The use of nasal dilator strips as a placebo for trials evaluating continuous positive airway pressure

OBJECTIVES: The aim of the current study was to compare the objective and subjective effects of continuous positive airway pressure to the use of nasal dilator strips in patients with acromegaly and moderate to severe obstructive sleep apnea. METHODS: We studied 12 patients with acromegaly and moderate to severe obstructive sleep apnea (male/females = 8/4, age = 52 +/- 8 ys, body mass index = 33.5 +/- 4.6 Kg/m(2), apnea-hypopnea index = 38 +/- 14 events/h) who had been included in a randomized, crossover study to receive three months of treatment with continuous positive airway pressure and nasal dilator strips. All patients were evaluated at study entry and at the end of each treatment by polysomnography, and Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index and treatment satisfaction questionnaires. ClinicalTrials.gov: NCT01265121 RESULTS: The apnea-hypopnea index values decreased significantly with continuous positive airway pressure treatment but did not change with the use of nasal dilator strips. All of the subjective symptoms improved with both treatments, but these improvements were significantly greater with continuous positive airway pressure than with the nasal dilator strips. CONCLUSION: The use of nasal dilator strips had a much smaller effect on the severity of obstructive sleep apnea in patients with acromegaly and moderate to severe obstructive sleep apnea in comparison to the use of continuous positive airway pressure. Moreover, the improvement in several subjective parameters without any significant objective improvement in obstructive sleep apnea resulting from the use of nasal dilator strips is compatible with a placebo effect.

Extracellular matrix in airway smooth muscle is associated with dynamics of airway function in asthma

Background: Altered deposition of extracellular matrix (ECM) in the airway smooth muscle (ASM) layer as observed in asthma may influence ASM mechanical properties. We hypothesized that ECM in ASM is associated with airway function in asthma. First, we investigated the difference in ECM expression in ASM between asthma and controls. Second, we examined whether ECM expression is associated with bronchoconstriction and bronchodilation in vivo. Methods: Our cross-sectional study comprised 19 atopic mild asthma patients, 15 atopic and 12 nonatopic healthy subjects. Spirometry, methacholine responsiveness, deep-breath-induced bronchodilation (Delta R-rs) and bronchoscopy with endobronchial biopsies were performed. Positive staining of elastin, collagen I, III and IV, decorin, versican, fibronectin, laminin and tenascin in ASM was quantified as fractional area and mean density. Data were analysed using Pearson's or Spearman's correlation coefficient. Results: Extracellular matrix expression in ASM was not different between asthma and controls. In asthmatics, fractional area and mean density of collagen I and III were correlated with methacholine dose-response slope and DRrs, respectively (r = 0.71, P < 0.01; r = 0.60, P = 0.02). Furthermore, ASM collagen III and laminin in asthma were correlated with FEV1 reversibility (r = -0.65, P = 0.01; r = -0.54, P = 0.04). Conclusion: In asthma, ECM in ASM is related to the dynamics of airway function in the absence of differences in ECM expression between asthma and controls. This indicates that the ASM layer in its full composition is a major structural component in determining variable airways obstruction in asthma.

Effects of aerobic exercise on chronic allergic airway inflammation and remodeling in guinea pigs

We evaluated the effects of aerobic exercise (AE) on airway inflammation, exhaled nitric oxide levels (ENO), airway remodeling, and the expression of Thl, Th2 and regulatory cytokines in a guinea pig asthma model. Animals were divided into 4 groups: non-trained and non-sensitized (C), non-sensitized and AE (AE), ovalbumin-sensitized and non-trained (OVA), and OVA-sensitized and AE (OVA + AE). OVA inhalation was performed for 8 weeks, and AE was conducted for 6 weeks beginning in the 3rd week of OVA sensitization. Compared to the other groups, the OVA + AE group had a reduced density of eosinophils and lymphocytes, reduced expression of interleukin (IL)-4 and IL-13 and an increase in epithelium thickness (p < 0.05). AE did not modify airway remodeling or ENO in the sensitized groups (p > 0.05). Neither OVA nor AE resulted in differences in the expression of IL-2, IFN-gamma, IL-10 or IL1-ra. Our results show that AE reduces the expression of Th2 cytokines and allergic airway inflammation and induces epithelium remodeling in sensitized guinea pigs. (c) 2012 Elsevier B.V. All rights reserved.

