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1.
Nils P Nickel Ralf Lichtinghagen Heiko Golpon Karen M Olsson Korbinian Brand Tobias Welte Marius M Hoeper 《Respiratory research》2013,14(1):130
Objective
To determine the levels of circulating copeptin in patients with pulmonary arterial hypertension (PAH), and to evaluate its relation with disease severity, outcome and response to treatment.Background
Vasopressin is a key regulator of body fluid homeostasis. The co-secreted protein copeptin serves as surrogate for plasma vasopressin levels and increases in acute and chronic left ventricular dysfunction. Copeptin has not been studied in PAH.Methods
Serum copeptin levels were evaluated in a retrospective cohort of 92 treatment-naïve patients with PAH, 39 patients with normal right ventricular hemodynamics (diseased controls) and 14 apparently healthy individuals (healthy controls). In a second prospective cohort of 15 patients with PAH, serial changes of copeptin levels after initiation of PAH treatment were measured. Copeptin levels were compared with clinical, biochemical and hemodynamic parameters as well as response to treatment and clinical outcome.Results
Circulating copeptin levels were elevated in PAH patients compared to diseased controls (20.1 pmol/l vs. 5.1 pmol/l; p = 0.001). Baseline levels of copeptin correlated with NYHA functional class (r = 0.46; p = 0.01), 6 minute walking distance (r = -0.26; p = 0.04), NT-proBNP (r = 0.49, p = 0.01), creatinine (r = 0.39, p = 0.01) and estimated glomerular filtration rate (r = -0.32, p = 0.01). Copeptin levels did not correlate with hemodynamics but decreased after initiation of PAH therapy (p = 0.001). Elevated copeptin levels were associated with shorter survival (p < 0.001) and independent predictors of mortality in a multiple Cox regression analysis (HR1.4; 95% confidence interval 1.1-2.0; p = 0.02).Conclusions
Patients with PAH had elevated copeptin levels. High circulating levels of copeptin were independent predictors of poor outcome, which makes copeptin a potentially useful biomarker in PAH. 相似文献2.
Laura C. Price Gaetano Caramori Frederic Perros Chao Meng Natalia Gambaryan Peter Dorfmuller David Montani Paolo Casolari Jie Zhu Konstantinos Dimopoulos Dongmin Shao Barbara Girerd Sharon Mumby Alastair Proudfoot Mark Griffiths Alberto Papi Marc Humbert Ian M. Adcock S. John Wort 《PloS one》2013,8(10)
3.
Leonardo Glutz von Blotzheim Felix C Tanner Georg Noll Matthias Brock Manuel Fischler Jürg Hafner Rudolf Speich Silvia Ulrich Lars C Huber 《Respiratory research》2012,13(1):45
Background
Martorell hypertensive ischemic leg ulcer (Martorell ulcer) is characterized by distinct alterations in the arteriolar wall of subcutaneous vessels, leading to progressive narrowing of the vascular lumen and increase of vascular resistance. These changes are similar to the alterations observed in pulmonary arterioles in patients with chronic pulmonary hypertension (PH). This study was aimed to assess an association between the two disorders.Methods
In this case–control study, 14 patients with Martorell ulcer were clinically assessed for the presence of pulmonary hypertension using transthoracic Doppler echocardiography. Data from patients were compared to 28 matched hypertensive controls.Results
Systolic pulmonary arterial pressure (sPAP) in patients with Martorell ulcer was significantly higher than in the control group (33.8 ± 16.9 vs 25.3 ± 6.5 mmHg, p = 0.023); the prevalence of pulmonary hypertension was 31% (5/14) in patients and 7% (2/28) in controls (p = 0.031). No differences were seen in left heart size and function between patients and controls.Conclusion
This study provides first evidence that subcutaneous arteriolosclerosis, the hallmark of Martorell ulcer, is associated with PH. These findings suggest that patients with Martorell leg ulcer might be at significant risk to develop elevated pulmonary arterial pressure. Patients with leg ulcers who present with dyspnea should be evaluated by echocardiography for the presence of pulmonary hypertension. 相似文献4.
