The clinical and integrated management of COPD.

COPD is a chronic pathological condition of the respiratory system characterized by persistent and partially reversible airflow obstruction, to which variably contribute remodeling of bronchi (chronic bronchitis), bronchioles (small airway disease) and lung parenchyma (pulmonary emphysema). COPD can cause important systemic effects and be associated with complications and comorbidities. The diagnosis of COPD is based on the presence of respiratory symptoms and/or a history of exposure to risk factors, and the demonstration of airflow obstruction by spirometry. GARD of WHO has defined COPD "a preventable and treatable disease". The integration among general practitioner, chest physician as well as other specialists, whenever required, assures the best management of the COPD person, when specific targets to be achieved are well defined in a diagnostic and therapeutic route, previously designed and shared with appropriateness. The first-line pharmacologic treatment of COPD is represented by inhaled long-acting bronchodilators. In symptomatic patients, with pre-bronchodilator FEV1 < 60%predicted and ≥ 2 exacerbations/year, ICS may be added to LABA. The use of fixed-dose, single-inhaler combination may improve the adherence to treatment. Long term oxygen therapy (LTOT) is indicated in stable patients, at rest while receiving the best possible treatment, and exhibiting a PaO2 ≤ 55 mmHg (SO2<88%) or PaO2 values between 56 and 59 mmHg (SO2 < 89%) associated with pulmonary arterial hypertension, cor pulmonale, or edema of the lower limbs or hematocrit > 55%. Respiratory rehabilitation is addressed to patients with chronic respiratory disease in all stages of severity who report symptoms and limitation of their daily activity. It must be integrated in an individual patient tailored treatment as it improves dyspnea, exercise performance, and quality of life. Acute exacerbation of COPD is a sudden worsening of usual symptoms in a person with COPD, over and beyond normal daily variability that requires treatment modification. The pharmacologic therapy can be applied at home and includes the administration of drugs used during the stable phase by increasing the dose or modifying the route, and adding, whenever required, drugs as antibiotics or systemic corticosteroids. In case of patients who because of COPD severity and/or of exacerbations do not respond promptly to treatment at home hospital admission should be considered. Patients with "severe or "very severe COPD who experience exacerbations should be carried out in respiratory unit, based on the severity of acute respiratory failure. An integrated system is required in the community in order to ensure adequate treatments also outside acute care hospital settings and rehabilitation centers. This article is being simultaneusly published in Multidisciplinary Respiratory Medicine 2014; 9:25.

Non-occupational malignant pleural mesothelioma due to asbestos and non-asbestos fibres.

BACKGROUND AND AIM: The occurrence of malignant pleural mesothelioma (MPM) has been reported among population groups with no documented professional exposure to asbestos fibres living in different geographic areas. This paper reviews existing data related to non occupational MPM including its occurrence in the province of Catania (Sicily, Italy). METHODS: An electronic search of literature related to non occupational MPM was performed including the year 2005. RESULTS: Non occupational MPM in subjects living in areas contaminated by a variety of asbestos and non asbestos fibres has been well documented through a number of epidemiologic studies including cases series, case-control studies, and a cohort study. In addition, the observation of familial clustering of MPM, suggests that genetic factors may play a role in the pathogenesis of this malignancy. The epidemiological evidence also suggests that MPM may occur as a result of the interaction between environmental carcinogens, genetic factors, and virus infection. CONCLUSION: It is likely that genetic predisposition and non-occupational exposure to low doses of asbestos and asbestos-like fibres may concur to the development of malignant mesothelioma. However, additional epidemiological and laboratory studies are needed to further understand the relationship between environmental exposure and individual susceptibility to this malignancy.

Sleep-related hypoxaemia and excessive erythrocytosis in Andean high-altitude natives.