Rho-kinase inhibition attenuates airway responsiveness, inflammation, matrix remodeling, and oxidative stress activation induced by chronic inflammation

Possa SS, Charafeddine HT, Righetti RF, da Silva PA, Almeida-Reis R, Saraiva-Romanholo BM, Perini A, Prado CM, Leick-Maldonado EA, Martins MA, Tiberio ID. Rho-kinase inhibition attenuates airway responsiveness, inflammation, matrix remodeling, and oxidative stress activation induced by chronic inflammation. Am J Physiol Lung Cell Mol Physiol 303: L939-L952, 2012. First published September 21, 2012; doi:10.1152/ajplung.00034.2012.-Several studies have demonstrated the importance of Rho-kinase in the modulation of smooth muscle contraction, airway hyperresponsiveness, and inflammation. However, the effects of repeated treatment with a specific inhibitor of this pathway have not been previously investigated. We evaluated the effects of repeated treatment with Y-27632, a highly selective Rho-kinase inhibitor, on airway hyperresponsiveness, oxidative stress activation, extracellular matrix remodeling, eosinophilic inflammation, and cytokine expression in an animal model of chronic airway inflammation. Guinea pigs were subjected to seven ovalbumin or saline exposures. The treatment with Y-27632 (1 mM) started at the fifth inhalation. Seventy-two hours after the seventh inhalation, the animals' pulmonary mechanics were evaluated, and exhaled nitric oxide (E-NO) was collected. The lungs were removed, and histological analysis was performed using morphometry. Treatment with Y-27632 in sensitized animals reduced E-NO concentrations, maximal responses of resistance, elastance of the respiratory system, eosinophil counts, collagen and elastic fiber contents, the numbers of cells positive for IL-2, IL-4, IL-5, IL-13, inducible nitric oxide synthase, matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, transforming growth factor-beta, NF-kappa B, IFN-gamma, and 8-iso-prostaglandin F2 alpha contents compared with the untreated group (P < 0.05). We observed positive correlations among the functional responses and inflammation, remodeling, and oxidative stress pathway activation markers evaluated. In conclusion, Rho-kinase pathway activation contributes to the potentiation of the hyperresponsiveness, inflammation, the extracellular matrix remodeling process, and oxidative stress activation. These results suggest that Rho-kinase inhibitors represent potential pharmacological tools for the control of asthma.

Long-term amphetamine treatment exacerbates inflammatory lung reaction while decreases airway hyper-responsiveness after allergic stimulus in rats

Asthma is an allergic lung disease can be modulated by drugs that modify the activity of central nervous system (CNS) such as amphetamine (AMPH). AMPH is a highly abused drug that exerts potent effects on behavior and immunity. In this study we investigated the mechanism involved in the effects of long-term AMPH treatment on the increased magnitude of allergic lung response. We evaluated mast cells degranulation, cytokines release, airways responsiveness and, expression of adhesion molecules. Male Wistar rats were treated with AMPH or vehicle (PBS) for 21 days and sensitized with ovalbumin (OVA) one week after the first injection of vehicle or AMPH. Fourteen days after the sensitization, the rats were challenged with an OVA aerosol, and 24 h later their parameters were analyzed. In allergic rats, the treatment with AMPH exacerbated the lung cell recruitment due increased expression of ICAM-1, PECAM-1 and Mac-1 in granulocytes and macrophages recovered from bronchoalveolar lavage. Elevated levels of IL-4, but decreased levels of IL-10 were also found in samples of lung explants after AMPH treatment. Conversely, the ex-vivo tracheal hyper-responsiveness to methacholine (MCh) was reduced by AMPH treatment, whereas the force contraction of tracheal segments due to in vitro antigen challenge remained unaltered. Our findings suggest that lung inflammation and airway hyper-responsiveness due to OVA challenge are under the distinct control of AMPH during long-term treatment. Our data strongly indicate that AMPH positively modulates allergic lung inflammation via the increase of ICAM-1, PECAM-1, Mac-1 and IL-4. AMPH also abrogates the release of the anti-inflammatory cytokine IL-10. (c) 2012 Elsevier B.V. All rights reserved.

