bluuebunny/crossref_metadata_2025 huggingface dataset:
Human alveolar epithelial cells induce nitric oxide synthase‐2 expression in alveolar macrophages
Authors: Pechkovsky D.V. , Zissel G. , Stamme C. , Goldmann T. , Ari Jaffe H. , Einhaus M. , Taube C. , Magnussen H. , Schlaak M. , Müller­Quernheim J.
Published: September 2008

It was hypothesized that cell­to­cell interaction between human alveolar macrophages (AM) and alveolar epithelium, might be an important factor leading to nitric oxide synthase‐2 (NOS2) messenger ribonucleic acid (mRNA) and protein expression by constituent cells of the alveolar wall and/or AM.

NOS2 mRNA and the protein expression patterns of human AM and alveolar epithelial cells type II (AEC­II) isolated from normal parts of lung resections of patients with pulmonary malignancies were determined. In addition, NOS2 mRNA expression in human AM co­cultured with autologous AEC­II in the presence of pro­inflammatory cytokines interleukin (IL)‐1β, tumour necrosis factor (TNF)‐α, interferon (IFN)‐γ or lipopolysaccharide (LPS) was investigated. The effect of human surfactant protein‐A (SP‐A) on IFN‐γ‐mediated NOS2 mRNA expression in human AM was also studied.

Neither NOS2 mRNA nor protein could be detected in freshly isolated, unstimulated or cytokine­stimulated AEC­II. In contrast, freshly isolated AM from bronchoalveolar lavage or lung tissue samples expressed immunoreactivity for NOS2 protein, but no NOS2 mRNA could be detected by reverse transcriptase polymerase chain reaction. All stimuli tested failed to induce NOS2 mRNA expression in human AMin vitro. Only AM­AEC­II co­culture in the presence of IFN‐γ led to NOS2 mRNA and protein expression.In situhybridization of NOS2 mRNA on lung tissue explants and immunohistochemical staining of cytospin preparations of AM­AEC­II co­cultures demonstrated that NOS2 is expressed in AM but not in AEC­II. This co­culture effect could not be reproduced by substitution of AEC­II with SP‐A.

These data give evidence of a regulatory network controlling human nitric oxide synthase‐2 expression in the lower respiratory tract.
Identification of a new cystic fibrosis transmembrane regulator mutation in a severely affected patient
Authors: Spitzer E. , Staab D. , Hanke R. , Wahn U. , Grosse R.
Published: September 2008

By using a combination of multiplex polymerase chain reaction and allele­specific labelled probes, the oligo­ligation assay is designed to detect known cystic fibrosis transmembrane regulator mutations. This study shows that this assay may also be useful to detect new mutations.

The second child of a family of Bosnic origin showed all the symptoms of intestinal and pulmonary manifestations of cystic fibrosis. No signal could be obtained for the allele­specific probe 1898+1G>A. This could be explained by a nearby localized sequence change that prevented polymerase chain reaction primers or oligonucleotide probes from binding to the target sequence. Indeed, sequence analysis revealed a new 1894G>T exchange (Glu587Stop). Both parents and the healthy brother carried this mutation. Thus, the index patient was homozygous for 1894G>T, which was inherited from both parents.
Sleep and breathing in neuromuscular disease
Authors: Bourke S.C. , Gibson G.J.
Published: September 2008

Respiratory muscle weakness in neuromuscular disease causes significant morbidity and mortality. The published data on respiratory muscle activity and breathing during sleep in normal subjects, the impact of respiratory muscle weakness on sleep and breathing and the relations to daytime respiratory function in neuromuscular disease are reviewed here. In normal subjects during sleep upper airway resistance increases, chemosensitivity is reduced and the wakefulness drive to breathe is lost, resulting in a fall in ventilation. During rapid eye movement (REM) sleep, ribcage and accessory breathing muscles are suppressed, particularly during bursts of eye movements, and breathing is more irregular, rapid and shallow, with a further fall in ventilation.

In subjects with respiratory muscle weakness sleep is fragmented, with shorter total sleep time, frequent arousals, an increase in stage 1 sleep and a reduction in, or complete suppression of, REM sleep. Sleep­disordered breathing and nocturnal desaturation are common and most severe during REM sleep. Correlations between daytime respiratory function and nocturnal desaturation are moderate or weak, but daytime respiratory function has greater prognostic value than nocturnal measurements.

Noninvasive ventilation improves sleep quality and breathing in subjects with respiratory muscle weakness. However, the optimal criteria for initiation of ventilation and its role in rapidly progressive neuromuscular diseases are unclear.
Oxidant metabolism in chronic obstructive pulmonary disease
Authors: Boots A.W. , Haenen G.R.M.M. , Bast A.
Published: September 2008

The development and progression of chronic obstructive pulmonary disease (COPD) have been associated with increased oxidative stress or reduced antioxidant resources. Several indicators of oxidative stress, such as hydrogen peroxide exhalation, lipid peroxidation products and degraded proteins, are indeed elevated in COPD patients. As a result, the antioxidant capacity decreases in COPD patients.

The fall in antioxidant capacity of blood from COPD patients should not only be regarded as a reflection of the occurrence of oxidative stress but also as evidence that oxidative stress spreads out to the circulation and can therefore generate a systemic effect.

COPD is linked to weight loss and in particular to loss in fat­free mass by skeletal muscle wasting. This systemic effect can be mediated by both oxidative stress and oxidative stress­mediated processes like apoptosis and inflammation. Furthermore, COPD is a predisposition for lung cancer through several mechanisms including oxidative stress and oxidative stress­mediated processes such as inflammation and disruption of genomic integrity.