To determine whether nocturnal hypoxaemia contributes to the excessive erythrocytosis (EE) in Andean natives, standard polysomnographies were performed in 10 patients with EE and in 10 controls (mean haematocrit 76.6 +/- 1.3% and 5.4 +/- 0.8%, respectively) living at an altitude of 4,380 m. In addition, the effect of O2 administration for 1 h prior to sleep, and the relationship between the hypoxic/hypercapnic ventilatory response and the apnoea/hypopnoea index (AHI) during sleep were studied. Awake arterial oxygen saturation (Sa,O2) was significantly lower in patients with EE than in controls (83.7 +/- 0.3% versus 85.6 +/- 0.4%). In both groups, the mean Sa,O2 significantly decreased during sleep (to 80.0 +/- 0.8% in EE and to 82.8 +/- 0.5% in controls). The mean Sa,O2 values remained significantly lower in patients with EE than in controls at all times of the night, and patients with EE spent significantly more time than the controls with an Sa,O2 of <80%. There were no differences between the two groups in the number and duration of the apnoeas/hypopnoeas. None of these variables were affected by O2 administration. In both groups the AHI positively correlated with the hypercapnic ventilatory response. Andean natives undergo minor respiratory disorders during sleep. The reduction in oxygen saturation found in subjects with excessive erythrocytosis was small, yet consistent and potentially important, as it remained below the threshold known for the increase in erythropoietin stimulation. This may be an important factor promoting erythropoiesis, but its relevance needs to be further explored.

The effect of inhaled furosemide and acetazolamide on bronchoconstriction induced by deep inspiration in asthma.

In some asthmatics deep inspiration causes a sustained bronchoconstration, which is dependent on Ca2+ uptake. Inhaled diuretics protect against bronchoconstriction induced by a variety of indirect stimuli, by inhibiting the ionic fluxes involving Ca2+ uptake across the cell membrane of airway epithelium. The aim of this study was therefore to investigate the protective effect of inhaled furosemide on the bronchoconstriction induced by deep inspiration in asthma and to compare it with the effect of acetazolamide, an inhibitor of carbonic anhydrase devoid of effect on ion cotransport but possessing inhibitory effects on chloride ion influx and Na+/K+ exchange. The study was carried out on three different study days according to a randomized, double-blind, placebo-controlled, crossover design. Nine non smoking asthmatic subjects first performed a series of 9 controlled deep inspirations to TLC followed by forced expirations to RV within 20 min, which caused a decrease of FEV1 > 20% from baseline. Two hours later, the subjects inhaled either furosemide (40 mg), or acetazolamide (500 mg), or saline (placebo) in random order, and then two more deep-inspiration challenges were performed after 30 and 140 mins. The progressive percent decrement of FEV1 caused by deep-inspiration challenge was taken as an index of bronchoconstriction. Bronchoconstriction was significantly blunted at 30 mins, but not 140 mins, after inhaling furosemide (p < 0.01) or acetazolamide (p < 0.05) compared to control. We interpret these results as due to a modulation of ionic fluxes across the smooth muscle cell membrane afforded by inhaled furosemide and acetazolamide.

The protective role of epithelium-derived nitric oxide in isolated bovine trachea.

Airway epithelial cells from bovine airways can release relaxant factors such as nitric oxide (NO) and prostaglandin E(2) and the removal of airway epithelium results in an increased responsiveness of smooth muscle to spasmogen stimuli. In this study, we assessed whether or not epithelial NO modulates the contractile response of bovine trachea in vitro.Cumulative concentration-response curves to acetylcholine (ACh), histamine (Hist) and 5-hydroxytryptamine (5-HT) were obtained in both intact and epithelium denuded tracheal strips in the presence of indomethacin (10 microM).In intact, but not in epithelium denuded strips, preincubation with the NO synthase inhibitor L-N((G))-Nitro-arginine methyl ester (L-NAME), but not with D-NAME, shifted to the left the concentration-response curve to ACh (pD(2) values in the absence and in the presence of L-NAME were 3.47+/-0.1 and 4.60+/-0.1, respectively; P<0.05) and to Hist (pD(2) in the absence and in the presence of L-NAME: 3.89+/-0.1 and 4.54+/-0.1, respectively; P<0.05). This effect was reversed by L-arginine (1mM), but not by D-arginine. The contractile response to 5-HT was not affected by L-NAME in either intact or epithelium denuded strips. These data suggest that NO is an epithelial relaxant factor modulating airway cholinergic and histaminergic contraction of bovine trachea and that the activation of the epithelial NO synthase is a mediator-specific process.

Making, disseminating and using clinical guidelines.