3,4-Methylenedioxymethamphetamine (Ecstasy) Decreases Inflammation and Airway Reactivity in a Murine Model of Asthma

Objective:3,4-Methylenedioxymethamphetamine(MDMA), or ecstasy, is a synthetic drug used recreationally, mainly by young people. It has been suggested that MDMA has a Th cell skewing effect, in which Th1 cell activity is suppressed and Th2 cell activity is increased. Experimental allergic airway inflammation in ovalbumin (OVA)-sensitized rodents is a useful model to study Th2 response; therefore, based on the Th2 skewing effect of MDMA, we studied MDMA in a model of allergic lung inflammation in OVA-sensitized mice. Methods: We evaluated cell trafficking in the bronchoalveolar lavage fluid, blood and bone marrow; cytokine production; L-selectin expression and lung histology. We also investigated the effects of MDMA on tracheal reactivity in vitro and mast cell degranulation. Results: We found that MDMA given prior to OVA challenge in OVA-sensitized mice decreased leukocyte migration into the lung, as revealed by a lower cell count in the bronchoalveolar lavage fluid and lung histologic analysis. We also showed that MDMA decreased expression of both Th2-like cytokines (IL-4, IL-5 and IL-10) and adhesion molecules (L-selectin). Moreover, we showed that the hypothalamus-pituitary-adrenal axis is partially involved in the MDMA-induced reduction in leukocyte migration into the lung. Finally, we showed that MDMA decreased tracheal reactivity to methacholine as well as mast cell degranulation in situ. Conclusions:Thus, we report here that MDMA given prior to OVA challenge in OVA-sensitized allergic mice is able to decrease lung inflammation and airway reactivity and that hypothalamus-pituitary-adrenal axis activation is partially involved. Together, the data strongly suggest an involvement of a neuroinnmune mechanism in the effects of MDMA on lung inflammatory response and cell recruitment to the lungs of allergic animals. Copyright (C) 2012 S. Karger AG, Basel

Upper airway expansion after rapid maxillary expansion evaluated with cone beam computed tomography

Objective: Cone-beam computed tomography (CBCT) is a reliable method of assessing the oral cavity and upper airways. We conducted this study to examine the changes introduced by rapid maxillary expansion in the nasal cavity, nasopharynx, and oropharynx as seen with images obtained by CBCT. Materials and Methods: We evaluated 15 patients with maxillary width deficiency treated with RME. Patients were subjected to CBCT at the beginning of RME and after the retention period of 4 months. Results: The nasal cavity presented a significant transverse increase in the lower third, in the anterior (1.08 mm +/- 0.15), medium (1.28 mm +/- 0.15), and posterior regions (0.77 mm +/- 0.12). No significant change occurred in the nasopharynx in volume (P = .11), median sagittal area (P = .33), or lower axial area (P = .29) resulting from the RME. A significant change was noted in the oropharynx in volume (P = .05), median sagittal area (P = .01), and lower axial area (P = .04) before and immediately after the RME. Conclusions: RME is able to increase the transverse width of the nasal cavity, but it does not have the same effect in the nasopharynx. Changes noted in the oropharynx may be due to the lack of a standardized position of the head and tongue at the time of image acquisition. (Angle Orthod. 2012;82:458-463.)

Recombinant DNA immunotherapy ameliorate established airway allergy in a IL-10 dependent pathway