Priscilla Henno Christelle Maurey Fran?oise Le Pimpec-Barthes Philippe Devillier Christophe Delclaux Dominique Isra?l-Biet 《Respiratory research》2015,16(1)
Background
Tobacco-induced pulmonary vascular disease is partly driven by endothelial dysfunction. The bioavailability of the potent vasodilator nitric oxide (NO) depends on competition between NO synthase-3 (NOS3) and arginases for their common substrate (L-arginine). We tested the hypothesis whereby tobacco smoking impairs pulmonary endothelial function via upregulation of the arginase pathway.Methods
Endothelium-dependent vasodilation in response to acetylcholine (Ach) was compared ex vivo for pulmonary vascular rings from 29 smokers and 10 never-smokers. The results were expressed as a percentage of the contraction with phenylephrine. We tested the effects of L-arginine supplementation, arginase inhibition (by N(omega)-hydroxy-nor-l-arginine, NorNOHA) and NOS3 induction (by genistein) on vasodilation. Protein levels of NOS3 and arginases I and II in the pulmonary arteries were quantified by Western blotting.Results
Overall, vasodilation was impaired in smokers (relative to controls; p < 0.01). Eleven of the 29 smokers (the ED+ subgroup) displayed endothelial dysfunction (defined as the absence of a relaxant response to Ach), whereas 18 (the ED− subgroup) had normal vasodilation. The mean responses to 10−4 M Ach were −23 ± 10% and 31 ± 4% in the ED+ and ED− subgroups, respectively (p < 0.01). Supplementation with L- arginine improved endothelial function in the ED+ subgroup (−4 ± 10% vs. -32 ± 10% in the presence and absence of L- arginine, respectively; p = 0.006), as did arginase inhibition (18 ± 9% vs. -1 ± 9%, respectively; p = 0.0002). Arginase I protein was overexpressed in ED+ samples, whereas ED+ and ED− samples did not differ significantly in terms of NOS3 expression. Treatment with genistein did not significantly improve endothelial function in ED+ samples.Conclusion
Overexpression and elevated activity of arginase I are involved in tobacco-induced pulmonary endothelial dysfunction. 相似文献5.
Wei-hua Zhang Mei-hong Qiu Xiao-jian Wang Kai Sun Yang Zheng Zhi-cheng Jing 《Respiratory research》2014,15(1)
Background
Pulmonary arterial hypertension (PAH) is a proliferative arteriopathy associated with a glycolytic shift during heart metabolism. An increase in glycolytic metabolism can be detected in the right ventricle during PAH. Expression levels of glycolysis genes in the right ventricle during glycolysis that occur in monocrotaline (MCT)-induced pulmonary hypertension (PH) remain unknown.Methods
PH was induced by a single subcutaneous injection of MCT (50 mg/kg) into rats, eventually causing right heart failure. Concurrently, a control group was injected with normal saline. The MCT-PH rats were randomly divided into three groups according to MCT treatment: MCT-2 week, 3 week, and 4 week groups (MCT-2w, 3w, 4w). At the end of the study, hemodynamics and right ventricular hypertrophy were compared among experimental groups. Expression of key glycolytic candidate genes was screened in the right ventricle.Results
We observed an increase in mean pulmonary arterial pressure, right ventricular systolic pressure and right ventricular hypertrophy index three weeks following MCT injection. Alterations in the morphology and structure of right ventricular myocardial cells, as well as the pulmonary vasculature were observed. Expression of hexokinase 1 (HK1) mRNA began to increase in the right ventricle of the MCT-3w group and MCT-4w group, while the expression of lactate dehydrogenase A (LDHA) was elevated in the right ventricle of the MCT-4w group. Hexokinase 2(HK2), pyruvate dehydrogenase complex α1 (PDHα1), and LDHA mRNA expression showed no changes in the right ventricle. HK1 mRNA expression was further confirmed by HK1 protein expression and immunohistochemical analyses. All findings underlie the glycolytic phenotype in the right ventricle.Conclusions
There was an increase in the protein and mRNA expression of hexokinase-1 (HK1) three and four weeks after the injection of monocrotaline in the right ventricle, intervention of HK1 may be amenable to therapeutic intervention. 相似文献6.
Reza Karimi G?ran Tornling Helena Forsslund Mikael Mikko ?sa M Wheelock Sven Nyrén Carl Magnus Sk?ld 《Respiratory research》2014,15(1):23
Background
Smokers have increased cell concentration in the lower respiratory tract indicating a chronic inflammatory state, which in some individuals may lead to development of chronic obstructive pulmonary disease (COPD). Computer tomography (CT) imaging provides means of quantifying pulmonary structure and early signs of disease. We investigated whether lung density on high resolution CT differs between smokers and never-smokers and if this were associated to intensity of inflammation.Methods
Forty smoking volunteers with normal pulmonary function, 40 healthy never-smokers and 40 patients with COPD of GOLD stage I-II, were included. Mean lung attenuation and percentage of pixels in the lung with attenuation between −750 and −900 HU (percentage higher density spectrum (%HDS)) were calculated on inspiratory CT-scans. Markers of systemic inflammation in blood and cell counts in bronchoalveolar lavage (BAL) fluid were recorded.Results
Lung density expressed as %HDS was increased in smokers (44.0 ± 5.8%) compared to both never-smokers (38.3 ± 5.8%) and patients with COPD (39.1 ± 5.8%), (p < 0.001, for both). Females had denser lungs than males, which was dependent on body height. Cell concentration in BAL were correlated to lung density in smokers (r = 0.50, p < 0.001).Conclusions
Lung density on CT is associated with cell concentration in BAL in smokers and may mirror an inflammatory response in the lung. Gender difference in lung density is dependent on height. In COPD with emphysema, loss of lung tissue may counterbalance the expected increase in density due to inflammation. The findings may help to interpret high resolution CT in the context of smoking and gender and highlight the heterogeneity of structural changes in COPD. 相似文献7.