Clinical guidelines are statements designed to help physicians make decisions about appropriate health care for specific circumstances. The constant rise in the number of published guidelines has been accelerated by the need of healthcare organizations to integrate evidence from clinical research with rational health policy, with the prospect of improving the quality and reducing the costs of health care at a local level. The best guidelines are developed from a systematic examination and appraisal of good evidence from well conducted trials, supported by appropriate clinical expertise, and leading to unambiguous recommendations. Great care needs to be taken both to maximize the validity of guidelines and to ensure their use within clinical practice. Moreover, the evidence on which clinical guidelines are based can change with time and therefore they should be reviewed regularly. The critical approaches to making high-quality guidelines, the value of implementation strategies, and how healthcare organizations and individual physicians can use medical guidelines to enhance clinical effectiveness will be discussed.

Effect of 8-iso-prostaglandin F(2 alpha) on acetylcholine release from parasympathetic nerves in guinea pig airways.

8-Iso-prostaglandin F(2 alpha) is present in increased amounts in airway inflammation. 8-Iso-prostaglandin F(2 alpha) constricts the airways via the activation of thromboxane A(2) receptors. However, thromboxane A(2) receptors are also present pre-junctionally on cholinergic nerve terminals innervating guinea pig trachea. We have demonstrated that 8-iso-prostaglandin F(2 alpha) inhibited electrical field stimulation-evoked [3H]acetylcholine release in a concentration-dependent manner, an effect that was not inhibited by the selective thromboxane A(2) receptor antagonist 4(Z)-6-[(2,4,5 cis)2-(2-chlorophenyl)-4-(2-hydroxyphenyl)1,3-dioxan-5-yl]hexenoic acid (ICI 192,605). These data suggest that 8-iso-prostaglandin F(2 alpha) inhibits acetylcholine release through a receptor distinct from the thromboxane A(2) receptor and provides evidence that isoprostanes may have a 'dual' role as both beneficial and deleterious mediators in airway disease.

Role of endogenous nitric oxide in asthma.

Endogenous nitric oxide (NO) is an ubiquitous signaling molecule with important regulatory functions such as regulation of blood pressure, neurotransmission, and host and immune defense. In the respiratory tract, NO is formed and released by various sources including endothelial and epithelial cells, nerves, airway smooth muscle, and inflammatory cells. Recent evidence suggests that endogenous NO is the neurotransmitter of the nonadrenergic noncholinergic inhibitory (iNANC) system, the only bronchorelaxant neural pathway of human airways. A number of studies also suggest that in some species epithelium-derived NO accounts for the functional bronchoprotective role of the so-called epithelium-derived relaxing factor. In human airways, endogenous NO counteracts the bronchoconstriction induced by pharmacologic stimuli such as bradykinin, histamine, and methacholine. On the basis of these and other observations, it is suggested that a reduced synthesis and/or activity of endogenous NO may contribute to the pathogenesis of airway hyperresponsiveness that characterizes asthma and other respiratory disorders. This short paper summarizes the activities of endogenous NO in the airways of experimental animals and man, and discusses the evidence supporting the view that NO confers bronchoprotection.

Bronchoconstriction induced by citric acid inhalation in guinea pigs: role of tachykinins, bradykinin, and nitric oxide.

Gastroesophageal acid reflux into the airways can trigger asthma attacks. Indeed, citric acid inhalation causes bronchoconstriction in guinea pigs, but the mechanism of this effect has not been fully clarified. We investigated the role of tachykinins, bradykinin, and nitric oxide (NO) on the citric acid- induced bronchoconstriction in anesthetized and artificially ventilated guinea pigs. Citric acid inhalation (2-20 breaths) caused a dose-dependent increase in total pulmonary resistance (RL). RL value obtained after 10 breaths of citric acid inhalation was not significantly different from the value obtained after 20 breaths (p = 0.22). The effect produced by a half-submaximum dose of citric acid (5 breaths) was halved by the bradykinin B2 receptor antagonist HOE 140 (0.1 micromol x kg-1, intravenous) and abolished by the tachykinin NK2 receptor antagonist SR 48968 (0.3 micromol x kg-1, intravenous). Bronchoconstriction induced by a submaximum dose of citric acid (10 breaths) was partially reduced by the administration of HOE 140, SR 48968, or the NK1 receptor antagonist CP-99,994 (8 micromol x kg-1, intravenous) alone and completely abolished by the combination of SR 48968 and CP-99,994. Pretreatment with the NO synthase inhibitor, L-NMMA (1 mM, 10 breaths every 5 min for 30 min) increased in an L-arginine-dependent manner the effect of citric acid inhalation on RL. HOE 140 and CP-99,994 markedly reduced the L-NMMA-potentiated bronchoconstriction to inhaled citric acid. We conclude that citric acid-induced bronchoconstriction is caused by tachykinin release from sensory nerves, which, in part, is mediated by endogenously released bradykinin. Simultaneous release of NO by citric acid inhalation counteracts tachykinin-mediated bronchoconstriction. Our study suggests a possible implication of these mechanisms in asthma associated with gastroesophageal acid reflux and a potential therapeutic role of tachykinin and bradykinin antagonists.

