Budesonide/formoterol maintenance and reliever therapy in Chinese patients with asthma / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Many studies have shown the superior efficacy of budesonide (BUD)/formoterol (FORM) maintenance and reliever therapy, but still lack evidence of its efficacy in Chinese asthma patients in a relative large patient-group. We finished this research to compare BUD/FORM maintenance and reliever therapy and high-dose salmeterol (SALM)/fluticasone (FP) maintenance plus an as-needed short-acting β(2)-agonist in Chinese patients with persistent uncontrolled asthma. This was a post hoc analysis based on a 6-month, multicenter, randomized, double-blind study (NCT00242775).</p><p><b>METHODS</b>A total of 222 eligible asthma patients from nine centers in China were randomized to either BUD/FORM+as-needed BUD/FORM (160/4.5 µg/inhalation) (640/18 µg/d; n = 111), or SALM/FP+as-needed terbutaline (0.4 mg/inhalation) (100/1000 µg/d; n = 111). The primary endpoint was time to first severe exacerbation while secondary endpoints included various measures of pulmonary function, symptom control and quality-of-life.</p><p><b>RESULTS</b>Time to first severe exacerbation over six months was lower with the BUD/FORM than with the SALM/FP treatment (risk ratio = 0.52, 95%CI 0.22 - 1.22), but the difference did not achieve statistical significance (P = 0.13). The cumulative number of severe exacerbations in the BUD/FORM group was lower than in the SALM/FP group (7.2% vs. 13.5%; risk ratio = 0.45, P = 0.028). BUD/FORM produced significantly better improvements in reliever use, cumulative mild exacerbations, symptom-free days (%), and morning/evening peak expiratory flow (PEF) than SALM/FP (P < 0.05 in all cases). The two groups achieved similar improvements in their time to first mild exacerbation, forced expiratory volume in one second (FEV(1)), asthma control questionnaire and asthma symptom scores, and percentage of nights with awakening(s). Both treatments were well tolerated.</p><p><b>CONCLUSIONS</b>In Chinese patients with persistent asthma, BUD/FORM decreased severe and mild exacerbations, decreased reliever use, increased symptom-free days, and improved morning/evening PEF compared with SALM/FP. There were no significant differences in time to first severe exacerbation or other assessments regarding daily asthma control between BUD/FORM and SALM/FP. BUD/FORM was more effective in this Chinese sub-group than in the total cohort involved in the original study.</p>

GATA3 siRNA inhibits the binding of NFAT1 to interleukin-13 promoter in human T cells / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Interleukin-13 (IL-13) is recognized to be a key modulator in the pathogenesis of Th2-induced allergic inflammation. Transcription factors GATA3 and NFAT1 have been both implicated in the regulation of Th2 cytokines. We previously demonstrated the GATA3-NFAT1 association during human T cell activation. However, the function of the GATA3-NFAT1 complex in Th2 cytokines regulation is still unknown. Small interference RNA (siRNA) was constructed to knock down GATA3 expression in Hut-78 cells to investigate the possible role of GATA3-NFAT1 complex in IL-13 transcription.</p><p><b>METHODS</b>Cells were stimulated with anti-CD3 plus anti-CD28 antibodies to mimic in vivo antigen-mediated co-stimulation; the expression of IL-13 mRNA was determined by real-time PCR; chromation immunoprecipitation (CHIP) assay was employed to investigate the NFAT1 binding to IL-13 promoter.</p><p><b>RESULTS</b>GATA3 siRNA suppressed the expression of GATA3 both in mRNA and protein levels in Hut-78 cells. The binding of NFAT1 to IL-13 promoter was inhibited by GATA3 siRNA in activated T cells, which was followed by the reduction of IL-13 transcription.</p><p><b>CONCLUSION</b>GATA3-NFAT1 complex may play an important role in the regulation of IL-13 transcription in human T cells.</p>

