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BACKGROUND: Obstructive sleep apnea syndrome (OSAS) has been shown to be associated to upper and lower airways inflammation. Continuous positive airway pressure (CPAP) is the elective treatment of OSAS. The aim of the present study was to assess the effect of CPAP-therapy on airway and nasal inflammation. METHODS: In 13 non-smoking subjects affected by untreated OSAS and in 11 non-smoking normal volunteers, airway inflammation was detected by analyses of the induced sputum. In the OSAS group measurements were repeated after 1, 10 and 60 days of the appropriate CPAP treatment. In addition, in 12 subjects of the OSAS group, nasal inflammation was detected by the analysis of induced nasal secretions at baseline, and after 1, 10 and 60 days of CPAP treatment. RESULTS: OSAS patients, compared to normal controls, showed at baseline a higher percentage of neutrophils and a lower percentage of macrophages in the induced sputum. One, 10 and 60 days of appropriate CPAP-therapy did not change the cellular profile of the induced sputum. In addition, in the OSAS patients, the high neutrophilic nasal inflammation present under baseline conditions was not significantly modified by CPAP-therapy. Finally, no patients developed airway hyper-responsiveness after CPAP therapy. CONCLUSIONS: In OSAS subjects, the appropriate CPAP-therapy, while correcting the oxygen desaturation, does not modify the bronchial and nasal inflammatory profile.

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The extracellular matrix is the main determinant of the structure and of mechanical behaviour of the lung. The extracellular matrix is also responsible for the mechanical interdependence between airway and parenchyma due to the alveolar attachments to the airways. Asthma is characterized by bronchial hyperresponsiveness, airway remodelling and inflammation, and an altered extracellular matrix may play a role in all these functional and structural abnormalities. The excessive airway narrowing observed in asthma may be related to the altered viscoelastic properties of lung parenchyma and airway wall, determining a decrease in the mechanical load opposing the airways' smooth muscle contraction. Indeed, an altered extracellular matrix deposition in asthma in humans, has been demonstrated. In addition, in the asthmatic lung, the matrix seems to contribute to airway inflammation, airway remodelling, and to those alterations of the smooth muscle function of the airway and morphology typical of asthma.

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Brittle asthma is a clinical phenotype of the disease at the severe end of the spectrum. Type 1 brittle asthma is characterised by a maintained wide PEF variability (> 40% diurnal variation for > 50% of the time over a period of at least 150 days) despite considerable medical therapy including a dose of inhaled steroids of at least 1500 pg of beclomethasone or equivalent. Type 2 brittle asthma is characterised by sudden acute attacks occurring in less than three hours without an obvious trigger on a background of apparent normal airway function or well controlled asthma. Mechanisms behind the development of brittle asthma include smooth muscle contraction and edema of the airways, which are supported by chronic airway inflammation. Allergy reactions, impairment of local immunity, respiratory infections, psycho-social disorders and reduced perception of worsening airway function are the risk factors for brittle asthma. The diagnosis is based on the analysis of specific symptoms, role of triggers, personal or family history, measurement of lung function and PEF monitoring. Pharmacological treatment of type 1 brittle asthma in addition to the high doses of inhaled and/or oral steroids and bronchodilators includes subcutaneous injections of beta2 agonist and inhalation of long acting beta2 agonist. The treatment of patients with type 2 brittle asthma includes exclusion of allergen exposure, identification of triggers, self management and management of acute attacks.

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Obstructive sleep apnea (OSA) is characterised by repetitive episodes of upper airway occlusion during sleep. OSA has been shown to be associated with a variable degree of nasal inflammation, uvula mucosal congestion and airway hyperreactivity. The upper airway inflammation, whose clinical importance is uncertain, is characterised by leukocytes infiltration and interstitial oedema. In addition, recent data has shown the presence of neutrophilic inflammation in the lower airways. The current opinion is that airway inflammation is caused by the local, repeated mechanical trauma related to the intermittent airway occlusion typical of the disease. Another potential mechanism involves the intermittent nocturnal hypoxemia that through the phenomenon of the ischemia-reperfusion injury may induce the production of oxygen free radicals and therefore cause local and systemic inflammation. Finally, a state of low-grade systemic inflammation may be related to obesity per se with the pro-inflammatory mediators synthesised in the visceral adipose cells. Several authors stress the role of circulating and local inflammatory mediators, such as pro-inflammatory cytokines, exhaled nitric oxide, pentane and 8-isoprostane as the determinants of inflammation in OSA.