The relationship between cardiac output and posthyperventilation hyperpnoea in patients with essential hypertension.

Posthyperventilation hyperpnoea (PHVH) is the progressive decline in minute ventilation (V'E) that follows abrupt cessation of voluntary hyperventilation. It has been hypothesized that the increase in cardiac output (CO) during hyperventilation could contribute to the duration of PHVH. This hypothesis was tested by measuring the duration of PHVH in patients with essential hypertension, in whom the increase in CO as a result of various stimuli is less pronounced. Twenty male hypertensives (mean arterial blood pressure+/-SEM: 178/ 107+/-3/1 mmHg), and 12 age-matched male healthy subjects were studied. The study consisted of three periods: control (5 min), voluntary hyperventilation (2 min), and recovery (3 min). V'E, CO, end-tidal CO2 and O2 tensions were measured, and the time constant (tau) of the V'E decay during recovery calculated. The V'E decay was faster in hypertensives (tau: 0-8.4 s) than in healthy subjects (tau: 12-59 s; p<0.01). During voluntary hyperventilation, CO increased to a lesser extent in hypertensives (6.8+0.7 L.min(-1)) than in healthy subjects (12.9+/-1.1 L.min(-1); p<0.01). In hypertensives, changes in CO during voluntary hyperventilation were significantly related to tau (r=0.646; n=20; p=0.002). The less pronounced rise in cardiac output during hyperventilation in hypertensives could account for the shorter duration of posthyperventilation hyperpnoea.

Regulation of airway neurogenic inflammation by neutral endopeptidase.

Airway neurogenic inflammation is caused by tachykinins released from peripheral nerve endings of sensory neurons within the airways, and is characterized by plasma protein extravasation, airway smooth muscle contraction and increased secretion of mucus. Tachykinins are degraded and inactivated by neutral endopeptidase (NEP), a membrane-bound metallopeptidase, which is located mainly at the surface of airway epithelial cells, but is also present in airway smooth muscle cells, submucosal gland cells and fibroblasts. The key role of NEP in limiting and regulating the neurogenic inflammation provoked by different stimuli has been demonstrated in a large series of studies published in recent years. It has also been shown that a variety of factors, which are relevant for airway diseases, including viral infections, allergen exposure, inhalation of cigarette smoke and other respiratory irritants, is able to reduce NEP activity, thus enhancing the effects of tachykinins within the airways. On the basis of these observations, the reduction of neutral endopeptidase activity may be regarded as a factor that switches neurogenic airway responses from their physiological and protective functions to a detrimental role that increases and perpetuates airway inflammation. However, further studies are needed to assess the role of neutral endopeptidase down regulation in the pathogenesis of asthma and other inflammatory airway diseases.

Increased prevalence of cardiac arrhythmias and transient episodes of myocardial ischemia in hypertensives with left ventricular hypertrophy but without clinical history of coronary heart disease.