Current therapeutic interventions against the far­reaching consequences of the systemic oxidative stress in chronic obstructive pulmonary disease are not yet optimised. A diet designed to reduce chronic metabolic stress might form an effective therapeutic strategy in chronic obstructive pulmonary disease.
Fluid homeostasis in chronic obstructive lung disease
Authors: de Leeuw P.W. , Dees A.
Published: September 2008

Chronic obstructive pulmonary disease (COPD) often leads to massive oedema and the development of what is usually called cor pulmonale. The mechanisms by which patients with COPD retain salt and water are not completely understood. Several abnormalities have been found including reduced renal blood flow with relatively preserved glomerular filtration rate and elevated levels of renin, aldosterone, arginine vasopressin and atrial natriuretic peptide. Generally, these abnormalities worsen with the severity of COPD and are most marked during the oedematous phases.

Cardiac output is remarkably normal, suggesting that “cor pulmonale” is not primarily a cardiac disorder but rather a condition of volume overload due to activation of sodium­retaining mechanisms. The stimulus for this activation could be underfilling of the arterial system (reduced effective circulating volume) secondary to a fall in total peripheral vascular resistance. The latter is caused by hypercapnia­induced dilation of the precapillary sphincters. Apparently, the massive sodium retention by the kidney is not able to restore the circulating volume and a vicious cycle ensues ultimately leading to a clinical picture which resembles right­sided heart failure. Predictably, only blockade of the effects of carbon dioxide at the level of the precapillary sphincters would be able to halt this process.
Incidence and short-term outcome of acute lung injury in mechanically ventilated children
Authors: Dahlem P. , van Aalderen W.M.C. , Hamaker M.E. , Dijkgraaf M.G.W. , Bos A.P.
Published: September 2008

The aim of this study was to determine the incidence and short-term outcome of mechanically ventilated children suffering from acute lung injury (ALI) on a paediatric intensive care unit (PICU).

Between January 1 1998 and January 1 2000, all mechanically ventilated children were evaluated using the criteria of an American-European Consensus Conference.

Of the 443 children eligible for analysis, 44 (9.9%) were diagnosed as suffering from ALI. Of these, 79.5% developed the acute respiratory distress syndrome (ARDS); 54.5% (24 of 44) fulfilled the ARDS criteria at inclusion and 25% (11 of 44) later. PICU mortality for ALI was 27.3% (12 of 44) and within the ARDS subgroup 31.4% (11 of 35). Of the 12 children who died, 11 had ARDS; the main cause of death was cerebral damage (seven of 12).

Acute lung injury and acute respiratory distress syndrome are rare diseases on apaediatric intensive care unit with a high mortality. Most of the children with acutelung injury develop acute respiratory distress syndrome. In the acute respiratory distress syndrome subgroup, mortality is higher than in the acute lung injury nonacute respiratory distress syndrome subgroup. Further investigations should confirm prognostic factors (e.g.respiratory parameters) for prediction of outcome.
Systemic inflammation in chronic obstructive pulmonary disease
Authors: Oudijk E­J.D. , Lammers J­W.J. , Koenderman L.
Published: September 2008

Chronic obstructive pulmonary disease (COPD) is characterised by a chronic inflammation in the pulmonary tissue. The disease is associated with a switch from a self­limiting inflammatory response, mainly initiated by smoke inhalation, to a chronic persistent inflammatory response after prolonged interaction with cigarette smoke. The extent of the inflammatory reaction is correlated with the severity of the disease.

Chronic inflammation in the pulmonary tissue is also associated with systemic effects. These effects range from cytokine­induced priming of peripheral leukocytes, to muscle wasting induced by cytokines such as tumour necrosis factor‐α. Despite a general consensus that chronic inflammation is a characteristic phenomenon of the disease, surprisingly little is known regarding the underlying pathogenetic mechanisms.

A clear communication is present between the disease mechanisms in the pulmonary compartment and peripheral tissues, leading to the concept of COPD as a systemic inflammatory disease. This communication can be mediated by: 1) leakage of reactive oxygen species and stress­induced cytokines directly into the peripheral blood, 2) (pre)activation of peripheral blood leukocytes that can result in aberrant homing and activation of inflammatory cells in distant tissues, and 3) the liberation of pro­inflammatory mediators by leukocytes and/or stromal cells present in the pulmonary tissues during progression of the disease.

The current authors hypothesise that the occurrence of a chronic inflammatory response after prolonged interaction of the pulmonary tissue with cigarette smoke causes aberrant homing of leukocytes to the tissue and delayed apoptosis. This leads to the autonomous characteristic of the inflammatory response in patients with chronic obstructive pulmonary disease.
Structure and function of the respiratory muscles in patients with COPD: impairment or adaptation?: Fig. 1.—
Authors: Orozco-Levi M.
Published: September 2008

Respiratory muscles are essential to alveolar ventilation. These muscles work against increased mechanical loads due to airflow limitation and geometrical changes of the thorax derived from pulmonary hyperinflation. Respiratory muscle fibres show several degrees of impairment in cellular and subcellular structures which, in many cases, are proportional to the severity of the disease and accompanying conditions (ageing, deconditioning, starvation, comorbidity). This structural impairment translates, from the functional point of view, to a loss of strength (capacity to generate tension) and an increased susceptibility to failure in the face of a particular load (early onset of fatigue).