Bishnuhari Paudyal Pramila Paudyal Dilip Shah Hideyuki Tominaga Yoshito Tsushima Keigo Endo 《Journal of biomedical science》2014,21(1):35
Background
The aim of this study was to develop the near infrared fluorescence (NIRF)-based imaging agent for the visualization of vascular endothelial growth factor (VEGF) in colon cancer. AlexaFluor 750 conjugating with bevacizumab, and injected intravenously into nude mice bearing VEGF over-expressing HT29 human colorectal cancer. Optical imaging was performed at 15 min, 24 h and 48 h post injection. Immunofluorescences staining of the tumor sections were performed. HT29 colorectal cancer xenografts were clearly visualized with bevacizumab-AlexaFluor 750.Results
Ex vivo analysis showed 2.1 ± 0.4%, 37.6 ± 6.3% and 38.5 ± 6.2% injected dose/g accumulated in the tumors at 15 min, 24 h and 48 h respectively. Tumor uptake was significantly decreased in pretreated with excess of bevacizumab (p = 0.002). Immunofluorescence analysis showed strong staining of anti-CD 31 antibody around the blood vessels. Anti-VEGF-A and bevacizumab showed heterogeneous expression throughout the tumor.Conclusions
Current study successfully detected the VEGF expression in HT29 colorectal cancer xenografts, signifying as a potential agent for non-invasive imaging of VEGF expression, which may be applied in clinical practice. 相似文献8.
Laura C. Price Dongmin Shao Chao Meng Frederic Perros Benjamin E. Garfield Jie Zhu David Montani Peter Dorfmuller Marc Humbert Ian M. Adcock Stephen J. Wort 《Respiratory research》2015,16(1)
Background
Dexamethasone suppressed inflammation and haemodynamic changes in an animal model of pulmonary arterial hypertension (PAH). A major target for dexamethasone actions is NF-κB, which is activated in pulmonary vascular cells and perivascular inflammatory cells in PAH. Reverse remodelling is an important concept in PAH disease therapy, and further to its anti-proliferative effects, we sought to explore whether dexamethasone augments pulmonary arterial smooth muscle cell (PASMC) apoptosis.Methods
Analysis of apoptosis markers (caspase 3, in-situ DNA fragmentation) and NF-κB (p65 and phospho-IKK-α/β) activation was performed on lung tissue from rats with monocrotaline (MCT)-induced pulmonary hypertension (PH), before and after day 14–28 treatment with dexamethasone (5 mg/kg/day). PASMC were cultured from this rat PH model and from normal human lung following lung cancer surgery. Following stimulation with TNF-α (10 ng/ml), the effects of dexamethasone (10−8–10−6 M) and IKK2 (NF-κB) inhibition (AS602868, 0–3 μM (0-3×10−6 M) on IL-6 and CXCL8 release and apoptosis was determined by ELISA and by Hoechst staining. NF-κB activation was measured by TransAm assay.Results
Dexamethasone treatment of rats with MCT-induced PH in vivo led to PASMC apoptosis as displayed by increased caspase 3 expression and DNA fragmentation. A similar effect was seen in vitro using TNF-α-simulated human and rat PASMC following both dexamethasone and IKK2 inhibition. Increased apoptosis was associated with a reduction in NF-κB activation and in IL-6 and CXCL8 release from PASMC.Conclusions
Dexamethasone exerted reverse-remodelling effects by augmenting apoptosis and reversing inflammation in PASMC possibly via inhibition of NF-κB. Future PAH therapies may involve targeting these important inflammatory pathways. 相似文献9.