To evaluate the behavior of cardiac arrhythmias (CA) and transient episodes of myocardial ischemia (TEMI), in relation to the circadian pattern of blood pressure in patients suffering from arterial hypertension, with or without echocardiographically ascertained left ventricular hypertrophy (LVH), we studied 128 patients, 87 men (M) and 41 women (F), aging from 21 to 76 years, subdivided into two groups: Group I, including 66 patients with LVH (45 M and 21 F; mean age of 53.7 +/- 9.1 years; Group II, including 62 patients without LVH (42 M and 20 F; mean age of 49.7 +/- 9.5 years). Office blood pressure (OBP) as well as nighttime ambulatory blood pressure (ABP) were higher in patients with LVH (P < .05 and P < .01). CA were present in a higher number of patients of Group I (P < .001): premature supraventricular beats (PSVB) 22.7 v 4.8%, supraventricular couplets (SVC) 36.4 v 16.1%, supraventricular tachycardia runs (SVT runs) 27.3 v 12.9%, ventricular ectopic beats (VEB) 25.6 v 8.0%, ventricular couplets (VC) 30.3 v 12.9%, ventricular tachycardia runs (VT runs) 12.1 v 3.2%. The absolute number of ectopic beats was also significantly higher in patients of Group I. Ventricular arrhythmias were significantly related to ASBP (r = 0.83, P < .01), to ADBP (r = 0.74, P < .01) and to heart rate (r = 0.87, P < .01) in patients of Group I. TEMI were more frequent in patients of Group I (73 v 41 episodes, 39.39% v 25.8% of patients, P < .01) and were related to ABP peaks. In fact, in both groups of patients all TEMI without heart rate increase and most TEMI with heart rate increase were registered between 6:00 and midnight, hours in which ABP values were higher. We conclude that hypertensives with LVH, but without clinical history of coronary heart disease, have a higher prevalence of ventricular arrhythmias and of transient episodes of myocardial ischemia in relation to the circadian pattern of ABP.

Randomised double-blind placebo-controlled study of the effect of inhibition of nitric oxide synthesis in bradykinin-induced asthma.

BACKGROUND: Bronchoconstriction induced by bradykinin is reduced by the release of nitric oxide (NO) in the airways of guinea pigs. Inhaled NO is known to cause bronchodilatation in asthmatic patients. To find out the role of endogenous NO in airway response to bradykinin in asthma, we examined the effect of the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) on broncho-constriction after bradykinin challenge in ten patients with mild asthma. METHODS: The study had a randomised, double-blind, placebo-controlled, cross-over design. Participants were studied during two phases, each consisting of 2 study days. After baseline measurements of forced expiratory volume in 1 s (FEV1) participants inhaled an aerosol of L-NMMA or saline (placebo). After 5 min, saline and doubling doses of bradykinin (from 0.25 nmol) were inhaled until FEV1 fell by at least 20% of the post-saline value. The effect of L-NMMA and placebo on airway response to doubling concentrations of methacholine (from 0.03 mg/mL) was then examined. We also assessed the effect of the inactive enantiomer of L-NMMA, D-NMMA, and placebo on bronchoconstriction after bradykinin or methacholine challenge in six of the participants. FINDINGS: The geometric mean of the provocative dose producing a 20% fall in FEV1 to bradykinin was 138.0 nmol (range 48.2-475.2 nmol) after placebo and 11.2 nmol (range 0.9-51.3 nmol) after L-NMMA (p < 0.01). L-NMMA also caused a decrease in the provocative concentration of methacholine producing a 20% fall in FEV1 from 0.93 mg/mL (range 0.12-2.55 mg/mL) to 0.38 mg/mL (range 0.06-0.92 mg/mL; p < 0.01). In contrast, D-NMMA did not affect airway response to bradykinin or methacholine. INTERPRETATION: The results suggest that bronchoconstriction after bradykinin inhalation is greatly inhibited by the formation of NO in airways of asthmatic patients and that NO could have a bronchoprotective role in asthma.

Neutral endopeptidase inhibitor thiorphan increases airway narrowing to inhaled sodium metabisulfite in normal subjects.

