Contrasting effects of ATP and adenosine on capsaicin challenge in asthmatic patients.

Background: Adenosine 5'-triphosphate (ATP) stimulates pulmonary vagal slow conducting C-fibres and fast conducting Aδ-fibres with rapidly adapting receptors (RARs). Pulmonary C-fibres but not RARs are also sensitive to capsaicin, a potent tussigenic agent in humans. Thus, the aim of this study was to determine the effects of ATP and its metabolite adenosine (given as adenosine 5'-monophosphate, AMP) on capsaicin challenge in asthmatic patients.

Effects of Aerosolized Adenosine 5'-Triphosphate in Smokers and Patients With COPD.

Background: Extracellular adenosine 5'-triphosphate (ATP) stimulates vagal C and Aδ fibers in the lung, resulting in pronounced bronchoconstriction and cough mediated by P2X2/3 receptors located on vagal sensory nerve terminals. We investigated the effects of nebulized ATP on cough and symptoms in control subjects, healthy smokers, and patients with COPD and compared these responses to the effects of inhaled adenosine, the metabolite of ATP.

Methods: We studied the effects of inhaled ATP and adenosine monophosphate (AMP) on airway caliber, perception of dyspnea assessed by the Borg score, cough sensitivity, and ATP in exhaled breath condensate in healthy nonsmokers (n = 10), healthy smokers (n = 14), and patients with COPD (n = 7).

A novel approach to partition central and peripheral airway nitric oxide.

Background: Determining the site of airways inflammation may lead to the targeting of therapy. Nitric oxide (NO) is a biomarker of airway inflammation and can be measured at multiple exhalation flow rates to allow partitioning into bronchial (large/central airway maximal nitric oxide flux [J'awno]) and peripheral (peripheral/small airway/alveolar nitric oxide concentration [Cano]) airway contributions by linear regression. This requires a minimum of three exhalations.

Standardised exhaled breath collection for the measurement of exhaled volatile organic compounds by proton transfer reaction mass spectrometry.

Background: Exhaled breath volatile organic compound (VOC) analysis for airway disease monitoring is promising. However, contrary to nitric oxide the method for exhaled breath collection has not yet been standardized and the effects of expiratory flow and breath-hold have not been sufficiently studied. These manoeuvres may also reveal the origin of exhaled compounds.

Comparison of Symbicort® versus Pulmicort® on steroid pharmacodynamic markers in asthma patients.

Background: Combination therapy with inhaled corticosteroids (ICS) and long-acting β(2)-adrenergic agonists (LABA) is reported to have superior effects on controlling asthma symptoms to ICS alone; however, there is no molecular-based evidence to explain the clinical effects. Here, the effect of the ICS/LABA combination was compared with ICS on glucocorticoid receptor (GR) activation in sputum macrophages.

Methods: In a randomised, double-blind cross-over placebo-controlled 6-visit study, 10 patients with mild asthma were given placebo, formoterol (Oxis(®) 12 μg), budesonide (Pulmicort(®) 200 μg :BUD200, or 800 μg :BUD800), or budesonide/formoterol combination (Symbicort(®)) as a single 100/6 μg (SYM100) or double 200/12 μg (SYM200) dose.

Assessment of reproducibility of exhaled hydrogen peroxide concentration and the effect of breathing pattern in healthy subjects.

Background: Hydrogen peroxide (H2O2) is detectable in exhaled breath condensate (EBC) and has been proposed to be a surrogate marker of oxidative stress in the airways. In this study we tested whether the breathing pattern during EBC collection influences the concentration of exhaled H2O2.

Methods: EBC was collected during (1) tidal breathing and (2) breathing with increased tidal volume for 10 min from 16 healthy volunteers.

Inflammatory markers: exhaled nitric oxide and carbon monoxide during the ovarian cycle.

Nitric oxide (NO) production and carbon monoxide (CO) production are increased in inflammatory lung diseases. Although there are some pieces of evidence for hormonal modulation by estrogen, little is known about exhaled NO and CO during the ovarian cycle. In 23 subjects, we measured exhaled NO and CO by an online analyzer.

Osteoprotegerin in sputum is a potential biomarker in COPD.

Background: COPD is characterized by chronic airflow limitation and inflammation of the respiratory tract. Several inflammatory biomarkers have been evaluated in COPD but are poorly related to disease severity and progression. Osteoprotegerin (OPG) is a glycoprotein mediator that is expressed in the lung and macrophages, so we have studied its concentration in induced sputum and macrophages of patients with COPD.