Association among plasma interleukin-18 levels, carotid intima- media thickness and severity of obstructive sleep apnea / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Epidermic studies have suggested a pathophysiological link between obstructive sleep apnea hypopnea syndrome (OSAHS) and atherosclerosis (AS); for which carotid intima-media thickness (IMT) has been considered as an early marker. The pathogenesis by which OSAHS can induce AS has not been elucidated. This study was conducted to investigate the association among plasma interleukin-18 (IL-18) levels, carotid IMT and the severity of OSAHS.</p><p><b>METHODS</b>Based on the apnea hypopnea index (AHI) during sleep monitored by polysomnography, 52 male patients with OSAHS were recruited as the OSAHS group which was further divided into mild OSAHS (n = 16), moderate OSAHS (n = 18), and severe OSAHS (n = 18) subgroups. Eighteen healthy subjects were selected as the control group. Of all OSAHS patients, 20 with moderate-to-severe OSAHS underwent continuous positive airway pressure (CPAP) treatment for 90 days. HDL5000 color Doppler ultrasonography was used to measure carotid IMT. Plasma IL-18 levels were measured by ELISA.</p><p><b>RESULTS</b>Compared with the plasma IL-18 levels in the control group ((250.27 +/- 76.48) pg/ml), there was a significant increase in the mild OSAHS subgroup ((352.08 +/- 76.32) pg/ml), the moderate subgroup ((600.17 +/- 83.91) pg/ml), and the severe OSAHS subgroup ((9797.64 +/- 109.83) pg/ml) (all P < 0.01). Moreover, there was a significant difference in plasma IL-18 levels among the three OSAHS subgroups (P < 0.01). Carotid IMT was significantly greater in the severe OSAHS subgroup than in the mild OSAHS subgroup (P < 0.01). Before CPAP treatment, plasma IL-18 levels were positively correlated with carotid IMT (r = 0.486, P < 0.001) and with AHI (r = 0.865, P < 0.001). On day 90 of CPAP treatment, plasma IL-18 levels were significantly declined but carotid IMT was not changed significantly.</p><p><b>CONCLUSIONS</b>In untreated OSAHS patients carotid IMT and plasma IL-18 were positively correlated and were significantly higher than in normal controls; the elevation of plasma IL-18 levels was correlated with the severity of OSAHS. Inflammatory response associated with OSAHS may be related to the development of AS. By improving AHI, miniSaO(2), and reducing plasma IL-18 levels, CPAP treatment may slow down or prevent the development of AS in OSAHS patients.</p>

Inhibitory effects of sunitinib on ovalbumin-induced chronic experimental asthma in mice / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Tyrosine kinase signaling cascades play a critical role in the pathogenesis of allergic airway inflammation. Sunitinib, a multitargeted receptor tyrosine kinase inhibitor, has been reported to exert potent immunoregulatory, anti-inflammatory and anti-fibrosis effects. We investigated whether sunitinib could suppress the progression of airway inflammation, airway hyperresponsiveness (AHR), and airway remodeling in a murine model of chronic asthma.</p><p><b>METHODS</b>Ovalbumin (OVA)-sensitized mice were chronically challenged with aerosolized OVA for 8 weeks. Some mice were intragastrically administered with sunitinib (40 mg/kg) daily during the period of OVA challenge. Twelve hours after the last OVA challenge, mice were evaluated for the development of airway inflammation, AHR and airway remodeling. The levels of total serum immunoglobulin E (IgE) and Th2 cytokines (interleukin (IL)-4 and IL-13) in bronchoalveolar lavage fluid (BALF) were measured by ELISA. The expression of phosphorylated c-kit protein in the lungs was detected by immunoprecipitation/Western blotting (IP/WB) analysis.</p><p><b>RESULTS</b>Sunitinib significantly inhibited eosinophilic airway inflammation, persistent AHR and airway remodeling in chronic experimental asthma. It reduced levels of total serum IgE and BALF Th2 cytokines and also lowered the expression of phosphorylated c-kit protein in remodelled airways.</p><p><b>CONCLUSIONS</b>Sunitinib may inhibit the development of airway inflammation, AHR and airway remodeling. It is potentially beneficial to the prevention or treatment of asthma.</p>