Background Previous studies have established that mycobacterial infections ameliorate allergic inflammation. However, a non-infectious approach that controls allergic responses might represent a safer and more promising strategy. The 60-65 kDa heat shock protein (Hsp) family is endowed with anti-inflammatory properties, but it is still unclear whether and how single mycobacterial Hsp control allergic disorders. Objective Therefore, in this study we determined whether the administration of Mycobacterial leprae Hsp65 expressed by recombinant a DNA plasmid could attenuate a previously established allergic response. Methods We used an experimental model of airway allergic inflammation to test the effects of immunotherapy with DNA encoding Hsp65. Allergic mice, previously sensitized and challenged with ovalbumin, were treated with tree intramuscular doses of recombinant DNA encoding Hsp65. After treatment, mice received a second allergen challenge and the allergic response was measured. Results We found that immunotherapy attenuated eosinophilia, pulmonary inflammation, Th2 cytokine and mucus production. Moreover, we showed that the inhibition of allergic response is dependent on IL-10 production. Both Hsp65 and allergen-specific IL-10-producing cells contributed to this effect. Cells transferred from DNA-immunized mice to allergic mice migrated to allergic sites and down-modulated the Th2 response. Conclusions and Clinical Relevance Our findings clearly show that immunotherapy with DNA encoding Hsp65 can attenuate an established Th2 allergic inflammation through an IL-10-dependent mechanism; moreover, the migration of allergen-and Hsp65-specific cells to the allergic sites exerts a fundamental role. This work represents a novel contribution to the understanding of immune regulation by Hsp65 in allergic diseases.

Effects of Repeated Stress on Distal Airway Inflammation, Remodeling and Mechanics in an Animal Model of Chronic Airway Inflammation

Background/Aims: Epidemiological studies suggest that stress has an impact on asthmatic exacerbations. We evaluated if repeated stress, induced by forced swimming, modulates lung mechanics, distal airway inflammation and extracellular matrix remodeling in guinea pigs with chronic allergic inflammation. Methods: Guinea pigs were submitted to 7 ovalbumin or saline aerosols (1-5 mg/ml during 4 weeks; OVA and SAL groups). Twenty-four hours after the 4th inhalation, guinea pigs were submitted to the stress protocol 5 times a week during 2 weeks (SAL-S and OVA-S groups). Seventy-two hours after the 7th inhalation, guinea pigs were anesthetized and mechanically ventilated. Resistance and elastance of the respiratory system were obtained at baseline and after ovalbumin challenge. Lungs were removed, and inflammatory and extracellular matrix remodeling of distal airways was assessed by morphometry. Adrenals were removed and weighed. Results: The relative adrenal weight was greater in stressed guinea pigs compared to non-stressed animals (p < 0.001). Repeated stress increased the percent elastance of the respiratory system after antigen challenge and eosinophils and lymphocytes in the OVA-S compared to the OVA group (p < 0.001, p = 0.003 and p < 0.001). Neither collagen nor elastic fiber contents were modified by stress in sensitized animals. Conclusions: In this animal model, repeated stress amplified bronchoconstriction and inflammatory response in distal airways without interfering with extracellular matrix remodeling. Copyright (C) 2011 S. Karger AG, Basel

Insulin modulates cytokine release and selectin expression in the early phase of allergic airway inflammation in diabetic rats

Abstract Background Clinical and experimental data suggest that the inflammatory response is impaired in diabetics and can be modulated by insulin. The present study was undertaken to investigate the role of insulin on the early phase of allergic airway inflammation. Methods Diabetic male Wistar rats (alloxan, 42 mg/Kg, i.v., 10 days) and controls were sensitized by s.c. injection of ovalbumin (OA) in aluminium hydroxide 14 days before OA (1 mg/0.4 mL) or saline intratracheal challenge. The following analyses were performed 6 hours thereafter: a) quantification of interleukin (IL)-1β, tumor necrosis factor (TNF)-α and cytokine-induced neutrophil chemoattractant (CINC)-1 in the bronchoalveolar lavage fluid (BALF) by Enzyme-Linked Immunosorbent Assay, b) expression of E- and P- selectins on lung vessels by immunohistochemistry, and c) inflammatory cell infiltration into the airways and lung parenchyma. NPH insulin (4 IU, s.c.) was given i.v. 2 hours before antigen challenge. Results Diabetic rats exhibited significant reduction in the BALF concentrations of IL-1β (30%) and TNF-α (45%), and in the lung expression of P-selectin (30%) compared to non-diabetic animals. This was accompanied by reduced number of neutrophils into the airways and around bronchi and blood vessels. There were no differences in the CINC-1 levels in BALF, and E-selectin expression. Treatment of diabetic rats with NPH insulin, 2 hours before antigen challenge, restored the reduced levels of IL-1β, TNF-α and P-selectin, and neutrophil migration. Conclusion Data presented suggest that insulin modulates the production/release of TNF-α and IL-1β, the expression of P- and E-selectin, and the associated neutrophil migration into the lungs during the early phase of the allergic inflammatory reaction.