Nitric oxide synthase isoenzyme expression and activity in peripheral lung tissue of patients with chronic obstructive pulmonary disease.

Rationale: Nitric oxide (NO) is increased in the lung periphery of patients with chronic obstructive pulmonary disease (COPD). However, expression of the NO synthase(s) responsible for elevated NO has not been identified in the peripheral lung tissue of patients with COPD of varying severity.

Methods: Protein and mRNA expression of nitric oxide synthase type I (neuronal NOS [nNOS]), type II (inducible NOS [iNOS]), and type III (endothelial NOS [eNOS]) were quantified by Western blotting and reverse transcription-polymerase chain reaction, respectively, in specimens of surgically resected lung tissue from nonsmoker control subjects, patients with COPD of varying severity, and smokers without COPD, and in a lung epithelial cell line (A549).

Effects of aminoguanidine, an inhibitor of inducible nitric oxide synthase, on nitric oxide production and its metabolites in healthy control subjects, healthy smokers, and COPD patients.

Background: Nitric oxide (NO) is produced by resident and inflammatory cells in the respiratory tract by the enzyme NO synthase (NOS), which exists in three isoforms: neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS. NO production is increased in patients with COPD, and the production of NO under oxidative stress conditions generates reactive nitrogen species that may amplify the inflammatory response in COPD.

Methods: To examine the role of increased NO in COPD, we administered a relatively selective iNOS inhibitor, aminoguanidine, by nebulization in a double-blind, placebo-controlled study in COPD patients, healthy smokers, and healthy nonsmoking subjects.

Airway responsiveness and inflammation in adolescent elite swimmers.

Background: Whereas increased airway hyperresponsiveness (AHR) and airway inflammation are well documented in adult elite athletes, it remains uncertain whether the same airway changes are present in adolescents involved in elite sport.

Objective: To investigate airway responsiveness and airway inflammation in adolescent elite swimmers.

Methods: We performed a cross-sectional study on adolescent elite swimmers (n = 33) and 2 control groups: unselected adolescents (n = 35) and adolescents with asthma (n = 32).

Lipopolysaccharide challenge of humans as a model for chronic obstructive lung disease exacerbations.

Endotoxin, or lipopolysaccharide (LPS), is a constituent of the outer cell membrane of Gram-negative bacteria. LPS is a highly potent proinflammatory substance, that, when inhaled, dose-dependently causes fever, chills, and bronchoconstriction. These symptoms are accompanied by a proinflammatory response in sputum and bronchoalveolar lavage fluid with elevation of neutrophils, macrophages and certain cytokines/chemokines.

Loss of control of asthma following inhaled corticosteroid withdrawal is associated with increased sputum interleukin-8 and neutrophils.

Background: The role of neutrophils in exacerbations of asthma is poorly understood. We examined the effect of withdrawal of inhaled corticosteroids on sputum inflammatory indexes in a double-blind study in patients with moderate, stable asthma.

Methods: Following a 2-week run in period, 24 subjects were randomized to receive either budesonide (400 microg bid) or placebo, and the study was continued for another 10 weeks.

Effect of an inducible nitric oxide synthase inhibitor on differential flow-exhaled nitric oxide in asthmatic patients and healthy volunteers.

Nitric oxide (NO) is produced by a variety of cells within the respiratory tract, particularly airway epithelial cells, and its increased concentration in asthma is likely to derive from inducible NO synthase (iNOS) expressed in inflamed airways. To evaluate whether an increased bronchial flux of NO (ie, airway wall NO flux [Jno] in picoliters per second) produced in the large airways is due to an enzyme overexpression, we administered a relatively selective iNOS inhibitor, aminoguanidine, by nebulization in a double-blind, placebo-controlled manner in asthmatic and healthy subjects and also investigated whether the same concentration of inhibitor has any effect on NO produced in the peripheral lungs (ie, alveolar NO concentration [Calv] in parts per billion [ppb]) or on the diffusing capacity of NO (Dno) [in picoliters per second(-1) per ppb(-1)) in the airways. Aminoguanidine administration resulted in a significant reduction in Jno compared with administration of the saline solution control in eight healthy subjects and in eight patients with asthma but caused no significant changes in Calv or in Dno in either group.

Differential flow analysis of exhaled nitric oxide in patients with asthma of differing severity.

Background: The majority of asthmatic patients achieve control of their illness; others do not. It is therefore crucial to validate/develop strategies that help the clinician monitor the disease, improving the response to treatment.