On the other hand, there is accumulating evidence that the diaphragm and other respiratory muscles are also able to express adaptive changes in response to the chronic mechanical load imposed by the disease. In most cases, impairment and adaptation of the respiratory muscles reaches a balance that permits enough ventilation for patients' survival. However, this balance can be altered for additional increments of the mechanical or metabolic load on the muscles (e.g.abdominal or thoracic surgeries, pneumonia, pulmonary embolism,etc.). Moreover, loss of balance is not always associated with extreme situations. Many patients develop ventilatory failure and require hospital admission even if the cause of the exacerbation is less dramatic (bronchial infections, pain of any nature, electrolyte disturbances,etc.).

Although the physiopathology of chronic obstructive pulmonary disease exacerbations is multifactorial, the above-mentioned fragility suggests the existence of a “fragile balance” between respiratory muscle overload and respiratory muscle adaptations. Assessment of respiratory muscle function through specific tests evaluating the strength and endurance could offer valuable information about this particular susceptibility to muscle imbalance. Identification of patients possessing a fragile respiratory muscle balance could have important implications for the application of specific strategies such as respiratory muscle training, nutrition, or anabolic treatment.
Osteoporosis in chronic obstructive pulmonary disease
Authors: Ionescu A.A. , Schoon E.
Published: September 2008

Osteoporosis is one of the systemic effects associated with chronic obstructive pulmonary disease (COPD). Potential risk factors of osteoporosis may be due to the lifestyle, genetics, treatment with corticosteroids, endocrine abnormalities or the impairment of the body composition and peripheral skeletal muscles. Evidence for the possible contribution of such factors is reviewed.

The occurrence of fractures, as a consequence of osteoporosis, can contribute to the disability and mortality of patients with COPD and add to the economic burden of the disease. The treatment with corticosteroids for the lung disease is associated with increased prevalence of fractures, but other factors may contribute.

There is a remarkable paucity of interventional studies targeting the osteoporosis in patients with COPD. The results of studies on the treatment of osteoporosis in chronic lung diseases, some including small numbers of patients with COPD, are reviewed in the paper.

Prospective longitudinal studies on the incidence of osteoporosis in chronic obstructive pulmonary disease need to assess patients with various degrees of disease severity and investigate the possible contribution of etiological factors. Randomised placebo-controlled trials are required to assess the effect of intervention, such as bisphosphonates, hormone replacement, calcium supplementation, on the prevention and treatment of osteoporosis and fractures in chronic obstructive pulmonary disease.
Endocrinological disturbances in chronic obstructive pulmonary disease
Authors: Creutzberg E.C. , Casaburi R.
Published: September 2008

In this overview, the available literature on endocrinological disturbances in chronic obstructive pulmonary disease (COPD) is reviewed, with stress on growth hormone/insulin-like growth factor I (IGF‐I), thyroid hormone and the anabolic steroids.

In COPD, little is known about circulating growth hormone or IGF‐I concentrations. Some authors find a decrease in growth hormone or IGF‐I, others an increase. An increase of growth hormone might reflect a nonspecific response of the body to stress (for instance, hypoxaemia). Until now, only one controlled study on growth hormone supplementation has been published, which however did not reveal any functional benefits. Before growth hormone supplementation can be advised as part of the treatment in COPD, further controlled studies must be performed to investigate its functional efficacy. The prevalence of thyroid dysfunction in COPD and its role in pulmonary cachexia has not been extensively studied. So far, there is no evidence that thyroid function is consistently altered in COPD, except perhaps in a subgroup of patients with severe hypoxaemia. Further research is required to more extensively study the underlying mechanisms and consequences of disturbed thyroid function in this subgroup of COPD patients.

A few studies have reported the results of anabolic steroid supplementation in chronic obstructive pulmonary disease. Although some studies have discerned that low circulating levels of testosterone are common in males with chronic obstructive pulmonary disease, little is known about the prevalence, the underlying causes or functional consequences of hypogonadism in these patients. The use of systemic glucocorticosteroids and an influence of the systemic inflammatory response have been suggested as contributing to low testosterone levels. It can be hypothesised that low anabolic hormones will reduce muscle mass and eventually result in a diminished muscle function. Further evidence is required before testosterone replacement can be recommended for males with chronic obstructive pulmonary disease.
Nutritional and metabolic modulation in chronic obstructive pulmonary disease management
Authors: Schols A.M.W.J.
Published: September 2008

In this paper the perspective for nutritional modulation of systemic impairment in patients with chronic obstructive pulmonary disease (COPD) is discussed. Progressive weight loss is characterised by disease-specific elevated energy requirements unbalanced by dietary intake. Weight gainper secan be achieved by caloric supplementation while future studies may prove efficacy of amino acid modulation to stimulate protein synthesis and enhance muscle anabolism.

Disproportionate muscle wasting resembles the cachexia syndrome as described in other chronic wasting diseases (cancer, chronic heart failure, acquired immunodeficiency syndrome (AIDS)). There is yet no adequate nutritional strategy available to treat cachexia in COPD. Muscle substrate metabolism has hardly been investigated, but the few data available point towards a decreased fat oxidative capacity that may show similarities with the “metabolic syndrome” as described in type II diabetes and obesity and could theoretically benefit from polyunsaturated fatty acid modulation.