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Obstructive sleep apnea syndrome (OSAS) has been shown to be associated to upper airway inflammation. The object of the present study was to establish the presence of bronchial inflammation in OSAS subjects. In 16 subjects affected by OSAS, and in 14 healthy volunteers, airway inflammation was detected by the cellular analysis of the induced sputum. OSAS patients, as compared to control subjects, showed a higher percentage of neutrophils (66.7+/-18.9 vs. 25.8+/-15.6) (P<0.001) and a lower percentage of macrophages (29.4+/-18.4 vs. 70.8+/-15.3) (P<0.001). The percentage of eosinophils and lymphocytes were not significantly different in the two groups. OSAS subjects show bronchial inflammation characterized by a significant increase in neutrophils.

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Large amplitude oscillations of contracted airway smooth muscle cause relative relaxation of the preparation. However, little is known about the effect of mechanical stretch on distal lung behaviour. Rat parenchymal strips were suspended in an organ bath and attached at one end to a force transducer and at the other end to a servo-controlled lever arm that effected length changes. Mechanical impedance of the strip was measured by applying a complex signal consisting of pseudorandom length oscillations of varying frequencies (0.5-19.75 Hz). A constant phase model was fit to changes in length and tension to calculate tissue damping (G) and elastance (H). Hysteresivity was calculated as G/H. Impedance was measured before and after sinusoidal length oscillation at different amplitudes (1, 3, 10 and 25% of resting length) at a frequency of 1 Hz under baseline conditions and after acetylcholine-induced constriction. Oscillations of 10 and 25% amplitudes significantly decreased the G and H of the lung strip. The effect of length oscillations was no different in control versus constricted strips. These data suggest that in the distal lung, large stretches affect the structural components of the extracellular matrix rather than the contractile elements.

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The lung parenchyma is anatomically and mechanically connected to the intraparenchymal airways. Due to forces of interdependence the lung parenchyma represents a mechanical load that opposes bronchial narrowing during airway smooth muscle activation. The mechanical load caused by the parenchyma is a function of the number of the alveolar attachments to the airways, and of the mechanical properties of the parenchyma. The extracellular matrix is a major component of the lung parenchyma responsible of most of its mechanical properties. The excessive airway narrowing observed in the asthmatic population may be the consequence of the altered mechanical properties of the extracellular matrix reducing the mechanical load that opposes airway smooth muscle contraction.

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Asthma is characterized by increased airway responsiveness and airway inflammation. Airway hyperresponsiveness may be caused by increased airway smooth muscle contractility or by a decrease in the mechanical load that opposes airway smooth muscle contraction. Under static conditions, the equilibrium between contractility and load will determine the final airway smooth muscle length and therefore airway caliber. Because of tidal breathing, however, lungs normally function under dynamic conditions where both airway contractility and opposing load are affected. The capability of tidal breathing to appropriately modulate airway function might be the mechanism that differentiates airways of asthmatics from those of normal subjects.

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When isolated constricted airway smooth muscle is oscillated, muscle tone decreases. We investigated whether changing tidal volume (VT) would affect induced bronchoconstriction in an in vivo canine model. Open-chest dogs were intubated with a double-lumen endotracheal tube, which isolated each main bronchus, and mechanically ventilated with a dual-cylinder ventilator. Bronchial pressure (Pbr) and flow were measured separately in each lung. Resistance and elastance were calculated by fitting the changes in Pbr, flow, and volume to the equation of motion. After baseline measurements at the same VT (150 ml), the two lungs were ventilated with different VT (50 vs. 250 ml) at a constant positive end-expiratory pressure. A continuous infusion of methacholine was begun, and measurements were repeated. The two lungs were then ventilated with the same VT (250 ml), and measurements were again repeated. A similar protocol was performed in a second group of dogs in which mean Pbr was kept constant. Bronchoconstriction was more severe in the lung ventilated with lower VT in both protocols. When VT was reset to the same amplitude in the two lungs, the difference in bronchoconstriction was abrogated. These results demonstrate that large VT inhibits airway smooth muscle contraction, regardless of mean Pbr.

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When airways constrict, the surrounding parenchyma undergoes stretch and distortion. Because of the mechanical interdependence between airways and parenchyma, the material properties of the parenchyma are important factors that modulate the degree of bronchoconstriction. The purpose of this study was to investigate the effect of changes in transpulmonary pressure (Ptp) and induced constriction on parenchymal bulk (k) and shear (mu) moduli. In excised rat lungs, pressure was measured at the airway opening, and pressure-volume curves were obtained by imposing step decreases in volume with a calibrated syringe from total lung inflation. Calculation was made of k during small-volume oscillations (1 Hz). Absolute lung volume at 0 cmH2O Ptp was obtained by saline displacement. To calculate mu, a lung-indentation test was performed. The lung surface was deformed with a cylindrical punch (diameter = 0.45 cm) in 0.25-mm increments, and the force required to effect this displacement was measured by a weight balance. Measurements of k and mu were obtained at 4 and 10 cmH2O Ptp, and again at 4 cmH2O Ptp, after delivery of methacholine aerosol (100 mg/ml) into the trachea. Values of k and mu in rat lungs were similar to those reported in other species. In addition, k and mu were dependent on Ptp. After induced constriction, k and mu increased significantly. That k and mu can increase after induced constriction has important implications vis a vis the factors modulating airway narrowing.

