Current Issue : April - June Volume : 2014 Issue Number : 2 Articles : 6 Articles
Background: Spirometric parameters are the mainstay for diagnosis of COPD, but cannot distinguish airway\r\nobstruction from emphysema. We aimed to develop a computer model that quantifies airway collapse on forced\r\nexpiratory flowââ?¬â??volume loops. We then explored and validated the relationship of airway collapse with computed\r\ntomography (CT) diagnosed emphysema in two large independent cohorts.\r\nMethods: A computer model was developed in 513 Caucasian individuals with =15 pack-years who performed\r\nspirometry, diffusion capacity and CT scans to quantify emphysema presence. The model computed the two best\r\nfitting regression lines on the expiratory phase of the flow-volume loop and calculated the angle between them.\r\nThe collapse was expressed as an Angle of collapse (AC) which was then correlated with the presence of emphysema.\r\nFindings were validated in an independent group of 340 individuals.\r\nResults: AC in emphysema subjects (N = 251) was significantly lower (131Ã?° Ã?± 14Ã?°) compared to AC in subjects without\r\nemphysema (N = 223), (152Ã?° Ã?± 10Ã?°) (p < 0.0001). Multivariate regression analysis revealed AC as best indicator of visually\r\nscored emphysema (R2 = 0.505, p < 0.0001) with little significant contribution of KCO, %predicted and FEV1, %predicted\r\nto the total model (total R2 = 0.626, p < 0.0001). Similar associations were obtained when using CT-automated density\r\nscores for emphysema assessment. Receiver operating characteristic (ROC) curves pointed to 131Ã?° as the best cut-off\r\nfor emphysema (95.5% positive predictive value, 97% specificity and 51% sensitivity). Validation in a second group\r\nconfirmed the significant difference in mean AC between emphysema and non-emphysema subjects. When applying\r\nthe 131Ã?° cut-off, a positive predictive value of 95.6%, a specificity of 96% and a sensitivity of 59% were demonstrated.\r\nConclusions: Airway collapse on forced expiration quantified by a computer model correlates with emphysema. An\r\nAC below 131Ã?° can be considered as a specific cut-off for predicting the presence of emphysema in heavy smokers...
Background: The endoplasmic reticulum (ER) stress response participates in many chronic inflammatory and\r\nautoimmune diseases. In the current study, we sought to examine the contribution of ER stress transducers in the\r\npathogenesis of three principal facets of allergic asthma: inflammation, airway fibrosis, and airways\r\nhyperresponsiveness.\r\nMethods: House Dust Mite (HDM) was used as an allergen for in vitro and in vivo challenge of primary human and\r\nmurine airway epithelial cells. ER stress transducers were modulated using specific small interfering RNAs (siRNAs)\r\nin vivo. Inflammation, airway remodeling, and hyperresponsiveness were measured by total bronchoalveolar lavage\r\n(BAL) cell counts, determination of collagen, and methacholine responsiveness in mice, respectively.\r\nResults: Challenge of human bronchiolar and nasal epithelial cells with HDM extract induced the ER stress\r\ntransducer, activating transcription factor 6 a (ATF6a) as well as protein disulfide isomerase, ERp57, in association\r\nwith activation of caspase-3. SiRNA-mediated knockdown of ATF6a and ERp57 during HDM administration in mice\r\nresulted in a decrease in components of HDM-induced ER stress, disulfide mediated oligomerization of Bak, and\r\nactivation of caspase-3. Furthermore, siRNA-mediated knockdown of ATF6a and ERp57 led to decreased\r\ninflammation, airway hyperresponsiveness and airway fibrosis.\r\nConclusion: Collectively, our work indicates that HDM induces ER stress in airway epithelial cells and that ATF6a\r\nand ERp57 play a significant role in the development of cardinal features of allergic airways disease. Inhibition of ER\r\nstress responses may provide a potential therapeutic avenue in chronic asthma and sub-epithelial fibrosis associated\r\nwith loss of lung function....
Background: Inhaled lipopolysaccharide (LPS) induces a dose-dependent, acute neutrophilic response in the\r\nairways of healthy volunteers that can be quantified in induced sputum. Chemokines, such as CXCL1 and CXCL8,\r\nplay an important role in neutrophilic inflammation in the lung through the activation of CXCR2 and small molecule\r\nantagonists of these receptors have now been developed. We investigated the effect of AZD8309, a CXCR2\r\nantagonist, compared with placebo on LPS-induced inflammation measured in sputum of healthy volunteers.\r\nMethods: Twenty healthy subjects were randomized in a double-blind placebo-controlled, cross-over study.\r\nAZD8309 (300 mg) or placebo was dosed twice daily orally for 3 days prior to challenge with inhaled LPS and\r\ninduced sputum was collected 6 h later.\r\nResults: Treatment with AZD8309 showed a mean 77% reduction in total sputum cells (p < 0.001) and 79%\r\nreduction in sputum neutrophils (p < 0.05) compared with placebo after LPS challenge. There was also a reduction\r\nin neutrophil elastase activity (p < 0.05) and CXCL1 (p < 0.05) and trends for reductions in sputum macrophages\r\n(47%), leukotriene B4 (39%) and CXCL8 (52%).\r\nConclusions: AZD8309 inhibited LPS-induced inflammation measured in induced sputum of normal volunteers,\r\nindicating that this treatment may be useful in the treatment of neutrophilic diseases of the airways, such as COPD,\r\nsevere asthma and cystic fibrosis.\r\nTrial registration: NCT00860821....