Effect of valsartan on the expression of angiotensin II receptors in the lung of chronic antigen exposure rats / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Many studies have suggested that angiotensin II (Ang II) and its receptors may be involved in the development of asthma. However, the expression of angiotensin II receptors (AGTR) is not clear in the lung tissue of chronic asthmatics. This study was designed to determine the relationship between airway remodeling, dysfunction and the expression of AGTRs in a rat model of asthma.</p><p><b>METHODS</b>Rats were sensitized with ovalbumin (OVA) for 2 weeks. Sixty minutes before an inhalation challenge, the rats were pretreated either with valsartan (15, 30, 50 mg x kg(-1) x d(-1)) or saline intragastrically. Then the rats received an OVA challenge for 30 alternative days. Acetylcholine (Ach)-induced bronchoconstriction was measured after the final antigen challenge. White cell counts in bronchoalveolar lavage fluid (BALF) and morphological changes in the airways were then assessed. The levels of transforming growth factor-beta 1 (TGF-beta(1)) and platelet-derived growth factor (PDGF) in BALF were detected by ELISA. The levels of AGTR1 and AGTR2 mRNA and protein in lung tissues were measured by RT-PCR and Western blotting.</p><p><b>RESULTS</b>AGTR1 mRNA and protein levels in repeatedly OVA-challenged rats were significantly increased as compared with negative controls. The AGTR1 mRNA expression versus white cell counts of BALF and airway wall thickness (mainly in small airways) in lungs of chronic antigen-exposed rats were positively correlated. Valsartan decreased the level of AGTR1 in repeatedly OVA-challenged rats. However, AGTR2 mRNA and protein levels in the OVA-challenged rats and high-dose valsartan-treated rats (50 mg x kg(-1) x d(-1)) were also increased. Valsartan significantly decreased inflammatory cell accumulation and attenuated Ach-evoked bronchoconstriction in repeatedly antigen-challenged rats. Valsartan also decreased allergen-induced structural changes in rat airway (including total airway wall thickness and smooth muscle area) and the levels of TGF-beta(1) and PDGF in BALF.</p><p><b>CONCLUSIONS</b>AGTR1 expression is potentially associated with airway remodeling and dysfunction in asthma. Ang II and AGTR1 may participate in airway inflammation and airway remodeling of chronic antigen-exposed rats. Valsartan, a AGTR1 antagonist, could inhibit AGTR1 expression and partially inhibits structural airway changes as well as airway inflammation in chronic OVA-exposed rats.</p>

Expression of surface markers on peripheral CD4+CD25high T cells in patients with atopic asthma: role of inhaled corticosteroid / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>CD4(+)CD25(+) regulatory T cells (Tregs) mediate immune suppression through cell-cell contact with surface molecules, particularly cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR), and transforming growth factor beta (TGF-beta), but little is known about the exact role of Tregs in the pathogenesis of asthma. This study sought to characterize the expression of surface markers on peripheral blood mononuclear cells-derived Tregs in patients with atopic asthma and healthy subjects, and to investigate the effect of inhaled corticosteroid on them.</p><p><b>METHODS</b>The expression of surface molecules on CD4(+)CD25(high) Tregs was detected by flow cytometry. The effect of inhaled corticosteroid on expression of the surface molecules on Tregs was determined in vivo and in vitro. Total serum immunoglobulin E (IgE) and high-sensitivity C-reactive protein were measured by enzyme linked immunosorbent assay and latex enhanced immunoturbidimetric assay, respectively.</p><p><b>RESULTS</b>Equivalent numbers of peripheral Tregs were found in patients with atopic asthma (stable and acute) and healthy subjects. Tregs preferentially expressed CTLA-4, GITR, toll-like receptor 4 (TLR4), latency-associated peptide (LAP/TGF-beta1), and forkhead box P3 (FOXP3). Patients with acute asthma had decreased numbers of CD4(+)CD25(high)LAP(+) T cells compared to healthy subjects and stable asthmatics. Inhaled corticosteroid enhanced the percentage of Tregs expressing LAP in vivo and in vitro dose-dependently. Furthermore, the percentages of Tregs expressing LAP were negatively correlated with total serum IgE levels and severity of asthma, but positively correlated with forced expiratory volume in one second percentage of the predicted value in patients with asthma.</p><p><b>CONCLUSIONS</b>The results suggest that membrane-bound TGF-beta1 is a potential candidate for predicting the severity of asthma, and may contribute to the sustained remission of asthma. Strategies targeting Tregs on their surface markers, especially TGF-beta1, are promising for future therapy of asthma.</p>