Gianmarco M Balestra Egbert G Mik Otto Eerbeek Patricia AC Specht Willem J van der Laarse Coert J Zuurbier 《Respiratory research》2015,16(1)
Background
The leading cause of mortality due to pulmonary arterial hypertension (PAH) is failure of the cardiac right ventricle. It has long been hypothesized that during the development of chronic cardiac failure the heart becomes energy deprived, possibly due to shortage of oxygen at the level of cardiomyocyte mitochondria. However, direct evaluation of oxygen tension levels within the in vivo right ventricle during PAH is currently lacking. Here we directly evaluated this hypothesis by using a recently reported technique of oxygen-dependent quenching of delayed fluorescence of mitochondrial protoprophyrin IX, to determine the distribution of mitochondrial oxygen tension (mitoPO2) within the right ventricle (RV) subjected to progressive PAH.Methods
PAH was induced through a single injection of monocrotaline (MCT). Control (saline-injected), compensated RV hypertrophy (30 mg/kg MCT; MCT30), and RV failure (60 mg/kg MCT; MCT60) rats were compared 4 wk after treatment. The distribution of mitoPO2 within the RV was determined in mechanically-ventilated, anaesthetized animals, applying different inspired oxygen (FiO2) levels and two increment dosages of dobutamine.Results
MCT60 resulted in RV failure (increased mortality, weight loss, increased lung weight), MCT30 resulted in compensated RV hypertrophy. At 30% or 40% FiO2, necessary to obtain physiological arterial PO2 in the diseased animals, RV failure rats had significantly less mitochondria (15% of total mitochondria) in the 0-20 mmHg mitoPO2 range than hypertrophied RV rats (48%) or control rats (54%). Only when oxygen supply was reduced to 21% FiO2, resulting in low arterial PO2 for the MCT60 animals, or when oxygen demand increased with high dose dobutamine, the number of failing RV mitochondria with low oxygen became similar to control RV. In addition, metabolic enzyme analysis revealed similar mitochondrial mass, increased glycolytic hexokinase activity following MCT, with increased lactate dehydrogenase activity only in compensated hypertrophied RV.Conclusions
Our novel observation of increased mitochondrial oxygenation suggests down-regulation of in vivo mitochondrial oxygen consumption, in the absence of hypoxia, with transition towards right ventricular failure induced by pulmonary arterial hypertension. 相似文献10.
Yukari Sadamura-Takenaka Takashi Ito Satoshi Noma Yoko Oyama Shingo Yamada Ko-ichi Kawahara Hiromasa Inoue Ikuro Maruyama 《PloS one》2014,9(7)
Rationale
Pulmonary arterial hypertension (PAH) is characterized by increased pulmonary vascular resistance leading to right ventricular failure and death. Recent studies have suggested that chronic inflammatory processes are involved in the pathogenesis of PAH. However, the molecular and cellular mechanisms driving inflammation have not been fully elucidated.Objectives
To elucidate the roles of high mobility group box 1 protein (HMGB1), a ubiquitous DNA-binding protein with extracellular pro-inflammatory activity, in a rat model of PAH.Methods
Male Sprague-Dawley rats were administered monocrotaline (MCT). Concentrations of HMGB1 in bronchoalveolar lavage fluid (BALF) and serum, and localization of HMGB1 in the lung were examined over time. The protective effects of anti-HMGB1 neutralizing antibody against MCT-induced PAH were tested.Results
HMGB1 levels in BALF were elevated 1 week after MCT injection, and this elevation preceded increases of other pro-inflammatory cytokines, such as TNF-α, and the development of PAH. In contrast, serum HMGB1 levels were elevated 4 weeks after MCT injection, at which time the rats began to die. Immunohistochemical analyses indicated that HMGB1 was translocated to the extranuclear space in periarterial infiltrating cells, alveolar macrophages, and bronchial epithelial cells of MCT-injected rats. Anti-HMGB1 neutralizing antibody protected rats against MCT-induced lung inflammation, thickening of the pulmonary artery wall, and elevation of right ventricular systolic pressure, and significantly improved the survival of the MCT-induced PAH rats.Conclusions
Our results identify extracellular HMGB1 as a promoting factor for MCT-induced PAH. The blockade of HMGB1 activity improved survival of MCT-induced PAH rats, and thus might be a promising therapy for the treatment of PAH. 相似文献11.
Pablo Maureira Pierre-Yves Marie Fengxu Yu Sylvain Poussier Yihua Liu Frederique Groubatch Aude Falanga Nguyen Tran 《Journal of biomedical science》2012,19(1):93
Background
Tissue engineering scaffold constitutes a new strategy of myocardial repair. Here, we studied the contribution of a patch using autologous mesenchymal stem cells (MSCs) seeded on collagen-1 scaffold on the cardiac reconstruction in rat model of chronic myocardial infarction (MI).Methods
Patches were cultured with controlled MSCs (growth, phenotype and potentiality). Twenty coronary ligated rats with tomoscingraphy (SPECT)-authenticated transmural chronic MI were referred into a control group (n = 10) and a treated group (n = 10) which beneficiated an epicardial MSC-patch engraftment. Contribution of MSC-patch was tested 1-mo after using non-invasive SPECT cardiac imaging, invasive hemodynamic assessment and immunohistochemistry.Results
3D-collagen environment affected the cell growth but not the cell phenotype and potentiality. MSC-patch integrates well the epicardial side of chronic MI scar. In treated rats, one-month SPECT data have documented an improvement of perfusion in MI segments compared to control (64 ± 4% vs 49 ± 3% p = 0.02) and a reduced infarction. Contractile parameter dp/dtmax and dp/dtmin were improved (p & 0.01). Histology showed an increase of ventricular wall thickness (1.75 ± 0.24 vs 1.35 ± 0.32 mm, p &0.05) and immunochemistry of the repaired tissue displayed enhanced angiogenesis and myofibroblast-like tissue.Conclusion
3D-MSC-collagen epicardial patch engraftment contributes to reverse remodeling of chronic MI. 相似文献12.