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The object of this study was to investigate how changes in the contractile state of smooth muscle would modify oscillatory mechanics of tracheal muscle and lung parenchyma during agonist challenge. Guinea pig tracheal and parenchymal lung strips were suspended in an organ bath. Measurements of length (L) and tension (T) were recorded during sinusoidal oscillations under baseline conditions and after challenge with 1 mM ACh. Measurements were also obtained in strips pretreated with the calmodulin inhibitor calmidazolium (Cmz) or staurosporine (Stauro), a protein kinase C inhibitor. Elastance (E) and resistance (R) were calculated by fitting changes in T, L, and DeltaL/Deltat to the equation of motion. Hysteresivity (eta) was obtained from the following equation: eta = (R/E)2pif, where f is frequency. Finally, maximal unloaded shortening velocity during electrical field stimulation was measured in Cmz-pretreated and control tracheal strips. In tracheal strips, pretreatment with Cmz caused a significant decrease in the eta response to ACh challenge and in maximal unloaded shortening velocity measured during electrical field stimulation; Stauro decreased the T, E, and R response to ACh. In parenchymal strips, Cmz decreased the eta response, whereas Stauro had no effect. These results suggest that modifications in the contractile state of the smooth muscle are reflected in changes in the hysteretic behavior and that T and eta may be controlled independently. Second, inasmuch as changes in eta were similar in parenchymal and tracheal strips, the contractile element is implicated as the structure responsible for constriction-induced changes in the mechanical behavior of the lung periphery.

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Constricted guinea pig (GP) airways are much less sensitive to changes in transpulmonary pressure (Ptp) than are those of the rat. The object of this study was to investigate whether differences in the mechanical behavior of the lung parenchyma could explain differences between the two species in the interdependence of the airway and parenchyma. Subpleural lung strips from guinea pigs and rats were excised and suspended in an organ bath. One end of each strip was attached to a force transducer and the other to a servo-controlled lever arm that effected length (L) changes in the strip. Sinusoidal oscillations at varying frequencies and amplitudes were applied at different resting tensions. Measurements of L and resting tension (T) were recorded during baseline conditions and after acetylcholine (ACh) challenge. Elastance (E) and resistance (R) were calculated by fitting changes in T and L to the equation of motion. During sinusoidal oscillations, E and R in the two species were different in both the unconstricted and constricted states. The effect of T on E was significantly different in rats and GPs; E was less dependent on T in GPs. Insofar as E is a measure of the load against which airway smooth muscle (ASM) contracts, this difference may represent a potential mechanism to explain why constricted GP airways are less sensitive to changes in Ptp.

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There is evidence that the mode of smooth muscle agonist delivery affects the changes induced in lung mechanical properties. The object of this investigation was to study modifications in airway behaviour associated with different modes of agonist delivery. Tracheal (Ptr) and alveolar pressure (PA) and flow (V) were measured in open-chested, mechanically ventilated (f = 1 Hz, VT = 10 ml/kg, PEEP = 4 cm H2O) rats under baseline conditions and during administration of repeated intravenous (i.v.) bolus, i.v. continuous infusion and aerosols of methacholine (MCh). We calculated lung elastance (EL) and lung resistance (RL) by fitting the equation of motion to changes in Ptr and V. We assessed the patency of the airway pathways and local dynamic hyperinflation by comparing Ptr vs PA. Comparison of the three different modes of MCh delivery showed a difference in the functional behaviour of the airways. In the aerosol group a larger incidence of highly constricted airways was observed. Conversely, the i.v. groups showed a larger incidence of regional dynamic hyperinflation. In the bolus group a different time course in the development of dynamic hyperinflation was observed for different pathways within the same animal. For consecutive challenges a given pathway tended to behave in the same manner, suggesting the response was characteristic for that pathway. In this study we have shown that, even though different airway pathways show different intrinsic reactivity, the mode of agonist delivery plays a role in determining functional airway behaviour.