Increased RhoGDI2 and peroxiredoxin 5 levels in asthmatic murine model of beta2-adrenoceptor desensitization: a proteomics approach / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Beta(2)-adrenoceptor (beta(2)AR) desensitization is a common problem in clinical practice. beta(2)AR desensitization proceeds by at least such three mechanisms as heterologous desensitization, homologous desensitization and a kind of agonist-induced rapid phosphorylation by a variety of serine/threonine kinases. It is not clear whether there are other mechanisms. This study aimed to investigate potential mechanisms of beta(2)AR desensitization.</p><p><b>METHODS</b>Twenty-four BALB/c (6-8 weeks old) mice were divided into three groups, which is, group A, phosphate buffered saline (PBS)-treated; group B, ovalbumin (OVA)-induced; and group C, salbutamol-treated. Inflammatory cell counts, cytokine concentrations of bronchoalveolar lavage fluid (BALF), pathological sections, total serum IgE, airway responsiveness, membrane receptor numbers and total amount of beta(2)AR were observed. Asthmatic mouse model and beta(2)AR desensitization asthmatic mouse model were established. Groups B and C were selected for two-dimensional gel electrophoresis (2DE) analysis so as to find key protein spots related to beta(2)AR desensitization.</p><p><b>RESULTS</b>Asthmatic mouse model and beta(2)AR desensitization asthmatic mouse model were verified by inflammatory cell count, cytokine concentration of BALF, serum IgE level, airway hyperreactivity measurement, radioligand receptor binding assay, Western blot analysis, and pathologic examination. Then the two groups (groups B and C) were subjected to 2DE. Two key protein spots associated with beta(2)AR desensitization, Rho GDP-dissociation inhibitor 2 (RhoGDI(2)) and peroxiredoxin 5, were found by comparative proteomics (2DE and mass spectrum analysis).</p><p><b>CONCLUSION</b>Oxidative stress and small G protein regulators may play an important role in the process of beta(2)AR desensitization.</p>

Validity of Asthma Control Test in Chinese patients / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>So far, in China, there has been no effective or easy procedure to define the control of asthma. This study assesses the validity of Asthma Control Test in Chinese patients.</p><p><b>METHODS</b>Three questionnaires (Asthma Control Test, Asthma Control Questionnaire and the 30 second asthma test) were administered to 305 asthma patients from 10 teaching hospitals across China. Spirometry was also used. Asthma specialists rated the control of asthma according to patients' symptoms, medications and forced expiratory volume in first second. The patients were divided into noncontrolled group and controlled group according to the specialists' rating. Reliability, empirical validity and screening accuracy were conducted for Asthma Control Test scores. Screening accuracy was compared among 3 questionnaires. The patients' self rating and the specialists' rating were also compared.</p><p><b>RESULTS</b>The internal consistency reliability of the 5-item Asthma Control Test was 0.854. The correlation coefficient between Asthma Control Test and the specialists' rating was 0.729, which was higher than other instruments. Asthma Control Test scores discriminated between groups of patients differing in the percent predicted forced expiratory volume in first second (F = 26.06, P < 0.0001), the specialists' rating of asthma control (F = 88.24, P < 0.0001) and the Asthma Control Questionnaire scores (F = 250.57, P < 0.0001). Asthma Control Test showed no significant difference with Asthma Control Questionnaire in the percent correctly classified, while the percent correctly classified by Asthma Control Test was much higher than 30 second asthma test. The patients' self rating was the same as assessment of the specialists (t = 0.65, P = 0.516).</p><p><b>CONCLUSION</b>The Asthma Control Test is an effective and practicable method for assessing asthma control in China.</p>

Adeno-associated virus-mediated CD40 ligand transfer into human lung cancer cells / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To investigate the transduction efficiency of serotype 1, 2, 5, 6, 7, 8, 9, 10 recombinant adeno-associated viruses (rAAV) in human lung cancer cell line A549 cells and compare the transduction efficiency of conventional AAV vectors with that of self-complementary AAV (scAAV) vectors. Furthermore, the capacity of A549 cells expressing transgenic CD40L to stimulate dendritic cells (DCs) was evaluated.</p><p><b>METHODS</b>Lung cancer A549 cells were infected with 1 x 10(4) particules per cell of AAV encoding the green fluorescent protein (GFP) or human CD40L driven by CMV promotor, and transgene expression was analyzed by flow cytometry and fluorescence microscopy. Stimulation of isolated human dendritic cells by CD40L-expressing tumor cells was quantified by measuring secreted interleukin-12 with immunoassay.</p><p><b>RESULTS</b>Serotype AAV2/5 transduced A549 cells much more efficiently than serotypes AAV2/1, AAV2/2, AAV2/6, AAV2/7, AAV2/8, AAV2/9 and AAV2/10. The transduction efficiency of scAAV2/5 was significantly higher than that of conventional AAV2/5. Furthermore, pre-treatment with carboplatin substantially increased AAV-mediated transgene expression. The scAAV2/5 vectors encoding human CD40L was used to generate CD40L. A549 cells transduce by these vectors were co-cultured with immature human DCs. As a consequence, interleukin-12 was released and measured in the culture supernatant. Specificity of immunostimulatory effect of CD40L was confirmed by blocking with a monoclonal antibody binding to human CD40L.</p><p><b>CONCLUSION</b>scAAV2/5 transduce lung adenocarcinoma A549 cell efficiently, and co-administration of chemotherapeutic agent carboplatin further enhances its transduction efficiency. It is confirmed that lung cancer cells infected with a CD40L-encoding scAAV2/5 construct can activate human DCs to secrete interleukin-12. Our findings provided a basis for future immunotherapeutic approaches including intratumoral transfer of stimulating factors.</p>