Methods: We have quantified the inflammation in central and peripheral airways by measuring exhaled nitric oxide (NO) at multiple exhalation flows in 56 asthmatics at different levels of severity (mild, n = 10; moderate stable, n = 17; moderate during exacerbation, n = 11; severe, n = 18, 7 of whom were receiving oral corticosteroids) and 18 healthy control subjects.

Normal bronchial blood flow in COPD is unaffected by inhaled corticosteroids and correlates with exhaled nitric oxide.

Background: In COPD patients, there is reduced vascularity and inflammation of the bronchi, which may have opposite effects on bronchial blood flow (QAW). We studied the relationship of QAW with the fraction of exhaled nitric oxide (FENO), which is a potent vasodilator. We also investigated the vascular response to budesonide and a beta(2)-agonist.

Exhaled biomarkers.

Assessing airway and lung inflammation is important for investigating the underlying mechanisms of asthma and COPD. Yet these cannot be measured directly in clinical research and practice because of the difficulties in monitoring inflammation. Noninvasive monitoring may assist in early recognition of asthma and COPD, assessment of its severity, and response to treatment, especially during disease exacerbations.

Measurement of bronchial and alveolar nitric oxide production in normal children and children with asthma.

Rationale: Airway inflammation is characteristic of asthma. Distal inflammation may be particularly important.

Objective: To calculate alveolar nitric oxide (NO) concentration (C(alv)) and bronchial flux NO (J(NO)) in children.

Exhaled breath condensate cysteinyl leukotrienes and airway remodeling in childhood asthma: a pilot study.

Background: It has been suggested that cysteinyl leukotrienes (cysLTs) play an important role in airway remodeling. Previous reports have indicated that cysLTs augment human airway smooth muscle cell proliferation. Recently, cysLTs have been measured in exhaled breath condensate (EBC).

Pulmonary biomarkers in chronic obstructive pulmonary disease.

There has been increasing interest in using pulmonary biomarkers to understand and monitor the inflammation in the respiratory tract of patients with chronic obstructive pulmonary disease (COPD). In this Pulmonary Perspective we discuss the merits of the various approaches by reviewing the current literature on pulmonary biomarkers in COPD and underscore the need for more systematic studies in the future. Bronchial biopsies and bronchoalveolar lavage provide valuable information about inflammatory cells and mediators, but are invasive, so that repeated measurements have to be very limited in assessing any interventions.

Effect of montelukast on exhaled leukotrienes and quality of life in asthmatic patients.

Study Objectives: In some patients with asthma treated with inhaled corticosteroids, suppression of inflammation is incomplete. This may be because the effect of corticosteroids on cysteinyl-leukotriene (cys-LT) biosynthesis is limited. Montelukast is a cys-LT antagonist that significantly improves asthma control in corticosteroid-treated asthmatic patients.

Formoterol attenuates neutrophilic airway inflammation in asthma.

Study Objectives: Airway neutrophil levels are increased in patients with severe asthma and during asthma exacerbations. Long-acting beta2-agonists (LABAs), such as formoterol, reduce the number of asthma exacerbations. While beta2-agonists may affect neutrophil function in vitro, it is uncertain whether they have effects on neutrophilic inflammation in asthmatic patients in vivo.

Effects of aerosolized adenosine 5'-triphosphate vs adenosine 5'-monophosphate on dyspnea and airway caliber in healthy nonsmokers and patients with asthma.

Study Objectives: Extracellular adenosine 5'-triphosphate (ATP) causes neurogenic bronchoconstriction, inflammation, and coughs, and may play a mechanistic role in obstructive airway diseases. The aims of this study were to determine the effects of inhaled ATP on airway function, and to compare these effects with those of adenosine 5'-monophosphate (AMP).

Design: Prospective, randomized, double-blind study.

Influence of different therapeutic strategies on exhaled NO and lung inflammation in asthma and COPD.

Nitric oxide (NO), a simple free radical gas, elicits a diverse range of physiological and pathophysiological effects, and plays an important role in pulmonary diseases. Nitrosative stress and nitration of proteins in airway epithelium maybe responsible for steroid resistance in asthma and their ineffectiveness in chronic obstructive pulmonary disease (COPD), supporting the potential role of future therapeutic strategies aimed at regulating NO synthesis in asthma and COPD. Here, we have reviewed the potential role of NO modulators (NO synthase inhibitors and NO donors), which if given on a regular basis may have clinical benefit in asthma and COPD.