Possible mechanisms involved in inhaled sodium metabisulfite (MBS)-induced bronchoconstriction include cholinergic reflex and release of tachykinins from sensory nerve endings. Tachykinins are potent bronchoconstrictors cleaved and inactivated by neutral endopeptidase (NEP) in the airways. To investigate the role of tachykinins in airway response to MBS, we assessed the effect of NEP-inhibitor thiorphan on airway response to MBS in nine nonatopic, nonasthmatic subjects. Two inhalational challenges with doubling doses of MBS (0.03 to 16 mumol) were performed 3 d apart. Ten minutes before MBS challenge, subjects randomly inhaled either thiorphan (1.25 mg) or placebo according to a double-blind cross-over design. Airflow at 30% of vital capacity (V30p) from partial expiratory flow-volume curves was measured at baseline, 10 min after thiorphan or placebo, and 2 min after each MBS dose. The dose of MBS causing 40% fall in V30p (PD40V30p) was calculated. Neither thiorphan nor placebo affected baseline airway caliber. Thiorphan caused a leftward shift of the dose-response curve to MBS. After placebo a measurable PD40V30p was obtained in four of nine subjects. In these subjects PD40V30p fell significantly after thiorphan inhalation. Four of five subjects who did not exhibit PD40V30p after placebo showed measurable PD40V30p after thiorphan. Percent fall in V30p caused by highest dose of MBS was significantly greater after thiorphan compared with placebo (55.9 +/- 4.6% versus 30.8 +/- 5.6%; mean +/- SE; p < 0.001). Results of this study demonstrate that the NEP-inhibitor thiorphan increases MBS-induced bronchoconstriction in normal subjects, suggesting that tachykinins are involved in airway responses to inhaled MBS.

Inhaled platelet-activating factor increases airway sensitivity but not maximal airway narrowing to methacholine in normal subjects.

To examine the effect of inhaled platelet-activating factor (PAF) on airway sensitivity and on maximal airway narrowing, we measured airway response to doubling concentrations of methacholine (MCh) 48 h before and 48 h after inhalation of 10, 50 and 100 micrograms of PAF in six nonatopic, nonasthmatic subjects. The forced expiratory volume in one second (FEV1) and airflow at 30 percent of vital capacity (V30) from partial forced expiration were used to assess changes in airway calibre. Inhalation of PAF caused only minor changes in FEV1. In contrast, inhalation of 100 micrograms of PAF caused a significant fall in V30 from 2.64 +/- 0.35 to 1.35 +/- 0.43 l.min-1 (p < 0.05). Two days after PAF inhalation a leftward shift of the concentration-response curve to MCh was observed. The MCh concentration causing a 20% fall in FEV1 (PC20FEV1) was 11.25 +/- 1.78 and 2.38 +/- 1.29 mg.ml-1 (geometric mean +/- GSEM; p < 0.05) before and after PAF inhalation, respectively. PAF did not affect the maximal airway response to MCh. The maximum percentage fall in FEV1 was 36.2 +/- 1.9% at baseline and 37.6 +/- 1.8% after PAF inhalation. Likewise, maximum percentage change in V30 was 72.8 +/- 3.7% at baseline and 73.6 +/- 3.4% after PAF inhalation. The results of this study show that PAF inhalation increases airway sensitivity without altering the maximal bronchoconstrictive response to MCh in normal subjects.

Cyclooxygenase products mediate the cutaneous vasodilation induced by endothelin-1 in humans.

Intradermal injection of endothelin-1 (ET-1) causes vasoconstriction (pallor) at the injection site, surrounded by a larger area of vasodilation (flare) in humans. Some of the vasomotor responses to ET-1 are thought to be mediated by prostaglandins. In the present study, we investigated the involvement of cyclooxygenase-derived products of arachidonic acid metabolism on the cutaneous vasomotor responses to ET-1. Ten normal subjects (25-44 years) were studied after treatment with either indomethacin (50 mg t.i.d.) or placebo according to a double blind cross-over design. Five doses of ET-1 (5 x 10(-5) to 5 x 10(-1) pmol) were injected intradermally 2 h after the last dose of indomethacin or placebo. Pallor and flare areas measured by planimetry 15 min after the injection were analyzed to evaluate cutaneous vasomotor responses to ET-1. ET-1 induced dose-dependent pallor and flare responses that were significant at the dose of 5 x 10(-3) pmol or greater. Indomethacin did not affect the ET-1-induced pallor but significantly shifted to the right the flare dose-response curve to ET-1. The inhibition of the flare response to 5 x 10(-1) pmol ET-1 was 58.9 +/- 8.5%. These results indicate that the cutaneous vasodilation induced by intradermal injection of ET-1 is mediated by the release of vasodilating cyclooxygenase products.