Effect of continuous positive airway pressure treatment on serum adiponectin level and mean arterial pressure in male patients with obstructive sleep apnea syndrome / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Recent research suggested that obstructive sleep apnea syndrome (OSAS) might be independently associated with hypoadiponectinemia, which was linked to some complications of OSAS, such as hypertension, diabetes, etc. This study was conducted to investigate the effect of continuous positive airway pressure (CPAP) treatment on changes of both serum adiponectin levels and mean arterial pressure and their possible links in male OSAS patients.</p><p><b>METHODS</b>Twenty-three adult male patients with moderate-to-severe OSAS but without obesity, coronary heart disease and diabetes were recruited. Their blood samples were collected and morning mean arterial pressure (MAP) was measured before CPAP treatment and on day 3, 7, 14 of CPAP treatment respectively. The serum adiponectin concentration was tested with radioimmunoassay.</p><p><b>RESULTS</b>Compared with the serum adiponectin level before CPAP treatment, no significant change was found in OSAS patients on day 3 and day 7 of CPAP treatment (P > 0.05). It was not until day 14 of CPAP treatment did a significant elevation in serum adiponectin level occur (P < 0.01). Meanwhile, the MAP showed no statistically significant difference among its levels before CPAP, on day 3 and day 7 of CPAP treatment (P > 0.05). However, on day 14 of CPAP treatment, a significantly lower MAP than that obtained before treatment was observed (P < 0.05).</p><p><b>CONCLUSIONS</b>CPAP treatment can gradually reverse hypoadiponectinemia and reduce MAP in OSAS patients. Hypoadiponectinemia might be involved in the pathogenesis of OSAS-mediated hypertension.</p>

Efficacy of adaptive servoventilation in patients with congestive heart failure and Cheyne-Stokes respiration / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Congestive heart failure (CHF) is associated with Cheyne-Stokes respiration (CSR), which may hasten CHF. Adaptive servoventilation (ASV) is a novel method of ventilatory support designed for removal of CSF in CHF patients. This study compares the efficacy of ASV in patients with CHF and CSR with the efficacy of oxygen therapy.</p><p><b>METHODS</b>Fourteen patients with CHF and CSR were recruited. During sleep, nasal oxygen therapy and ASV treatment were each performed for two weeks. Comparison before and after each treatment was made for the following items: a) parameters of sleep respiration, sleep structure and quality; b) left ventricle ejection fraction (LVEF) and 6-minute walk distance.</p><p><b>RESULTS</b>Compared with the baseline levels of apnoea hypopnoea index of 34.5 +/- 6.1 before treatment, the apnoea hypopnoea index significantly decreased following oxygen therapy to 27.8 +/- 8.2, P < 0.05 and further reduced following ASV treatment to 6.5 +/- 0.8, P < 0.01. The minimal pulse oxygen saturation markedly increased following oxygen therapy from a baseline of (84.3 +/- 2.6)% to (88.6 +/- 3.7)%, P < 0.05 and further increased following ASV treatment (92.1 +/- 4.9)%, P < 0.01. Stages I + II sleep as percentage of total sleep time decreased from (81.9 +/- 7.1)% to (78.4 +/- 6.7)% following oxygen therapy and further to (72.4 +/- 5.0)% following ASV treatment. Stages III + IV sleep as percentage of total sleep time decreased from (8.4 +/- 5.5)% to (6.0 +/- 3.0)% following oxygen therapy and but increased to (11.9 +/- 5.4)% following ASV treatment. The arousal index of 30.4 +/- 8.1 before treatment significantly decreased following oxygen therapy to 25.6 +/- 5.7, P < 0.05 and further declined following ASV treatment to 18.2 +/- 6.1, P < 0.01. No significant difference was shown in above percentages between day 14 of oxygen therapy and before treatment (P > 0.05). LVEF was significantly higher on day 14 of ASV treatment (37.2 +/- 4.1)% than on day 14 of oxygen therapy (33.2 +/- 5.1)% and before treatment (30.2 +/- 4.6)% (all P < 0.05). Six-minute walk distance was the shortest before treatment (226 +/- 28) m, longer on day 14 of oxygen therapy (289 +/- 26) m, and the longest on day 14 of ASV treatment (341 +/- 27) m (all P < 0.01).</p><p><b>CONCLUSION</b>ASV treatment is of better efficacy and greater clinical significance in improvement of CHF by eliminating CSR than oxygen therapy.</p>

