[Overview of the role of inhaled corticosteroids in chronic obstructive pulmonary disease from evolution of guidelines].

In the treatment of stable chronic obstructive pulmonary disease (COPD), international guidelines have updated the recommendations for inhaled corticosteroids (ICS) based on the accumulated clinical evidences, and the understanding has gone further from "controversy" to "affirmation" until the presence of the lastest guideline that indicates patients are divided into two phenotypes according to the clinical characteristics of dyspnea and acute exacerbation for adjustments in treatment strategy, and for patients with frequent acute exacerbations during the last one year, combined with their blood eosinophil counts, the individualized treatments including ICS are recommended.

[Association of plasma roundabout 4 concentration with pulmonary ventilation function decline in COPD patients].

Objective: To investigate the association of plasma roundabout 4 concentration with pulmonary ventilation function decline in chronic obstructive pulmonary disease (COPD) patients. Methods: To get the effective data, the study was conducted in the outpatient department of West China Hospital from September 2017 to September 2018. The subjects meeting the inclusion and exclusion criteria were continuously included. Among them, the COPD group (75 cases) was from the respiratory outpatient department, and the healthy control group (57 cases) was from the health examination center at the same time. Data of basic demographic characteristics, clinical characteristics, pulmonary ventilation function parameters and blood samples were collected. The concentrations of roundabout 4, C reactive protein (CRP), interleukin (IL)-6, IL-8, IL-1b and tumor necrosis factor (TNF)-α in plasma were detected, and the differences among groups were compared, the correlation between plasma roundabout 4 and pulmonary ventilation function parameters and inflammatory factors was analyzed. The diagnostic efficiency of roundabout 4 to COPD was analyzed according to receiver operating characteristic (ROC) curve. Results: The plasma concentration of roundabout 4 in COPD group was significantly higher than that in healthy control group [(41.3±14.2) vs (27.7±13.3) ng/L; P<0.001], the sensitivity and specificity of roundabout 4 in the diagnosis of COPD were 0.827 and 0.702 respectively. Correlation analysis showed that the plasma concentration of roundabout 4 was negatively correlated with lung function parameters forced expiratory volume in one second/forced vital capacity (FEV(1)/FVC), the first second forced expiratory volume as a percentage of the estimated value (FEV(1)%pred), forced exhalation of 50% and 25% lung capacity (MEF50, MEF25) and maximal mid-expiratory flow (MMEF) (r=-0.399, -0.321, -0.439, -0.363, -0.458; all P<0.001), positively correlated with CRP (adjusted r=0.311, P<0.001). Conclusion: The increased concentration of roundabout 4 in plasma leads to the decline of pulmonary ventilation function in COPD patients.

[Bioinformatics analysis of severe emphysema genome microarray based on GEO database].

Objective: To investigate differential genes (DEGs) between no/mild and severe emphysema by bioinformatics analysis. Methods: The microarray dataset GSE1650, of lung tissue in no/mild and severe emphysema, was downloaded from the GEO database, and DEGs were obtained by t test. Analysis of DEGs based on DAVID database was used to obtain gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) pathway. The protein-protein interaction network (PPI) was established using STRING database to identify hub genes. Results: A total of 76 DEGs were obtained, of which 62 genes were up-regulated and 14 genes were down-regulated in severe emphysema group. Gene ontology showed that the DEGs were mainly involved in neutrophil chemotaxis, cellular response to interleukin-1, extracellular matrix organization, immune response, and KEGG pathway involved cytokine-cytokine receptor interaction, ECM-receptor interaction, PI3K-Akt signaling pathway, platelet activation. Seventeen hub genes were recognized by PPI analysis, including CXCL8, RRAD, CLU, TIMP1, SEPP1, ISLR, BGN, COL1A1, COLIA2, ACTA2, ACTN1, FIGF, TPM1, TPM2, LUM, COL6A3 and TAGLN. Among them, fifteen genes (CLU, TIMP1, SEPP1, ISLR, BGN, COLIA2, COL1A1, ACTA2, ACTN1, FIGF, TPM1, TPM2, LUM, COL6A3, TAGLN) were up-regulated and two genes (CXCL8, RRAD) were down-regulated. Conclusion: Bioinformatics analysis based on GEO database showed that there were DEGs between non/mild and severe emphysema patients.