Hajime Kasai Toshihiko Sugiura Nobuhiro Tanabe Yoriko Sakurai Misuzu Yahaba Yukiko Matsuura Ayako Shigeta Naoko Kawata Seiichiro Sakao Yasunori Kasahara Koichiro Tatsumi 《PloS one》2014,9(11)
Background
We aimed to study whether pulmonary arterial distensibility (PAD) correlates with hemodynamic parameters in chronic thromboembolic pulmonary hypertension (CTEPH) using electrocardiogram (ECG)-gated 320-slice multidetector computed tomography (MDCT).Methods and Findings
ECG-gated 320-slice MDCT and right heart catheterization (RHC) was performed in 53 subjects (60.6±11.4 years old; 37 females) with CTEPH. We retrospectively measured the minimum and maximum values of the cross sectional area (CSA) of the main pulmonary artery (mainPA), right pulmonary artery (rtPA), and left pulmonary artery (ltPA) during one heartbeat. PAD was calculated using the following formula: PAD = [(CSAmaximum−CSAminimum)/CSAmaximum]×100(%). The correlation between hemodynamic parameters and PAD was assessed. Mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR) were 40.8±8.7 mmHg and 8.3±3.0 wood units, respectively. PAD values were as follows: mainPA (14.0±5.0%), rtPA (12.8±5.6%), and ltPA (9.7±4.6%). Good correlations existed between mainPAD, with mPAP (r = −0.594, p<0.001) and PVR (r = −0.659, p<0.001). The correlation coefficients between rtPAD and ltPAD with pulmonary hemodynamics were all lower or equal than for mainPAD.Conclusions
PAD measured using ECG-gated 320-slice MDCT correlates with pulmonary hemodynamics in subjects with CTEPH. The mainPA is suitable for PAD measurement. 相似文献13.
Jeanne-Marie Perotin Damien Adam Juliette Vella-Boucaud Gonzague Delepine Sebastian Sandu Anne-Carole Jonvel Alain Prevost Gérard Berthiot Christophe Pison Fran?ois Lebargy Philippe Birembaut Christelle Coraux Ga?tan Deslee 《Respiratory research》2014,15(1)
Background
Airway epithelium integrity is essential to maintain its role of mechanical and functional barrier. Recurrent epithelial injuries require a complex mechanism of repair to restore its integrity. In chronic obstructive pulmonary disease (COPD), an abnormal airway epithelial repair may participate in airway remodeling. The objective was to determine if airway epithelial wound repair of airway epithelium is abnormal in COPD.Methods
Patients scheduled for lung resection were prospectively recruited. Demographic, clinical data and pulmonary function tests results were recorded. Emphysema was visually scored and histological remodeling features were noted. Primary bronchial epithelial cells (BEC) were extracted and cultured for wound closure assay. We determined the mean speed of wound closure (MSWC) and cell proliferation index, matrix metalloprotease (MMP)-2, MMP-9 and cytokines levels in supernatants of BEC 18 hours after cell wounding. In a subset of patients, bronchiolar epithelial cells were also cultured for wound closure assay for MSWC analyze.Results
13 COPD and 7 non COPD patients were included. The severity of airflow obstruction and the severity of emphysema were associated with a lower MSWC in BEC (p = 0.01, 95% CI [0.15-0.80]; p = 0.04, 95% CI [−0.77;-0.03] respectively). Cell proliferation index was decreased in COPD patients (19 ± 6% in COPD vs 27 ± 3% in non COPD, p = 0.04). The severity of COPD was associated with a lower level of MMP-2 (7.8 ± 2 105 AU in COPD GOLD D vs 12.8 ± 0.13 105 AU in COPD GOLD A, p = 0.04) and a lower level of IL-4 (p = 0.03, 95% CI [0.09;0.87]). Moreover, higher levels of IL-4 and IL-2 were associated with a higher MSWC (p = 0.01, 95% CI [0.17;0.89] and p = 0.02, 95% CI [0.09;0.87] respectively). Clinical characteristics and smoking history were not associated with MSWC, cell proliferation index or MMP and cytokines levels. Finally, we showed an association of the MSWC of bronchial and corresponding bronchiolar epithelial cells obtained from the same patients (p = 0.02, 95% CI [0.12;0.89]).Conclusion
Our results showed an abnormal bronchial epithelial wound closure process in severe COPD. Further studies are needed to elucidate the contribution and the regulation of this mechanism in the complex pathophysiology of COPD.Electronic supplementary material
The online version of this article (doi:10.1186/s12931-014-0151-9) contains supplementary material, which is available to authorized users. 相似文献14.