Treatment of allergic airway inflammation and hyperresponsiveness by imiquimod modulating transcription factors T-bet and GATA-3 / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Imiquimod is an imidazoquinoline, which class of compounds are known to have antiviral and antitumoural properties. In recent studies, it was shown that imiquimod modulates the T helper cell type Th1/Th2 response by inducing the production of Th1 cytokines like IFN-gamma, and by inhibiting the Th2 cytokines like interleukin (IL)-4. Several investigators have shown that T-bet and GATA-3 are master Th1 and Th2 regulatory transcription factors. This study investigated whether imiquimod treatment inhibited airway inflammation by modulating transcription factors T-bet and GATA-3.</p><p><b>METHODS</b>Thirty-six male SD rats were randomly divided into a control group, an asthmatic group, and an imiquimod group, which was exposed to an aerosol of 0.15% imiquimod. Twenty-four hours after the last ovalbumin (OVA) challenge, airway responsiveness was measured and changes in airway histology were observed. The concentrations of IL-4, IL-5 and IFN-gamma in bronchoalveolar lavage fluid (BALF) and serum were measured by enzyme linked immunosorbent assay (ELISA). The mRNA expressions of IL-4, IL-5, IFN-gamma, T-bet and GATA-3 in lung and in CD4(+) T cells were determined by reverse transcription polymerase chain reaction (RT-PCR). The protein expressions of T-bet and GATA-3 were measured by Western blot.</p><p><b>RESULTS</b>It was demonstrated that imiquimod 1) attenuated OVA induced airway inflammation; 2) diminished the degree of airway hyperresponsiveness (AHR); 3) decreased the Th2 type cytokines and increased Th1 type cytokines mRNA and protein levels; 4) modulated the Th1/Th2 reaction by inhibiting GATA-3 production and increasing T-bet production.</p><p><b>CONCLUSION</b>Imiquimod treatment inhibits OVA induced airway inflammation by modulating key master switches GATA-3 and T-bet that result in committing T helper cells to a Th1 phenotype.</p>

Adenovirus-mediated overexpression of novel mutated IkappaBalpha inhibits nuclear factor kappaB activation in endothelial cells / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Nuclear factor kappaB (NF-kappaB) overactivation, requiring phosphorylation and degradation of its inhibitor IkappaBalpha, is the basis for chronicity of airway inflammation in asthma. Based on our previous plasmid pShuttle-IkappaBalpha, carrying an IkappaBalpha gene from human placenta, we optimized a novel IkappaBalpha mutant (IkappaBalphaM) gene, constructed and characterized its replication-deficient recombinant adenovirus (AdIkappaBalphaM), and tested whether AdIkappaBalphaM-mediated overexpression of IkappaBalphaM could inhibit the NF-kappaB activation in endothelial cells.</p><p><b>METHODS</b>IkappaBalphaM gene (203 - 1003 bp) encoding 267 amino acids, acquired by site-directed deleting N-terminal phosphorylation sites of serine 32/36, was subcloned into the pShuttle and pGEM-T vectors for further polymerase chain reaction (PCR), restriction digestion, deoxyribonucleic acid (DNA) sequencing and homology analyses. Subsequent to inserting the expression unit of pShuttle-IkappaBalphaM, containing cytomegalovirus (CMV) promoter, IkappaBalphaM complementary DNA (cDNA) and polyadenylic acid (PolyA) signals, into the type 5 adenovirus (Ad5) vector, the resultant AdIkappaBalphaM was packaged in human embryonic kidney (HEK) 293 cells by cotransfection with lipofectamine. Western blot analysis and electrophoretic mobility shift assay were utilized to detect the AdIkappaBalphaM-mediated overexpression of IkappaBalphaM in HEK293 cells and its suppressive effect on phorbol 12-myristate 13-acetate (PMA)-induced NF-kappaB activation in human umbilical vein endothelial (ECV304) cells, respectively.</p><p><b>RESULTS</b>The relevant nucleotides and deduced amino acids of 801 bp IkappaBalphaM gene were consistent with those of IkappaBalpha gene (GenBank accession number: M69043). The titer of the prepared AdIkappaBalphaM was 4.0 x 10 (12) plaque-forming units (pfu)/L. Moreover, the IkappaBalphaM gene was overexpressed in HEK293 cells, and potently inhibited the PMA-induced NF-kappaB activation in ECV304 cells dose-dependently.</p><p><b>CONCLUSIONS</b>AdIkappaBalphaM is a novel vector for both efficient transfer and specific overexpression of IkappaBalphaM gene, as well as potent inhibition of NF-kappaB activity, providing a promising strategy for gene therapy of asthma.</p>

