using RT-PCR analysis in lymphocytes and different tissue types from patients carrying the mutation, we showed that the PTC introduced by the mutation does neither elicit a degradation of the mRNA through NMD nor an alternative splicing through NAS. Moreover, immunocytochemical analysis in nasal epithelial cells revealed a significantly reduced amount of CFTR at the apical membrane providing a possible molecular explanation for the more severe phenotype observed in F508del/3905insT compound heterozygotes compared with F508del homozygotes. However, further experiments are needed to elucidate the fate of the 3905insT CFTR in the cell after its biosynthesis.

Expression, regulation and clinical significance of soluble and membrane CD14 receptors in pediatric inflammatory lung diseases

BACKGROUND: Inflammatory lung diseases are a major morbidity factor in children. Therefore, novel strategies for early detection of inflammatory lung diseases are of high interest. Bacterial lipopolysaccharide (LPS) is recognized via Toll-like receptors and CD14. CD14 exists as a soluble (sCD14) and membrane-associated (mCD14) protein, present on the surface of leukocytes. Previous studies suggest sCD14 as potential marker for inflammatory diseases, but their potential role in pediatric lung diseases remained elusive. Therefore, we examined the expression, regulation and significance of sCD14 and mCD14 in pediatric lung diseases. METHODS: sCD14 levels were quantified in serum and bronchoalveolar lavage fluid (BALF) of children with infective (pneumonia, cystic fibrosis, CF) and non-infective (asthma) inflammatory lung diseases and healthy control subjects by ELISA. Membrane CD14 expression levels on monocytes in peripheral blood and on alveolar macrophages in BALF were quantified by flow cytometry. In vitro studies were performed to investigate which factors regulate sCD14 release and mCD14 expression. RESULTS: sCD14 serum levels were specifically increased in serum of children with pneumonia compared to CF, asthma and control subjects. In vitro, CpG induced the release of sCD14 levels in a protease-independent manner, whereas LPS-mediated mCD14 shedding was prevented by serine protease inhibition. CONCLUSIONS: This study demonstrates for the first time the expression, regulation and clinical significance of soluble and membrane CD14 receptors in pediatric inflammatory lung diseases and suggests sCD14 as potential marker for pneumonia in children.

Spectral-domain optical coherence tomography use in macular diseases: a review

The introduction of spectral-domain optical coherence tomography (SD-OCT) has improved the clinical value for assessment of the eyes with macular disease. This article reviews the advances of SD-OCT for the diagnostic of various macular diseases. These include vitreomacular traction syndrome, cystoid macular edema/diabetic macular edema, epiretinal membranes, full-thickness macular holes, lamellar holes, pseudoholes, microholes, and schisis from myopia. Besides offering new insights into the pathogenesis of macular abnormalities, SD-OCT is a valuable tool for monitoring macular disease.