[Prevalence and clinical characteristics of blood eosinophilia in patients with acute exacerbation of chronic obstructive pulmonary disease].

Objective: To investigate the prevalence and clinical characteristics of peripheral blood eosinophilia (EOS) in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Methods: From July 2014 to June 2016, AECOPD patients in the Department of Respiratory Medicine of Affiliated Hospital of Chengdu University, were retrospectively stratified into two groups according to two standards of eosinophilic exacerbations (the peripheral blood eosinophil count ≥2% or ≥3% on admission). Demography, clinical symptoms, laboratory results, length of stay, total hospitalization expenses, and defined daily expenses were compared between groups. Results: A total of 559 cases with AECOPD were finally recorded, the prevalence of eosinophilia was 43.1% (241 cases by EOS≥2%) and 27.2% (152 cases by EOS≥3%), respectively. According to either standard, there were no significant differences in sexes, age, course of disease (P>0.05), and there were no significant differences in global initiative for chronic obstructive lung disease (GOLD) grades, parameters of pulmonary function, modified british medical research council (mMRC) scores, rate of antibiotic use, systemic glucocorticoids administration, and average daily expenses (P>0.05). According to 2% standard, leucocytes, neutrophils, monocytes, hs-CRP were lower than non-eosinophilic patients [(5.9±2.0)×10(9)/L vs (8.2±4.0)×10(9)/L, (3.9±1.6)×10(9)/L vs (6.5±3.8)×10(9)/L, (0.446±0.169)×10(9)/L vs (0.501±0.276)×10(9)/L, (25.8±35.9) vs (46.2±55.6) mg/L, all P<0.01]; basophils, lymphocytes were higher than non-eosinophilic patients [(0.043±0.025)×10(9)/L vs (0.029±0.021) ×10(9)/L, (1.3±0.6) ×10(9)/L vs (1.1±0.6) ×10(9)/L, both P<0.01]; length of stay, total hospital expense were shorter (or lower) than non-eosinophilic patients [(10.6±5.0) vs (11.6±5.8) d, (11 851±7 491) vs (14 254±10 751) RMB, both P<0.05]. According to 3% standard, leucocytes, neutrophils, monocytes, hs-CRP were lower than non-eosinophilic patients (all P<0.05), and basophil were higher than non-eosinophilic patients (P<0.01), but no significant differences were observed in lymphocytes, length of stay and total hospital expense (all P>0.05). Conclusion: Eosinophilia is of relative high prevalence in AECOPD patients, and basophil in eosinophilic patients is higher than non-eosinophilic patients.

Polymorphisms in the XRCC1 gene are associated with treatment response to platinum chemotherapy in advanced non-small cell lung cancer patients based on meta-analysis.

X-ray repair cross complementing group 1(XRCC1) polymorphisms have been implicated in interindividual variability of efficacy of platinum chemotherapy for treating non-small cell lung cancer (NSCLC); however, results of different studies have been inconsistent. We conducted a meta-analysis to investigate the association between polymorphisms in the XRCC1 gene and response rate of platinum chemotherapy in advanced NSCLC patients. Searches were performed on MEDLINE, PubMed, EMBASE, Chinese Biological Medicine Database, China National Knowledge Infrastructure, and Wangfang Data, covering all relevant studies published up to August 1, 2012. Statistical analyses were performed using the Revman 5.0 and STATA 10.0 software. Two polymorphisms, Arg399Gln (G>A) and Arg194Trp (C>T), were investigated in 19 studies, involving 2152 advanced NSCLC patients. For XRCC1 Arg399Gln, patients carrying two G alleles had a significantly increased response rate of platinum chemotherapy, when compared with those carrying the A allele [odds ratio (OR) = 2.05, 95% confidence interval CI = 1.62-2.60 for GG vs GA+AA]. Similarly, the AA carriers had a 54% decreased response rate compared with the G allele carriers (OR = 0.46, 95%CI = 0.30-0.70 for AA vs GA+GG). For XRCC1 Arg194Trp, patients carrying two C alleles had a 62% decreased response rate compared with those carrying either one or two variant T alleles (OR = 0.38, 95%CI = 0.30-0.48 for CC vs CT+TT). However, although TT carriers had a better response rate compared with the C allele carriers, the difference was not significant (OR = 1.27, 95%CI = 0.92-1.77 for TT vs CC+CT). Based on this meta-analysis, we conclude that XRCC1 polymorphisms are associated with treatment response to platinum chemotherapy in advanced NSCLC patients.