Christopher Uhlig Pedro L Silva Débora Ornellas Raquel S Santos Paulo J Miranda Peter M Spieth Thomas Kiss Michael Kasper B?rbel Wiedemann Thea Koch Marcelo M Morales Paolo Pelosi Marcelo Gama de Abreu Patricia RM Rocco 《Respiratory research》2014,15(1):56
Introduction
We investigated the effects of intravenous and intratracheal administration of salbutamol on lung morphology and function, expression of ion channels, aquaporin, and markers of inflammation, apoptosis, and alveolar epithelial/endothelial cell damage in experimental pulmonary (p) and extrapulmonary (exp) mild acute respiratory distress syndrome (ARDS).Methods
In this prospective randomized controlled experimental study, 56 male Wistar rats were randomly assigned to mild ARDS induced by either intratracheal (n = 28, ARDSp) or intraperitoneal (n = 28, ARDSexp) administration of E. coli lipopolysaccharide. Four animals with no lung injury served as controls (NI). After 24 hours, animals were anesthetized, mechanically ventilated in pressure-controlled mode with low tidal volume (6 mL/kg), and randomly assigned to receive salbutamol (SALB) or saline 0.9% (CTRL), intravenously (i.v., 10 μg/kg/h) or intratracheally (bolus, 25 μg). Salbutamol doses were targeted at an increase of ≈ 20% in heart rate. Hemodynamics, lung mechanics, and arterial blood gases were measured before and after (at 30 and 60 min) salbutamol administration. At the end of the experiment, lungs were extracted for analysis of lung histology and molecular biology analysis. Values are expressed as mean ± standard deviation, and fold changes relative to NI, CTRL vs. SALB.Results
The gene expression of ion channels and aquaporin was increased in mild ARDSp, but not ARDSexp. In ARDSp, intravenous salbutamol resulted in higher gene expression of alveolar epithelial sodium channel (0.20 ± 0.07 vs. 0.68 ± 0.24, p < 0.001), aquaporin-1 (0.44 ± 0.09 vs. 0.96 ± 0.12, p < 0.001) aquaporin-3 (0.31 ± 0.12 vs. 0.93 ± 0.20, p < 0.001), and Na-K-ATPase-α (0.39 ± 0.08 vs. 0.92 ± 0.12, p < 0.001), whereas intratracheal salbutamol increased the gene expression of aquaporin-1 (0.46 ± 0.11 vs. 0.92 ± 0.06, p < 0.001) and Na-K-ATPase-α (0.32 ± 0.07 vs. 0.58 ± 0.15, p < 0.001). In ARDSexp, the gene expression of ion channels and aquaporin was not influenced by salbutamol. Morphological and functional variables and edema formation were not affected by salbutamol in any of the ARDS groups, regardless of the route of administration.Conclusion
Salbutamol administration increased the expression of alveolar epithelial ion channels and aquaporin in mild ARDSp, but not ARDSexp, with no effects on lung morphology and function or edema formation. These results may contribute to explain the negative effects of β2-agonists on clinical outcome in ARDS. 相似文献15.
Alessandro Tonacci Andrea Borghini Antonella Mercuri Giovanni Pioggia Maria Grazia Andreassi 《Journal of biomedical science》2013,20(1):57
Background
Brain- derived neurotrophic factor (BDNF) is linked to neurodegenerative diseases (e.g. Alzheimer disease and Parkinson disease) which are often characterized by olfactory impairment. A specific single nucleotide polymorphism of the BDNF gene, the Val66Met, modulates intracellular trafficking and activity-dependent secretion of BDNF protein. The aim of this study was to investigate a possible association between brain- derived neurotrophic factor Val66Met polymorphism and olfactory function, a well-known biomarker for neurodegeneration, in healthy young adults. A total of 101 subjects (45 males, age 38.7 ± 9.4 years) were assessed using the Sniffin’ Sticks Extended Test, a highly reliable commercial olfactory test composed of three sub-parts, calculating olfactory threshold (sensitivity), odor discrimination and odor identification. The Val66Met polymorphism was determined by polymerase chain reaction -restriction fragment length polymorphism (PCR-RFLP) analysis.Results
An impaired function in Met carriers was found, especially when compared to subjects with Val/Val genotype, in the threshold (5.5 ± 2.0 vs 6.5 ± 1.8, p = 0.009), discrimination (10.3± 2.5 vs 11.9 ± 2.2, p = 0.002), and identification task (13.3 ± 1.6 vs 14.1 ± 1.3, p = 0.007), as well as in the overall TDI Score (29.1 ± 4.5 vs 32.6 ± 3.9, p < 0.001).Conclusions
These findings appear to have implications for the evaluation of olfactory function and the relation of its impairment to cognitive decline and neurodegenerative disease. 相似文献16.