Convergence of two major pathophysiologic mechanisms in nasal polyposis: immune response to Staphylococcus aureus and airway remodeling

This review is addressed two pathophysiologic mechanisms implicated in the pathogenesis of nasal polyposis: the unique remodeling process found in nasal polyp tissue and the immune response of patients with nasal polyposis to Staphylococcus aureus. These two theories converge to the same direction in different aspects, including decreased extracellular matrix production, impaired T regulation and favoring of a Th2 immune response. In patients with nasal polyposis, an exaggerated immune response to Staphylococcus aureus may aggravate the airway remodeling process.

Airway disease: similarities and differences between asthma, COPD and bronchiectasis

Airway diseases are highly prevalent worldwide; however, the prevalence of these diseases is underestimated. Although these diseases present several common characteristics, they have different clinical outcomes. The differentiation between asthma, chronic obstructive pulmonary disease and bronchiectasis in the early stage of disease is extremely important for the adoption of appropriate therapeutic measures. However, because of the high prevalence of these diseases and the common pathophysiological pathways, some patients with different diseases may present with similar symptoms. The objective of this review is to highlight the similarities and differences between these diseases in terms of the risk factors, pathophysiology, symptoms, diagnosis and treatment.

Biphasic positive airway pressure minimizes biological impact on lung tissue in mild acute lung injury independent of etiology

Abstract Introduction Biphasic positive airway pressure (BIVENT) is a partial support mode that employs pressure-controlled, time-cycled ventilation set at two levels of continuous positive airway pressure with unrestricted spontaneous breathing. BIVENT can modulate inspiratory effort by modifying the frequency of controlled breaths. Nevertheless, the optimal amount of inspiratory effort to improve respiratory function while minimizing ventilator-associated lung injury during partial ventilatory assistance has not been determined. Furthermore, it is unclear whether the effects of partial ventilatory support depend on acute lung injury (ALI) etiology. This study aimed to investigate the impact of spontaneous and time-cycled control breaths during BIVENT on the lung and diaphragm in experimental pulmonary (p) and extrapulmonary (exp) ALI. Methods This was a prospective, randomized, controlled experimental study of 60 adult male Wistar rats. Mild ALI was induced by Escherichia coli lipopolysaccharide either intratracheally (ALIp) or intraperitoneally (ALIexp). After 24 hours, animals were anesthetized and further randomized as follows: (1) pressure-controlled ventilation (PCV) with tidal volume (Vt) = 6 ml/kg, respiratory rate = 100 breaths/min, PEEP = 5 cmH2O, and inspiratory-to-expiratory ratio (I:E) = 1:2; or (2) BIVENT with three spontaneous and time-cycled control breath modes (100, 75, and 50 breaths/min). BIVENT was set with two levels of CPAP (Phigh = 10 cmH2O and Plow = 5 cmH2O). Inspiratory time was kept constant (Thigh = 0.3 s). Results BIVENT was associated with reduced markers of inflammation, apoptosis, fibrogenesis, and epithelial and endothelial cell damage in lung tissue in both ALI models when compared to PCV. The inspiratory effort during spontaneous breaths increased during BIVENT-50 in both ALI models. In ALIp, alveolar collapse was higher in BIVENT-100 than PCV, but decreased during BIVENT-50, and diaphragmatic injury was lower during BIVENT-50 compared to PCV and BIVENT-100. In ALIexp, alveolar collapse during BIVENT-100 and BIVENT-75 was comparable to PCV, while decreasing with BIVENT-50, and diaphragmatic injury increased during BIVENT-50. Conclusions In mild ALI, BIVENT had a lower biological impact on lung tissue compared to PCV. In contrast, the response of atelectasis and diaphragmatic injury to BIVENT differed according to the rate of spontaneous/controlled breaths and ALI etiology.