To adequately target the different therapeutic options, clearly more clinical (intervention) studies are needed in chronic obstructive pulmonary disease patients that are adequately characterised by local and systemic impairment and in which molecular and metabolic markers are linked to functional outcome.
Indirect airway challenges
Authors: Joos G.F. , O'Connor B.
Published: September 2008

Indirect challenges act by causing the release of endogenous mediators that cause the airway smooth muscle to contract. This is in contrast to the direct challenges where agonists such as methacholine or histamine cause airflow limitation predominantlyviaa direct effect on airway smooth muscle.

Direct airway challenges have been used widely and are well standardised. They are highly sensitive, but not specific to asthma and can be used to exclude current asthma in a clinic population. Indirect bronchial stimuli, in particular exercise, hyperventilation, hypertonic aerosols, as well as adenosine, may reflect more directly the ongoing airway inflammation and are therefore more specific to identify active asthma. They are increasingly used to evaluate the prevalence of bronchial hyperresponsiveness and to assess specific problems in patients with known asthma,e.g.exercise-induced bronchoconstriction, evaluation before scuba diving.

Direct bronchial responsiveness is only slowly and to a modest extent, influenced by repeated administration of inhaled steroids. Indirect challenges may reflect more closely acute changes in airway inflammation and a change in responsiveness to an indirect stimulus may be a clinically relevant marker to assess the clinical course of asthma. Moreover, some of the indirect challenges,e.g.hypertonic saline and mannitol, can be combined with the assessment of inflammatory cells by induction of sputum.
Unsupervised self-testing of airway obstruction by forced oscillation at the patient's home
Authors: Rigau J. , Burgos F. , Hernández C. , Roca J. , Navajas D. , Farré R.
Published: September 2008

As active patient cooperation is not required, the forced oscillation technique (FOT) could be suitable for measuring airway obstruction in routine home applications. Nevertheless, FOT has never been used at the patient's home to date. The aim of this study was to assess the feasibility of FOT and the reproducibility of measured respiratory resistance (Rrs) in routine patient self-testing at home.

Altogether, nine asthmatic patients self-measured theirRrswith a portable FOT device and spirometry for 10–14 days, in the morning and evening, and before and after bronchodilator inhalation. During each measurement session, the patients carried out four consecutive FOT measurements. Grubbs' discordancy test for detecting outliers was used to evaluate intermeasure reliability.

Only 4.9% ofRrsdata reported by patients were rejected as artefacts. The coefficient of variation ofRrswas 7.9±6.3% (mean±sd). When compared with spirometry, the per cent change inRrsfor detecting a positive bronchodilator response showed an 83% sensitivity and 72% specificity.

Unsupervised self-measurement of respiratory resistance at the patient's home provided results similar to those obtained by a technician in a lung function lab. Forced oscillation technique could be a useful tool for the routine follow-up of asthmatic patients at home.
Biomarkers of lipid peroxidation, airway inflammation and asthma
Authors: Wood L.G. , Gibson P.G. , Garg M.L.
Published: September 2008

Oxidative stress, specifically lipid peroxidation, is believed to contribute to the pathophysiology of asthma. This review highlights the pathways through which reactive oxygen species (ROS) may lead to lipid peroxidation. The potential of both the innate and acquired immune systems to activate inflammatory cells and release ROS that may overwhelm the host antioxidant defences and cause lipid peroxidation, accompanied by detrimental pathophysiological effects, are discussed.

Despite the evidence demonstrating the importance of lipid peroxidation, systematic characterisation of oxidative stress and antioxidant defences has not been undertaken, largely due to the lack of appropriate biomarkers. This review discusses the emergence of isoprostanes (specifically 8‐iso­prostaglandin F2α) as reliable,in vivomarkers of lipid peroxidation, which provides an appropriate tool for studying oxidative stress. Furthermore, the development of techniques to study induced sputum and breath condensate, derived directly from the airway surface, enables the site of oxidative damage to be closely assessed.

Evidence suggests that dietary changes that have occurred over recent years have increased susceptibility to lipid peroxidation, due to reduced antioxidant defences. To date, the limited number of long­term (>1 week) supplementation trials have been promising. However, the development of techniques to study isoprostanes in airway­lining fluid pave the way for further studies investigating the potential for antioxidant supplements to be used as routine therapy in asthma.
OralN‐acetylcysteine reduces bleomycin-induced lung damage and mucin Muc5ac expression in rats
Authors: Mata M. , Ruíz A. , Cerdá M. , Martinez-Losa M. , Cortijo J. , Santangelo F. , Serrano-Mollar A. , Llombart-Bosch A. , Morcillo E.J.
Published: September 2008

Oxidative stress is involved in the pathogenesis of pulmonary fibrosis, therefore antioxidants may be of therapeutic value. Clinical work indicates thatN‐acetylcysteine (NAC) may be beneficial in this disease. The activity of this antioxidant was examined on bleomycin-induced lung damage, mucus secretory cells hyperplasia and mucin Muc5ac gene expression in rats.

NAC (3 mmol·kg−1·day−1) or saline was given orally to Sprague-Dawley rats for 1 week prior to a single intratracheal instillation of bleomycin (2.5 U·kg−1) and for 14 days postinstillation.

NAC decreased collagen deposition in bleomycin-exposed rats (hydroxyproline content was 4,257±323 and 3,200±192 µg·lung−1in vehicle- and NAC‐treated rats, respectively) and lessened the fibrotic area assessed by morphometric analysis. The bleomycin-induced increases in lung tumour necrosis factor‐α and myeloperoxidase activity were reduced by NAC treatment. The numbers of mucus secretory cells in airway epithelium, and the Muc5ac messenger ribonucleic acid and protein expression, were markedly augmented in rats exposed to bleomycin. These changes were significantly reduced in NAC‐treated rats.