Association of a disintegrin and metalloproteinase 33 (ADAM33) gene polymorphisms with chronic obstructive pulmonary disease in the Chinese population: a meta-analysis.

Numerous studies have evaluated the association between polymorphisms of a disintegrin and metalloproteinase 33 (ADAM33) gene and chronic obstructive pulmonary disease (COPD) risk; however, the results remain conflicting. The aim of this study was to investigate whether ADAM33S2 and -T1 polymorphisms are associated with susceptibility to COPD risk in the Chinese population. Publications addressing the association between ADAM33S2 or T1 polymorphisms and COPD risk were selected from the PubMed, Cochrane Library, Embase, CNKI, and Wanfang databases. Two independent reviewers extracted data from the studies. Statistical analysis was performed using the RevMan 5.0.25 and STATA 11.0 software. Six case-control studies were retrieved, including a total of 1201 COPD patients and 1203 controls. Meta-analysis results showed a significant association between the T1 polymorphism and COPD risk in both dominant model [odds ratio (OR) = 2.54, 95% confidence interval (CI) = 1.40-4.61, P = 0.002] and recessive model (OR = 3.50, 95%CI = 2.11-5.81, P < 0.00001) comparisons. For S2, no significant association was found in any genetic model. This suggests that the T1 polymorphism of ADAM33 would increase the risk of COPD in a Chinese individual, whereas the S2 polymorphism might not be a risk factor for COPD. To further evaluate the gene-to-gene and gene-to-environment interactions on ADAM33 genetic variations and COPD risk, more studies using large sample sizes of patients are needed.

Hydrogen-rich saline reduces airway remodeling via inactivation of NF-κB in a murine model of asthma.

BACKGROUND AND OBJECTIVES: Recent studies suggest that hydrogen has great therapeutic and prophylactic potential against organ injury caused by oxidative stress and inflammation. Here we investigated the effect of hydrogen-rich saline on airway inflammation and remodeling in a murine model of asthma. MATERIALS AND METHODS: Asthma was induced by ovalbumin (OVA) sensitization and challenge. Then mice were treated with normal saline or hydrogen-rich saline at low and high doses. Cell counts and cytokine levels in bronchoalveolar lavage fluid (BALF) were determined, bronchial tissue was analyzed for pathology, and expression of MUC5AC, collagen III, VEGF, and total and phosphorylated NF-κB p65 was measured. Immunohistochemistry was used to identify levels and localization of VEGF expression in lung. RESULTS: The results showed that hydrogen-rich saline reduced cell counts and levels of cytokines IL-4, IL-5, IL-13 and TNF-α in BALF. Hydrogen-rich saline treatment also significantly decreased mucus index, collagen deposition, and expression of MUC5AC, collagen III and VEGF. The ratio of phospho-NF-κB p65 to total NF-κB p65 was much lower in mice treated with hydrogen-rich saline than in untreated mice. These effects of hydrogen-rich saline on airway inflammation and remodeling were dose-dependent. CONCLUSIONS: These findings suggest that hydrogen-rich saline reduces airway inflammation and remodeling in OVA-exposed mice by inhibiting NF-κB.

Serum N-terminal pro-brain natriuretic peptide level is a significant prognostic factor in patients with severe sepsis among Southwest Chinese population.

BACKGROUND: This study aimed to determine the predictive value of elevated N-terminal pro-brain natriuretic peptide (NTproBNP) for mortality in patients with severe sepsis. PATIENTS AND METHODS: This was a retrospective study in Emergency Department of Sichuan Provincial People's Hospital, and patients were screened between January 1, 2009 and December 31, 2011. Demographic and clinical data as well as Acute Physiology And Chronic Health Evaluation II (APACHE II) and Sepsis Organ Failure Assessment (SOFA) scores were collected within the first day of admission. Survival was determined to establish its association with the NT-proBNP using logistic regression and receiver operating characteristic (ROC) curve. RESULTS: A total of 171 patients with severe sepsis were analyzed. The median APACHE IIⅡ and SOFA scores were 11 (IQR, 7-16) and 3 (IQR, 1-5), respectively. The median C-reactive protein (CRP), procalcitonin (PCT) and NT-proBNP was 10.3 mg/dL (IQR, 3.4-21.4 mg/dL), 0.4 ng/mL (IQR, 0.2-3.6 ng/mL), and 954 (321-1576) pg/mL, respectively. The median NT-proBNP in survivors was 584 pg/mL (IQR, 321-875 pg/mL) versus 1271 (IQR, 851-1576 pg/mL) in nonsurvivors (p < 0.001). In the ROC curves, the area value was 0.89 for serum NT-proBNP, and its potent cutoff value was 1500 pg/mL. After multivariate regression analysis, NT-proBNP was significantly correlated with the mortality of severe sepsis (OR = 1.58, 95% CI 1.36-1.77). CONCLUSIONS: Serum NT-proBNP is frequently increased in severe sepsis patients, and non-survivors have higher levels than survivors. High levels of admission NT-proBNP are associated with mortality.