Rationale
The demographics of patients with idiopathic pulmonary arterial hypertension (IPAH) are changing and this diagnosis is increasingly being made in older patients. However, diagnostic misclassifications are common as it may be difficult to differentiate between IPAH and pulmonary hypertension due to heart failure with preserved ejection fraction (PH-HFpEF). We investigated the hypothesis that the capillary pCO2 (pcCO2) may help distinguishing between idiopathic pulmonary arterial hypertension (IPAH) and pulmonary hypertension due to heart failure with preserved ejection fraction (PH-HFpEF).Methods
In a cross-sectional study, we retrospectively assessed pcCO2 levels (obtained from arterialized capillary blood at the time of diagnosis) from patients with IPAH or PH-HFpEF, respectively. Receiver operated characteristics (ROC) were used to determine the pcCO2 level providing the best discrimination between these two conditions. PcCO2 values were considered helpful if they were associated with a negative predictive value >0.9 to excluded either IPAH or PH-HFpEF.Results
The study enrolled 185 patients, 99 with IPAH (74% female; age 47 ± 17 years; body mass index 26 ± 5 kg/m2, PAPm 53 ± 12 mmHg, PAWP 8 ± 3 mmHg), and 86 with PH-HFpEF (64% female; age 69 ± 10 years; body mass index 30 ± 6 kg/m2, PAPm 47 ± 10 mmHg, PAWP 21 ± 5 mmHg). PcCO2 at time of diagnosis was 33 ± 4 mmHg in the IPAH group and 40 ± 5 mmHg in the PH-HFpEF group (p < 0.001), respectively. According to ROC analysis, a pcCO2 of 36 mmHg was the best discriminator between both entities with an area under curve of 0.87 (p < 0.001). The likelihood of PH-HFpEF was <10% in patients with a PcCO2 < 34 mmHg, whereas the likelihood of IPAH was <10% in patients with a PcCO2 > 41 mmHg.Conclusions
PcCO2 levels were significantly lower in IPAH compared to PH-HFpEF and may provide useful information in differentiating between both conditions. 相似文献17.
Computer quantification of airway collapse on forced expiration to predict the presence of emphysema
Marko Topalovic Vasileios Exadaktylos Anneleen Peeters Johan Coolen Walter Dewever Martijn Hemeryck Pieter Slagmolen Karl Janssens Daniel Berckmans Marc Decramer Wim Janssens 《Respiratory research》2013,14(1):131
Background
Spirometric parameters are the mainstay for diagnosis of COPD, but cannot distinguish airway obstruction from emphysema. We aimed to develop a computer model that quantifies airway collapse on forced expiratory flow–volume loops. We then explored and validated the relationship of airway collapse with computed tomography (CT) diagnosed emphysema in two large independent cohorts.Methods
A computer model was developed in 513 Caucasian individuals with ≥15 pack-years who performed spirometry, diffusion capacity and CT scans to quantify emphysema presence. The model computed the two best fitting regression lines on the expiratory phase of the flow-volume loop and calculated the angle between them. The collapse was expressed as an Angle of collapse (AC) which was then correlated with the presence of emphysema. Findings were validated in an independent group of 340 individuals.Results
AC in emphysema subjects (N = 251) was significantly lower (131° ± 14°) compared to AC in subjects without emphysema (N = 223), (152° ± 10°) (p < 0.0001). Multivariate regression analysis revealed AC as best indicator of visually scored emphysema (R2 = 0.505, p < 0.0001) with little significant contribution of KCO, %predicted and FEV1, %predicted to the total model (total R2 = 0.626, p < 0.0001). Similar associations were obtained when using CT-automated density scores for emphysema assessment. Receiver operating characteristic (ROC) curves pointed to 131° as the best cut-off for emphysema (95.5% positive predictive value, 97% specificity and 51% sensitivity). Validation in a second group confirmed the significant difference in mean AC between emphysema and non-emphysema subjects. When applying the 131° cut-off, a positive predictive value of 95.6%, a specificity of 96% and a sensitivity of 59% were demonstrated.Conclusions
Airway collapse on forced expiration quantified by a computer model correlates with emphysema. An AC below 131° can be considered as a specific cut-off for predicting the presence of emphysema in heavy smokers. 相似文献18.