These results indicate that bleomycin increases the number of airway secretory cells and their mucin production, and that oralN‐acetylcysteine improved pulmonary lesions and reduced the mucus hypersecretion in the bleomycin rat model.
Fatal primary pulmonary hypertension in a 30‐yr-old female with APECED syndrome
Authors: Korniszewski L. , Kurzyna M. , Stolarski B. , Torbicki A. , Smerdel A. , Ploski R.
Published: September 2008

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is caused by mutations in the autoimmune regulator (AIRE) gene, which has a central function in maintaining immunological tolerance. A number of conditions with proven or likely autoimmune pathogenesis occur in APECED: hypoparathyroidism, adrenocortical insufficency, candidiasis, hypogonadism, type 1 diabetes, hypothyroidism, hypophysitis, hepatitis, malabsorption, nail dystrophy, enamel hypoplasia and keratopathy. It is not clear which factors are responsible for variation in clinical picture of APECED, but human leukocyte antigen (HLA) genotype may be important.

The authors report the first description of a case of primary pulmonary hypertension (PPH) in patient with APECED, caused by R257X mutation in AIRE. The HLA genotype of the patient (DRB1*01/DRB1*11, DQB1*0301/DQB1*0501) has been previously reported as a predisposing factor to PPH.

The findings from this study, provided that other similar cases are reported, suggest that immune deregulation plays a role in the pathogenesis of primary pulmonary hypertension.
Increased inflammatory markers in the exhaled breath condensate of cigarette smokers
Authors: Carpagnano G.E. , Kharitonov S.A. , Foschino-Barbaro M.P. , Resta O. , Gramiccioni E. , Barnes P.J.
Published: September 2008

Cigarette smoking induces an inflammatory response in the airways that may play a key role in the pathogenesis of chronic obstructive pulmonary disease. Noninvasive markers of inflammation may, therefore, be useful in monitoring the airways of smokers as well as in the screening of subjects at high risk of developing airway obstruction.

The aim of the present study was to determine whether the concentrations of the pro-inflammatory cytokine, interleukin (IL)-6, is increased in the exhaled breath condensate of smokers and whether the number of cigarettes smoked has any influence on the exhaled concentrations. The possibility that exhaled IL-6 levels are related to exhaled carbon monoxide (CO) and lung function has also been explored. Another inflammatory marker, leukotriene (LT), was also measured.

Twenty-one smokers (39±7 yrs, 13 male) and 14 nonsmokers (45±6 yrs, eight male) were recruited. IL-6 and LTB4levels in the breath condensate were measured with an immunoassay kit and exhaled CO examined by means of a modified electrochemical sensor. Higher IL-6 and exhaled CO concentrations were found in current smokers (5.6±1.4 pg·mL−1and 16.7±5.5 parts per million (ppm)) than in nonsmokers (2.6±0.2 pg·mL−1and 2.1±0.6 ppm). Elevated concentrations of LTB4were also observed in smokers compared to nonsmokers (9.4±0.4 pg·mL−1versus6.1±0.3 pg·mL−1). In addition, there was a correlation between IL-6 concentrations, the number of cigarettes smoked per day, exhaled CO, LTB4and lung function.

Exhaled interleukin-6 and leukotriene B4levels may be useful noninvasive markers of airway inflammation in cigarette smokers.
N‐terminal pro-brain natriuretic peptide in patients with acute pulmonary embolism
Authors: Pruszczyk P. , Kostrubiec M. , Bochowicz A. , Styczyński G. , Szulc M. , Kurzyna M. , Fijałkowska A. , Kuch-Wocial A. , Chlewicka I. , Torbicki A.
Published: September 2008

Plasma brain natriuretic peptide (BNP), released from myocytes of ventricles upon stretch, has been reported to differentiate pulmonary from cardiac dyspnoea. Limited data have shown elevated plasma BNP levels in acute pulmonary embolism (APE), frequently accompanied by dyspnoea and right ventricular (RV) dysfunction. The aim of this study was to assess plasma N‐terminal proBNP (NT‐proBNP) in APE, and to establish whether it reflects the severity of RV overload and if it can be used to predict adverse clinical outcome.

On admission, NT‐proBNP and echocardiography for RV overload were performed in 79 APE patients (29 males), aged 63±16 yrs.

Plasma NT‐proBNP was elevated in 66 patients (83.5%) and was higher in patients with (median 4,650 pg·mL−1(range 61–60,958)) than without RV strain (363 pg·mL−1(16–16,329)). RV‐to-left ventricular ratio and inferior vena cava dimension correlated with NT‐proBNP. All 15 in-hospital deaths and 24 serious adverse events occurred in the group with elevated NT‐proBNP, while all 13 (16.5%) patients with normal values had an uncomplicated clinical course. Plasma NT‐proBNP predicted in-hospital mortality.