Background: Decreased physical activity is associated with higher mortality in subjects with COPD. The aim of this\r\nstudy was to assess clinical characteristics and physical activity levels (PALs) in subjects with COPD.\r\nMethods: Seventy-three subjects with COPD (67 �± 7 yrs, 44 female) with one-second forced expiratory volume\r\npercentage (FEV1%) predicted values of 43 �± 16 were included. The ratio of total energy expenditure (TEE) and\r\nresting metabolic rate (RMR) was used to define the physical activity level (PAL) (PAL = TEE/RMR). TEE was assessed\r\nwith an activity monitor (ActiReg), and RMR was measured by indirect calorimetry. Walking speed (measured over\r\n30-meters), maximal quadriceps muscle strength, fat-free mass and systemic inflammation were measured as clinical\r\ncharacteristics. Hierarchical linear regression was applied to investigate the explanatory values of the clinical\r\ncorrelates to PAL.\r\nResults: The mean PAL was 1.47 �± 0.19, and 92% of subjects were classified as physically very inactive or sedentary.\r\nThe walking speed was 1.02 �± 0.23 m/s, the quadriceps strength was 31.3 �± 11.2 kg, and the fat-free mass index\r\n(FFMI) was 15.7 �± 2.3 kg/m2, identifying 42% of subjects as slow walkers, 21% as muscle-weak and 49% as FFM-depleted.\r\nThe regression model explained 45.5% (p < 0.001) of the variance in PAL. The FEV1% predicted explained the largest\r\nproportion (22.5%), with further improvements in the model from walking speed (10.1%), muscle strength (7.0%) and\r\nFFMI (3.0%). Neither age, gender nor systemic inflammation contributed to the model.\r\nConclusions: Apart from lung function, walking speed and muscle strength are important correlates of physical activity.\r\nFurther explorations of the longitudinal effects of the factors characterizing the most inactive subjects are warranted....
Abstract\r\nThe overlap syndrome of obstructive sleep apnoea (OSA) and chronic obstructive pulmonary disease (COPD), in\r\naddition to obesity hypoventilation syndrome, represents growing health concerns, owing to the worldwide COPD\r\nand obesity epidemics and related co-morbidities. These disorders constitute the end points of a spectrum with distinct\r\nyet interrelated mechanisms that lead to a considerable health burden. The coexistence OSA and COPD seems to occur\r\nby chance, but the combination can contribute to worsened symptoms and oxygen desaturation at night, leading to\r\ndisrupted sleep architecture and decreased sleep quality. Alveolar hypoventilation, ventilation-perfusion mismatch and\r\nintermittent hypercapnic events resulting from apneas and hypopneas contribute to the final clinical picture, which is\r\nquite different from the ââ?¬Å?usualââ?¬Â COPD. Obesity hypoventilation has emerged as a relatively common cause of chronic\r\nhypercapnic respiratory failure. Its pathophysiology results from complex interactions, among which are respiratory\r\nmechanics, ventilatory control, sleep-disordered breathing and neurohormonal disturbances, such as leptin resistance,\r\neach of which contributes to varying degrees in individual patients to the development of obesity hypoventilation.\r\nThis respiratory embarrassment takes place when compensatory mechanisms like increased drive cannot be maintained\r\nor become overwhelmed.\r\nAlthough a unifying concept for the pathogenesis of both disorders is lacking, it seems that these patients are in a\r\nvicious cycle. This review outlines the major pathophysiological mechanisms believed to contribute to the\r\ndevelopment of these specific clinical entities. Knowledge of shared mechanisms in the overlap syndrome and obesity\r\nhypoventilation may help to identify these patients and guide therapy...
Background: Heat shock protein (HSP) 47 is a collagen-specific molecular chaperone that is required for molecular\r\nmaturation of various types of collagens. We recently reported that HSP47 serum levels were markedly higher in\r\npatients with acute exacerbations of idiopathic pulmonary fibrosis (IPF) when compared with patients with stable\r\nIPF, suggesting that serum HSP47 levels correlate with interstitial pneumonia activity. The aim of this study was to\r\nevaluate serum HSP47 levels in patients with drug-induced lung disease (DILD).\r\nMethods: Findings from high-resolution computed tomographic chest scans of 47 patients with DILD were classified\r\ninto one of four predominant patterns: organizing pneumonia (OP) (n = 4), nonspecific interstitial pneumonia (NSIP)\r\n(n = 24), hypersensitivity pneumonitis (HP) (n = 11), and diffuse alveolar damage (DAD) (n = 8). Serum levels of\r\nHSP47, Krebs von den Lungen-6 (KL-6), surfactant protein (SP)-A, and SP-D were measured in these patients.\r\nResults: The PaO2/fraction of inspired oxygen (FiO2) (P/F) ratios were significantly lower and the alveolar-arterial\r\ndifference of oxygen (A-a DO2) was significantly higher in the DAD group than in the other groups. Patients with DAD\r\nhad the worst outcomes among the different subgroups. Patients in the DAD group had significantly higher serum\r\nHSP47 levels than those in other groups. Receiver operating characteristic curves revealed that HSP47 was superior to\r\nKL-6, SP-A, and SP-D for discriminating between the DAD group and the other groups. The cut-off level for HSP47 that\r\nresulted in the highest diagnostic accuracy was 1711.5 pg/mL. The sensitivity, specificity, and diagnostic accuracy were\r\n87.5%, 97.4%, and 95.7%, respectively. Serum levels of HSP47 in the group of patients requiring glucocorticoids were\r\nsignificantly higher than those in patients who experienced clinical improvement without glucocorticoid administration.\r\nSerum HSP47 levels also significantly correlated with various respiratory parameters.\r\nConclusion: This study demonstrated that serum HSP47 levels were elevated in patients with DILD with a DAD pattern\r\nwho had the worst outcomes among the different subgroups, and that this was correlated with P/F ratio and A-a DO2....
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