Effects of glucocorticoid and cysteinyl leukotriene 1 receptor antagonist on CD(34+) hematopoietic cells in bone marrow of asthmatic mice / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Corticosteroids remain the most effective therapy available for asthma. They have widespread effects on asthmatic airway inflammation. However, little is known about the effects of corticosteroids on the production of bone marrow inflammatory cells in asthma. This study observed the effects of glucocorticoid and cysteinyl leukotriene 1 receptor antagonist on CD34+ hematopoietic cells, so as to explore the possible effectiveness of a bone marrow-targeted anti-inflammatory strategy.</p><p><b>METHODS</b>Balb/c mice were sensitized and challenged with ovalbumin (OVA) to establish an asthmatic model. For two consecutive weeks, asthmatic mice were challenged with OVA while being given either prednisone, montelukast, prednisone plus montelukast, or sterile saline solution. The mice were killed 24 hours after the last challenge with OVA, and bronchoalveolar lavage fluid (BALF), peripheral blood, and bone marrow were collected. Eosinophils in peripheral blood and BALF, and nucleated cells in BALF, peripheral blood, and bone marrow were counted. The percentages of CD34+ cells, CD4+ T lymphocytes and CD8+ T lymphocytes among nucleated cells in peripheral blood and bone marrow were counted by flow cytometry. Immunocytochemistry and in situ hybridization were employed to detect expression of CD34 and interleukin (IL)-5Ralpha mRNA (CD34+ IL-5Ralpha mRNA+ cells) among bone marrow hematopoietic cells.</p><p><b>RESULTS</b>Compared with the sterile saline solution group, the number of eosinophils in BALF and peripheral blood, CD34+ cells in peripheral blood and bone marrow, and CD34+ IL-5Ralpha mRNA+ cells in bone marrow of mice from the prednisone and prednisone plus montelukast groups were significantly lower (P < 0.01). The number of eosinophils in BALF from the montelukast group was also significantly lower (P < 0.05).</p><p><b>CONCLUSIONS</b>The results suggest that, in this asthmatic mouse model, prednisone probably inhibits proliferation, differentiation, and migration of CD34+ cells in bone marrow, blocks eosinophilopoiesis in bone marrow, and interferes with eosinophil migration into peripheral blood and subsequent recruitment in the airway. In addition, montelukast may suppress eosinophil infiltration into the lungs of asthmatic mice. However, a significant inhibitory effect of montelukast on the proliferation and migration of CD34+ cells and a cooperating effect with prednisone on bone marrow of asthmatic mice were not observed.</p>