Plasma N‐terminal pro-brain natriuretic peptide is elevated in the majority of cases of pulmonary embolism resulting in right ventricular overload. Plasma levels reflect the degree of right ventricular overload and may help to predict short-term outcome. Acute pulmonary embolism should be considered in the differential diagnosis of patients with dyspnoea and abnormal levels of brain natriuretic peptide.
Lung accumulations of eosinophil granulocytes after exposure to cornstarch glove powder
Authors: Grunewald J. , Eklund A. , Katchar K. , Moshfegh A. , Lidén C. , Lundgren L. , Skare L. , Tornling G.
Published: September 2008

Starch is a main component of wheat flour, which, besides being an occupational allergen can also induce irritative symptoms in the airways. A purified starch product (cornstarch glove powder) was used to investigate whether starch alone could induce airway inflammation. The aim of the study was to investigate a role for starch in wheat flour-induced airway inflammation.

Ten healthy individuals were exposed to cornstarch glove powder in a whole-body exposure chamber. Bronchoscopy with bronchoalveolar lavage (BAL) was performed 2–3 weeks before and 1 day after exposure, and the BAL cells were counted differentially. In addition, the expression of activation, adhesion and subset markers on alveolar macrophages and BAL T-cells were investigated using flow cytometry.

A three-fold increase in BAL cell concentrations was found, with a selective accumulation and activation of eosinophilic granulocytes, as well as an influx of nonactivated monocytes and polyclonal CD4+ T-cells into the airways.

The results show that inhalation of cornstarch glove powder leads to the development of a subclinical inflammation in the airways, with an accumulation of eosinophilic granulocytes. The authors suggest that such exposure may be an interesting model for studying factors contributing to lung accumulations of eosinophil granulocytes in humans.
Cytokines and dietary energy restriction in stable chronic obstructive pulmonary disease patients
Authors: Godoy I. , Campana Á.O. , Geraldo R.R.C. , Padovani C.R. , Paiva S.A.R
Published: September 2008

Tumour necrosis factor (TNF)‐α has been found to be increased in malnourished chronic obstructive pulmonary disease (COPD) patients; however, the main cause of this phenomenon remains undetermined. In normal subjects, TNF‐α production may be induced by dietary energy deprivation. The aim of this study was to investigate if stable COPD patients present alterations of inflammatory mediators after 48 h of dietary energy restriction.

Fourteen COPD patients were admitted to the hospital while receiving an experimental diet with an energy content of approximately one-third of their energy needs. Clinical evaluation, nutritional assessment and serum levels of interleukin (IL)‐6, TNF‐α and C‐reactive protein, and secretion of TNF‐α by peripheral blood monocytes were assessed on admission and after the experimental diet. For reference values of the laboratory parameters, blood was collected from 10 healthy, elderly subjects.

COPD patients showed significantly higher serum concentrations of IL‐6 than control subjects, however, the experimental diet was not associated with statistically significant changes in the inflammatory mediators.

The findings of this study, although preliminary because of the limited degree and duration of the energy restriction, suggest that the elevated levels of tumour necrosis factor‐α, previously described in undernourished or weight-losing chronic obstructive pulmonary disease patients, may not be linked to a decrease of dietary energy intake.
Maintenance therapy with budesonide and formoterol in chronicobstructive pulmonary disease
Authors: Calverley P.M. , Boonsawat W. , Cseke Z. , Zhong N. , Peterson S. , Olsson H.
Published: September 2008

Lung function in chronic obstructive pulmonary disease (COPD) can be improved acutely by oral corticosteroids and bronchodilators. Whether clinical improvement can be maintained by subsequent inhaled therapy is unknown.

COPD patients (n=1,022, mean prebronchodilator forced expiratory volume in one second (FEV1) 36% predicted) initially received formoterol (9 µgb.i.d.) and oral prednisolone (30 mgo.d.) for 2 weeks. After this time, patients were randomised tob.i.d.inhaled budesonide/formoterol 320/9 µg, budesonide 400 µg, formoterol 9 µg or placebo for 12 months.

Postmedication FEV1improved by 0.21 L and health-related quality of life using the St George's Respiratory Questionnaire (SGRQ) by 4.5 units after run-in. Fewer patients receiving budesonide/formoterol withdrew from the study than those receiving budesonide, formoterol or placebo. Budesonide/formoterol patients had a prolonged time to first exacerbation (254versus96 days) and maintained higher FEV1(99%versus87% of baseline), both primary variablesversusplacebo. They had fewer exacerbations (1.38versus1.80 exacerbations per patient per year), had higher prebronchodilator peak expiratory flow, and showed clinically relevant improvements in SGRQversusplacebo (−7.5 units). Budesonide/formoterol was more effective than either monocomponent in both primary variables.

Budesonide/formoterol in a single inhaler (Symbicort®) maintains the benefit of treatment optimisation, stabilising lung function and delaying exacerbations more effectively than either component drug alone or placebo.
The early allergic response in small airways of human precision-cut lung slices
Authors: Wohlsen A. , Martin C. , Vollmer E. , Branscheid D. , Magnussen H. , Becker W-M. , Lepp U. , Uhlig S.
Published: September 2008

To study the role of small airways in the early allergic response (EAR), the method of human precision-cut lung slices (PCLS) was developed and used to examine the bronchoconstriction elicited by passive sensitisation and allergen provocation.

Viable human PCLS of 250-µm thickness containing airways <1.5 mm in outer diameter were prepared from lung lobes obtained from lung resection and taken into culture. According to the low release of lactate dehydrogenase and the constant ciliary beat frequency, human PCLS were viable for at least 3 days.

Following overnight passive sensitisation with serum from allergic individuals, administration of grass-pollen extract or activating immunoglobulin E antibody resulted in immediate airway contraction that was quantified by videomicroscopy. The extent of the EAR increased with decreasing airway size (outer airway diameter), with the strongest response occurring in the terminal bronchioles.