Background
An antianginal KATP channel opener nicorandil has various beneficial effects on cardiovascular systems; however, its effects on pulmonary vasculature under pulmonary arterial hypertension (PAH) have not yet been elucidated. Therefore, we attempted to determine whether nicorandil can attenuate monocrotaline (MCT)-induced PAH in rats.Materials and Methods
Sprague-Dawley rats injected intraperitoneally with 60 mg/kg MCT were randomized to receive either vehicle; nicorandil (5.0 mg·kg−1·day−1) alone; or nicorandil as well as either a KATP channel blocker glibenclamide or a nitric oxide synthase (NOS) inhibitor N ω-nitro-l-arginine methyl ester (l-NAME), from immediately or 21 days after MCT injection. Four or five weeks later, right ventricular systolic pressure (RVSP) was measured, and lung tissue was harvested. Also, we evaluated the nicorandil-induced anti-apoptotic effects and activation status of several molecules in cell survival signaling pathway in vitro using human umbilical vein endothelial cells (HUVECs).Results
Four weeks after MCT injection, RVSP was significantly increased in the vehicle-treated group (51.0±4.7 mm Hg), whereas it was attenuated by nicorandil treatment (33.2±3.9 mm Hg; P<0.01). Nicorandil protected pulmonary endothelium from the MCT-induced thromboemboli formation and induction of apoptosis, accompanied with both upregulation of endothelial NOS (eNOS) expression and downregulation of cleaved caspase-3 expression. Late treatment with nicorandil for the established PAH was also effective in suppressing the additional progression of PAH. These beneficial effects of nicorandil were blocked similarly by glibenclamide and l-NAME. Next, HUVECs were incubated in serum-free medium and then exhibited apoptotic morphology, while these changes were significantly attenuated by nicorandil administration. Nicorandil activated the phosphatidylinositol 3-kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK) pathways in HUVECs, accompanied with the upregulation of both eNOS and Bcl-2 expression.Conclusions
Nicorandil attenuated MCT-induced vascular endothelial damage and PAH through production of eNOS and anti-apoptotic factors, suggesting that nicorandil might have a promising therapeutic potential for PAH. 相似文献19.
Yung-Kuo Lin Yao-Chang Chen Jen-Hung Huang Yenn-Jiang Lin Shiang-Suo Huang Shih-Ann Chen Yi-Jen Chen 《Journal of biomedical science》2013,20(1):94
Background
Obesity is an important risk factor for atrial fibrillation (AF). Leptin is an important adipokine. However, it is not clear whether leptin directly modulates the electrophysiological characteristics of atrial myocytes.Results
Whole cell patch clamp and indo-1 fluorescence were used to record the action potentials (APs) and ionic currents in isolated rabbit left atrial (LA) myocytes incubated with and without (control) leptin (100 nM) for 1 h to investigate the role of leptin on atrial electrophysiology. Leptin-treated LA myocytes (n = 19) had longer 20% of AP duration (28 ± 3 vs. 21 ± 2 ms, p < 0.05), but similar 50% of AP duration (51 ± 4 vs. 50 ± 3 ms, p > 0.05), and 90% of AP duration (89 ± 5 vs. 94 ± 4 ms, p > 0.05), as compared to the control (n = 22). In the presence of isoproterenol (10 nM), leptin-treated LA myocytes (n = 21) showed a lower incidence (19% vs. 54.2%, p < 0.05) of delayed afterdepolarization (DAD) than the control (n = 24). Leptin-treated LA myocytes showed a larger sodium current, but a smaller ultra-rapid delayed rectifier potassium current, and sodium-calcium exchanger current than the control. Leptin-treated and control LA myocytes exhibited a similar late sodium current, inward rectifier potassium current, transient outward current and L-type calcium current. In addition, the leptin-treated LA myocytes (n = 38) exhibited a smaller intracellular Ca2+ transient (0.21 ± 0.01 vs. 0.26 ± 0.01 R410/485, p < 0.05) and sarcoplasmic reticulum Ca2+ content (0.35 ± 0.02 vs. 0.43 ± 0.03 R410/485, p < 0.05) than the control LA myocytes (n = 42).Conclusions
Leptin regulates the LA electrophysiological characteristics and attenuates isoproterenol-induced arrhythmogenesis. 相似文献20.
Stephanie Korn Marisa Hübner Matthias Jung Maria Blettner Roland Buhl 《Respiratory research》2013,14(1):25