Mechanical Alterations in airway smooth muscle after interaction with indoor pollutant – A mathematical model.

The viscoelasticity of mammalian lung is determined by the mechanical properties and structural regulation of the airway smooth muscle (ASM). The exposure to polluted air may deteriorate these properties with harmful consequences to individual health. Formaldehyde (FA) is an important indoor pollutant found among volatile organic compounds. This pollutant permeates through the smooth muscle tissue forming covalent bonds between proteins in the extracellular matrix and intracellular protein structure changing mechanical properties of ASM and inducing asthma symptoms, such as airway hyperresponsiveness, even at low concentrations. In the experimental scenario, the mechanical effect of FA is the stiffening of the tissue, but the mechanism behind this effect is not fully understood. Thus, the aim of this study is to reproduce the mechanical behavior of the ASM, such as contraction and stretching, under FA action or not. For this, it was created a two-dimensional viscoelastic network model based on Voronoi tessellation solved using Runge-Kutta method of fourth order. The equilibrium configuration was reached when the forces in different parts of the network were equal. This model simulates the mechanical behavior of ASM through of a network of dashpots and springs. This dashpot-spring mechanical coupling mimics the composition of the actomyosin machinery of ASM through the contraction of springs to a minimum length. We hypothesized that formation of covalent bonds, due to the FA action, can be represented in the model by a simple change in the elastic constant of the springs, while the action of methacholine (MCh) reduce the equilibrium length of the spring. A sigmoid curve of tension as a function of MCh doses was obtained, showing increased tension when the muscle strip was exposed to FA. Our simulations suggest that FA, at a concentration of 0.1 ppm, can affect the elastic properties of the smooth muscle ¯bers by a factor of 120%. We also analyze the dynamic mechanical properties, observing the viscous and elastic behavior of the network. Finally, the proposed model, although simple, incorporates the phenomenology of both MCh and FA and reproduces experimental results observed with in vitro exposure of smooth muscle to FA. Thus, this new mechanical approach incorporates several well know features of the contractile system of the cells in a tissue level model. The model can also be used in different biological scales.

Mechanical alterations in airway smooth muscle after interaction with indoor pollutant - A mathematical model

The viscoelasticity of mammalian lung is determined by the mechanical properties and structural regulation of the airway smooth muscle (ASM). The exposure to polluted air may deteriorate these properties with harmful consequences to individual health. Formaldehyde (FA) is an important indoor pollutant found among volatile organic compounds. This pollutant permeates through the smooth muscle tissue forming covalent bonds between proteins in the extracellular matrix and intracellular protein structure changing mechanical properties of ASM and inducing asthma symptoms, such as airway hyperresponsiveness, even at low concentrations. In the experimental scenario, the mechanical effect of FA is the stiffening of the tissue, but the mechanism behind this effect is not fully w1derstood. Thus, the aim of this study is to reproduce the mechanical behavior of the ASM, such as contraction and stretching, under FA action or not. For this, it was created a two-dimensional viscoelastic network model based on Voronoi tessellation solved using Runge-Kutta method of fourth order. The equilibrium configuration was reached when the forces in different parts of the network were equal. This model simulates the mechanical behavior of ASM through of a network of dashpots and springs. This dashpot-spring mechanical coupling mimics the composition of the actomyosin machinery of ASM through the contraction of springs to a minimum length. We hypothesized that formation of covalent bonds, due to the FA action, can be represented in the model by a simple change in the elastic constant of the springs, while the action of methacholinc (MCh) reduce the equilibrium length of the spring. A sigmoid curve of tension as a function of MCh doses was obtained, showing increased tension when the muscle strip was exposed to FA. Our simulations suggest that FA, at a concentration of 0.1 ppm, can affect the elastic properties of the smooth muscle fibers by a factor of 120%. We also analyze the dynamic mechanical properties, observing the viscous and elastic behavior of the network. Finally, the proposed model, although simple, ir1corporates the phenomenology of both MCh and FA and reproduces experirnental results observed with ir1 vitro exposure of smooth muscle to .FA. Thus, this new mechanical approach incorporates several well know features of the contractile system of the cells ir1 a tissue level model. The model can also be used in different biological scales.