Histamine receptor antagonism was ineffective, and leukotriene or thromboxane receptor antagonism attenuated the early allergic response only in some cases. However, simultaneous blockade of leukotriene and thromboxane receptors almost completely prevented the early allergic response in the precision-cut lung slices from all individuals, suggesting such a dual treatment as a potential future asthma therapy.
Substance P‐induced pulmonary vascular remodelling in precision cut lung slices
Authors: Springer J. , Fischer A.
Published: September 2008

Substance P (SP) levels have been reported to be elevated in animal models of pulmonary hypertension (PH) and chronic administration of SP has been shown to induce PH. In the present study, the role of reactive oxygen species (ROS) as mediators of SP‐induced vascular remodelling and PH was analysed.

Vascular remodelling was induced in precision cut lung slices by treatment with [Sar9,Met11(O2)]‐SP and by hypoxia. Functional analyses were used to study the chronic [Sar9,Met11(O2)]‐SP‐mediated effects on proliferation and generation of ROS, which is involved in the pathogenesis of PH. The nonpeptide NK‐1 receptor antagonist CP 96345 was used to block [Sar9,Met11(O2)]‐SP effects. ROS generation and proliferation was assayed by the dichloroflourescein­diacetate method and incorporation of 5‐Bromo‐2′‐Deoxyuridine, respectively.

ROS generation was induced by either 1% oxygen (5.8‐fold) or [Sar9,Met11(O2)]‐SP (8‐fold) in normoxia in the alveolar region. [Sar9,Met11(O2)]‐SP did not further elevate ROS levels in hypoxia, suggesting an oxygen­dependent mechanism. High ROS levels stabilised hypoxia inducible factor‐1α and induced proliferation in small vessels (4.3‐fold in hypoxia and [Sar9,Met11(O2)]‐SP). Both ROS generation and proliferation were blocked in the presence of CP 96345, nitroblue­tetrazolium,N‐acetylcysteine‐ and diphenylene­iodonium.

The results presented in this study indicate a role of SP in proliferative events associated with vascular remodelling in pulmonary hypertension.
Upregulated response to chemokines in oxidative metabolism of eosinophils in asthma and allergic rhinitis
Authors: Sannohe S. , Adachi T. , Hamada K. , Honda K. , Yamada Y. , Saito N. , Cui C‐H. , Kayaba H. , Ishikawa K. , Chihara J.
Published: September 2008

Reactive oxygen species (ROS) from eosinophils are known to cause tissue damage in allergic inflammation. CC chemokines, especially eotaxin and regulated on activation, normal T‐cell expressed and secreted (RANTES), are involved not only in chemotaxis but also in eosinophil activation, such as ROS production. It has been shown that eosinophils from allergic patients are not functionally equivalent to those from normal subjects. In the present study, the characteristics of chemokine­primed ROS production in eosinophils from allergic patients and normal controls were compared.

After pretreatment with chemokines, eosinophils were stimulated with calcium ionophore A23187. ROS production by eosinophils was measured using luminol­dependent chemiluminescence.

Both RANTES and eotaxin exhibited a priming effect on calcium ionophore­induced ROS production from eosinophils. Despite there being no difference in expression of CC chemokine receptor 3, the priming effect of RANTES and eotaxin was significantly enhanced in eosinophils from the patients. Interleukin‐5 further enhanced the priming effect of chemokines in eosinophils from normal subjects, but not those from allergic subjects.

The present results suggest an upregulated response to chemokines in eosinophils from allergic patients, and that interleukin‐5 can induce a similar phenotype to that foundin vivoin allergic patients.
Imbalance between vascular endothelial growth factor and endostatin in emphysema
Authors: Kanazawa H. , Hirata K. , Yoshikawa J.
Published: September 2008

Vascular endothelial growth factor (VEGF) stimulates endothelial cell proliferation, and endostatin directly antagonises the biological effects of VEGF. The maintenance of pulmonary endothelial cells is also thought to depend upon the local balance of VEGF and endostatin in the lung. Therefore, this study was designed to determine whether there is an imbalance between VEGF and endostatin levels in patients with pulmonary emphysema.

VEGF and endostatin levels were simultaneously measured from 25 emphysema patients and 12 normal control subjects, and their correlation and balance in induced sputum was evaluated.

VEGF levels in induced sputum were significantly lower in emphysema patients (854±307 pg·mL−1) than in normal controls (1,791±1,192 pg·mL−1). In contrast, there was no significant difference in endostatin levels among the two groups. Therefore, the ratio of VEGF to endostatin levels was markedly lower in emphysema patients (4.5±1.8) than in normal controls (8.1±2.6). Moreover, VEGF levels were correlated with endostatin levels in normal controls but not in emphysema patients. In addition, the ratio of VEGF to endostatin levels was correlated with forced expiratory volume in one second (FEV1), FEV1/forced vital capacity and carbon monoxide diffusing capacity of the lung in emphysema patients.

The findings in this study suggest that there is an imbalance between vascular endothelial growth factor and endostatin levels in induced sputum from emphysema patients.
Passive smoking and respiratory symptoms in the FinEsS Study
Authors: Larsson M.L. , Loit H-M. , Meren M. , Põlluste J. , Magnusson A. , Larsson K. , Lundbäck B.
Published: September 2008

The aim of the present study was to examine the relationship between reported environmental tobacco smoke (ETS) exposure and respiratory symptoms.