Serum adiponectin level in patients with obstructive sleep apnea hypopnea syndrome / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Adiponectin, secreted by adipocytes, has been found to be associated with diabetes, obesity and some cardiovascular diseases. Obstructive sleep apnea hypopnea syndrome (OSAHS) is also closely related to obesity and easily complicated with diabetes and some cardiovascular diseases. This study was carried out to explore the change of serum adiponectin level in patients with OSAHS.</p><p><b>METHODS</b>Polysomnography was performed in 71 patients with OSAHS (OSAHS group) and 26 simple obese controls (control group). The two groups had no significant difference in age and body mass index (BMI). Radioimmunoassy was used to test serum adiponectin level.</p><p><b>RESULTS</b>Serum adiponectin level was significantly lower in OSAHS group [(5.03 +/- 1.01) mg/L] than that in the control group [(7.09 +/- 1.29) mg/L, P < 0.05]. The differences between two groups were independent of gender. In OSAHS groups, serum adiponectin levels were negatively correlated with apnea hypopnea index (AHI) (r = -0.78, P < 0.01), BMI (r = -0.13, P < 0.05), waist circumference (r = -0.36, P < 0.01), and neck circumference (r = -0.42, P < 0.01), but positively correlated with the minimal pulse oxyhemoglobin saturation (r = 0.48, P < 0.01).</p><p><b>CONCLUSION</b>OSAHS may contribute to the decrease of serum adiponectin level independent of obesity.</p>

Effect of continuous positive airway pressure treatment on vascular endothelial function in patients with obstructive sleep apnea hypopnea syndrome and coronary artery disease / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Continuous positive airway pressure (CPAP) treatment has been proven to be effective in improving the symptoms of coexisting coronary heart disease (CHD) in patients with obstructive sleep apnea hypopnea syndrome (OSAHS). However, it is still unclear whether such improvements are linked to changes in vascular endothelial function. This research was carried out to investigate the effects of CPAP treatment on vascular endothelial function in patients with OSAHS and CHD.</p><p><b>METHODS</b>Thirty-six patients with moderate or severe OSAHS and CHD undergoing three months of CPAP treatment were recruited for this study. The changes in their morning plasma nitric oxide (NO) and endothelin (ET) levels, NO/ET ratio, total ischemic burden (TIB) of the myocardium, apnea hypopnea index (AHI), and minimal and mean pulse oxygen saturation (SpO2) were compared and analyzed before and during CPAP treatment.</p><p><b>RESULTS</b>Compared with the plasma levels of ET [(51.39 +/- 11.69) ng/L] and NO [(36.67 +/- 11.86) micromol/L], NO/ET (0.71 +/- 0.14), AHI (32.4 +/- 7.9), minimal SpO2 [(68.9 +/- 11.4)%], and myocardial TIB [(66.29 +/- 16.37) mm.min] before treatment, there were significant decreases in ET [(33.41 +/- 10.03) ng/L] (P < 0.05), increases in NO [(59.89 +/- 10.26) micromol/L] and NO/ET (1.79 +/- 0.38) (P < 0.01), decreases in AHI (1.9 +/- 0.5), and increases in minimal SpO2 [(90.6 +/- 1.8)%] (all P < 0.01) and myocardial TIB [(36.42 +/- 10.87) mm.min] (P < 0.05) after three months of CPAP treatment.</p><p><b>CONCLUSION</b>CPAP treatment may play an important role in the improvement and protection of vascular endothelial dysfunction and myocardial ischemia in OSAHS patients with CHD.</p>

Effect of arsenic trioxide on apoptosis of pulmonary eosinophile in asthmatic guinea-pigs / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To study the effect and mechanism of arsenic trioxide (As2O3) on apoptosis of pulmonary eosinophiles (PE) in asthmatic guinea-pigs.</p><p><b>METHODS</b>Thirty guinea-pigs were divided into 3 groups at random, the control group, the asthmatic group and the As2O3 group. The dosage of As2O3 used was 2 mg/kg. The apoptotic PE were labelled by TdT-mediated dUTP nick end labelling technique, and the PE infiltration and apoptosis were detected quantitatively using computerized image analysis technique.</p><p><b>RESULTS</b>In the control group, the amount of infiltrating PE was 4.4 +/- 2.5 cells/HP and the PE apoptotic index (AI) was 0.42 +/- 0.08%. In the asthmatic group, the amount increased (P < 0.01) and AI decreased significantly (P < 0.01). After the asthmatic animals had been treated with As2O3, the two parameters changed reversedly significantly (P < 0.01), and there was a significantly negative correlation between them (r = -0.949, P < 0.01).</p><p><b>CONCLUSION</b>The PE apoptosis abnormality is one of the important mechanisms that cause bronchial asthma, As2O3 could alleviate the airway inflammation through promoting PE apoptosis and lower PE infiltration. Low dose of As2O3 is proved to be effective with relative safety, it also has potential value in treating asthma.</p>