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1. When lung parenchymal strips are challenged with different smooth muscle agonists, the tensile and viscoelastic properties change. It is not clear, however, which of the different anatomical elements present in the parenchymal strip, i.e., small vessel, small airway or alveolar wall, contribute to the response. 2. Parenchymal lung strips from Sprague Dawley rats were suspended in an organ bath filled with Krebs solution (37 degrees C, pH = 7.4) bubbled with 95%O2/5%CO2. Resting tension (T) was set at 1.1 g and sinusoidal oscillations of 2.5% resting length (L0) at a frequency of 1 Hz were applied. Following 1 h of stress adaptation, measurements of length (L) and T were recorded under baseline conditions and after challenge with a variety of pharmacological agents, i.e., acetylcholine (ACh), noradrenaline (NA) and angiotensin II (AII). Elastance (E) and resistance (R) were calculated by fitting changes in T, L and delta L/ delta t to the equation of motion. Hysteresivity (eta, the ratio of the energy dissipated to that conserved) was obtained from the equation eta = (R/E)2 pi f. 3. In order to determine whether small airways or small vessels accounted for the responses to the different pharmacologic agents, further studies were carried out in lung explants. Excised lungs from Sprague Dawley rats were inflated with agarose. Transverse slices of lung (0.5-1.0 mm thick) were cultured overnight. By use of an inverted microscope and video camera, airway and vascular lumen area were measured with an image analysis system. 4. NA, ACh and AII constricted the parenchymal strips. Airways constricted after all agonists, vessels constricted only after All. Atropine (Atr) pre-incubation decreased the explanted airway and vessel response to AII, but no difference was found in the parenchymal strip response. 5. Preincubation with the arginine analogue N omega-nitro-L-arginine (L-NOARG) did not modify the response to ACh but mildly increased the oscillatory response to NA after co-preincubation with propranolol (Prop). 6. These results suggest that during ACh and NA challenge, small vessels do not contribute substantially to the parenchymal strip response. The discrepancy between results in airways, vessels and strips when Atr was administered prior to AII implicates a direct contractile response in the parenchymal strip.

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Parenchymal tissue strips have been used to investigate the mechanical behavior of the lung parenchyma. We questioned whether the relative amounts of alveolar, blood vessel, and bronchial walls would be important when the contractile response of parenchymal strips from Sprague-Dawley rats was studied. One group of strips was cut from the subpleural edge and another from between 1 and 3 mm proximal to the pleura. Strips were suspended in an organ bath filled with Krebs solution (37 degrees C, pH 7.4) bubbled with 95% O2-5% CO2. Resting tension (T) was set at 1.1 g, and sinusoidal oscillations of 2.5% resting length at a frequency of 1 Hz were applied. Measurements of length and T were recorded during baseline conditions and after acetylcholine (10(-3) M) was added to the bath. Elastance, resistance, and hysteresivity (the ratio of the energy dissipated to that conserved) were calculated. Strips were fixed in Formalin at a T of 1 g, histological sections were prepared, and the fractional areas of alveolar, blood vessel, and bronchial walls were measured by using point counting. Significant differences were found between the two groups of strips in the acetylcholine response and anatomic makeup. The magnitude of the changes of all the mechanical parameters were correlated with the volume proportions of the different anatomic constituents when all the strips were plotted together but not when the subpleural strips were considered alone. We conclude that subpleural parenchymal strips are a sound model of parenchymal lung behavior. When more proximal strips are studied, the amount of bronchial wall may play an important role in determining the hysteretic response.

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Challenges with high concentrations of constrictor agonist delivered by intravenous vs. aerosol result in different modifications of the mechanical properties of lung tissues. We questioned whether low doses of a smooth muscle agonist administered via different routes (aerosol, i.v. bolus, i.v. continuous infusion) or an increase in positive end-expiratory pressure (PEEP) would result in different mechanical perturbations of lung tissues. Tracheal and alveolar pressures and flow were measured in open-chest mechanically ventilated (frequency 1 Hz, tidal volume 10 ml/kg, PEEP 4 cmH2O) rats under baseline conditions and after administration of low doses of methacholine or after increases in PEEP. We calculated lung elastance (EL), lung resistance, and tissue resistance (Rti) by fitting the equation of motion to changes in tracheal and alveolar pressures. Airway resistance and hysteresivity (eta) were derived from the above measurements. For comparable increases in Rti, the aerosol and PEEP groups showed large increases in EL with a decrease in eta, whereas the two intravenous groups showed large increases in eta with smaller increases in EL. The largest contribution of eta to the overall increase in Rti was seen in the intravenous bolus group. When induced changes in EL vs. induced changes in eta were plotted, different relationships were found for the four groups. We conclude that despite similar increases in Rti a different kind of mechanical perturbation occurred in the lung tissues that depended on the nature of the stimulus.

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Patients affected by cutinegative, RAST negative, chronic hyperreactive rhinitis showed in 15/28 cases positive intradermal tests, nasal provocation test and RAST on nasal fluids. In 13/28 cases high IgE on nasal samples could be observed and seldom were the intradermal tests positive, but in no case were the nasal provocation or nasal RAST positive. Delayed and late positive provocation tests showed different features from early reactions. Criteria of positivity and checks during provocation tests look critical. The occurrence of sinusitis and polyposis can change clinical features. Mediators released from tissues lead to bronchial hyperreactivity.

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