In 1996, a postal questionnaire was randomly distributed in three areas of Estonia to a population-based sample, of which 4,995 females and 1,822 males had never smoked. The main outcome measures were current respiratory symptoms and the amount of reported ETS exposure outside the home.

ETS exposure at home was more common in females (31%versus19%), while exposure outside of the home was more common in males (53%versus7%). Females reported more symptoms from tobacco smoke than males (37.7%versus21.6%). If ETS exposure outside of the home exceeded 5 h daily, the risk for wheeze (odds ratio (OR) 2.67, 95% confidence interval (CI) 1.98–3.61) and physician-diagnosed asthma (OR 1.79, 1.02–3.16) were increased. ETS exposure outside of the home was shown to be strongly related to almost all respiratory symptoms in a dose/response manner. ETS exposure at home did not show significantly elevated ORs for any respiratory symptoms.

This study shows that females seem to be more troubled by environmental smoke exposure than males and provides further evidence of the serious health hazards associated with environmental smoke exposure. Indeed, the findings of this study support a ban on smoking in the workplace and public areas.
A method to preserve sputum for delayed examination
Authors: Kelly M.M. , Hargreave F.E. , Cox G.
Published: September 2008

Examination of sputum cell counts is limited by the need to process samples within hours of expectoration. The validity and repeatability of a method to preserve sputum for delayed processing and examination were investigated in this study.

Portions of selected sputum from 39 subjects were dispersed with dithiothreitol (routine method), or were fixed in a dithiothreitol-formaldehyde mixture for 48–72 h before dispersal with trypsin (preservation method). Total and differential cell counts using the two methods were compared; within-method repeatability of the preservation method was also examined.

The intraclass correlation coefficient (ICC) for total cell counts and percentage of eosinophils, neutrophils and macrophages in sputum processed by the two methods was 0.89, 0.86, 0.91 and 0.90, respectively. Within-method repeatability (ICC) of the preservation method for the same cellular indices was 0.99, 0.94, 0.97 and 0.97, respectively. The interobserver repeatability for eosinophils, neutrophils and macrophages was 0.96, 0.97 and 0.97 using the preservation method, and 0.96, 0.99 and 0.99 using the routine method, respectively.

This method of sputum preservation and dispersal is valid, reliable and convenient, and may be used for delayed processing and examination.
Bronchoalveolar lavage alterations during prolonged ventilation of patients without acute lung injury
Authors: Tsangaris I. , Lekka M.E. , Kitsiouli E. , Constantopoulos S. , Nakos G.
Published: September 2008

Mechanical ventilation deteriorates previously injured lung, but little is known about its effect on healthy human lung. This work was designed to assess the effect of prolonged mechanical ventilation on bronchoalveolar lavage (BAL) fluid composition of patients without acute lung injury.

Twenty-two ventilated patients (tidal volume 8–10 mL·kg−1, positive end-expiratory pressure 3–5 cmH2O) without lung injury, who did not develop any complication from the respiratory system during the 2‐week study period, were studied. They were subjected to three consecutive BALs, the first during 36 h from intubation, the second at the end of the first week of mechanical ventilation and the third at the end of the second week of mechanical ventilation.

Total BAL protein increased during mechanical ventilation (148±62, 381±288, 353±215 µg·mL−1BAL for the first, second and third BAL, respectively). In contrast, BAL phospholipids decreased (2.7±1.1, 1.4±0.6, 1.2±0.7 µg·mL−1BAL, respectively). Large surfactant aggregates were reduced and inflammatory markers, such as platelet activating factor (PAF), PAF-acetylhydrolase and neutrophils, significantly increased after 1 week, but partially remitted after 2 weeks of mechanical ventilation.

In summary, this study demonstrates that prolonged mechanical ventilation even of patients without acute lung injury is associated with the presence of inflammatory markers and surfactant alterations.
Exhaled breath condensate pH is a robust and reproducible assay of airway acidity
Authors: Vaughan J. , Ngamtrakulpanit L. , Pajewski T.N. , Turner R. , Nguyen T-A. , Smith A. , Urban P. , Hom S. , Gaston B. , Hunt J.
Published: September 2008

Exhaled breath condensate (EBC) pH is low in several lung diseases and it normalises with therapy.

The current study examined factors relevant to EBC pH monitoring. Intraday and intraweek variability were studied in 76 subjects. The pH of EBC collected orally and from isolated lower airways was compared in an additional 32 subjects. Effects of ventilatory pattern (hyperventilation/hypoventilation), airway obstruction after methacholine, temperature (−44 to +13°C) and duration of collection (2–7 min), and duration of sample storage (up to 2 yrs) were examined. All samples were collected with a disposable condensing device, and de-aerated with argon until pH measurement stabilised.

Mean EBC pH (n=76 subjects, total samples=741) was 7.7±0.49 (mean±sd). Mean intraweek and intraday coefficients of variation were 4.5% and 3.5%. Control of EBC pH appears to be at the level of the lower airway. Temperature of collection, duration of collection and storage, acute airway obstruction, subject age, saliva pH, and profound hyperventilation and hypoventilation had no effect on EBC pH.

The current authors conclude that in health, exhaled breath condensate pH is slightly alkaline, held in a narrow range, and is controlled by lower airway source fluid. Measurement of exhaled breath condensate pH is a simple, robust, reproducible and relevant marker of disease.