Diagnostic Value of p16 Methylation for Malignant Pleural Effusions: A Meta-analysis.

OBJECTIVE: To evaluate the overall diagnostic performance of the p16 methylation for diagnosing malignant pleural effusion (MPE). METHODS: All published literature in English and Chinese were reviewed. Sensitivity, specificity, likelihood ratio and diagnostic odds ratio (DOR) were pooled by using random-effects model or fixed-effects model. Summary receiver operating characteristic (SROC) curve was used to evaluate the overall diagnostic value. RESULTS: Six studies were included with a total of 378 cases. The sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR) and DOR of p16 methylation in the diagnosis of MPE were 0.41 [95% confidence interval (CI) 0.35, 0.48], 0.97 [95% CI 0.93, 0.99], 9.57 [95% CI 4.53, 20.20], 0.61 [95% CI 0.45, 0.82] and 19.82 [95% CI 8.35, 47.04], respectively. The area under the curve (AUC) was 0.864. CONCLUSION: Pleural p16 methylation test plays a useful role in the diagnosis of MPE.

The polymorphism -2548G/A in leptin and severity of chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease characterized by airway obstruction that is not fully reversible, and there is evidence of a hereditary component in COPD. We aimed to determine whether the polymorphisms -2548G/A of leptin (LEP) gene were associated with COPD and its severity in Chinese. A total of 456 subjects with COPD and 422 healthy controls from West China Hospital were enrolled in this study. COPD patients had been undergone a spirometry and a physical examination to refer the GOLD I-IV stages. The polymorphisms in the leptin promoter region at position -2548G/A were detected by Polymerase chain reaction-restriction fragment length polymorphism analysis. The genotypes and alleles were scored, and the frequencies of the alleles and genotypes in patients and controls were compared. A significantly higher risk for COPD was observed for carriers of the LEP -2548AA genotype [odds ratio (OR)=7.87, 95% confidence interval (CI) 4.19-14.77, P<0.001] and carriers of the LEP -2548GA genotype (OR=2.98, 95% CI 1.57-5.66, P=0.001). The LEP -2548A allele: frequency was significantly higher in the patient group compared with the control group (OR=2.75, 95% CI: 2.20-3.44, P<0.001). We also found a significant relationship between leptin gene polymorphism and the severity of COPD. In the present case-control study, we found an association between the -2548G/A variant of the leptin gene and pathogenesis, severity of COPD in the Chinese population. It suggests that leptin -2548G/A should be used as a genetic marker of COPD severity.

Cigarette smoke enhances {beta}-defensin 2 expression in rat airways via nuclear factor-{kappa}B activation.

ß-defensin 2 (BD-2), an antimicrobial peptide, participates in airway defence. Cigarette smoke (CS) is a major risk factor for the development of chronic obstructive pulmonary disease. This study mainly aims to investigate the effect of CS on rat BD-2 (rBD-2) expression in rat airways. Rats were exposed to CS and treated with caffeic acid phenethyl ester (CAPE), a nuclear factor (NF)-κB inhibitor, or astragaloside IV (AS-IV), an active ingredient of Astragalus mongholicus. Besides the analysis of bronchoalveolar lavage fluid (BALF) and histological changes after CS exposure, rBD-2 expression was investigated with immunohistochemistry, reverse transcription PCR and ELISA. Total glutathione and nitric oxide (NO) levels in rat lungs were also detected. CS exposure markedly increased rBD-2 immunoreactivity, as well as rBD-2 mRNA and protein levels in rat airways, which were inhibited by CAPE treatment. Moreover, associated airway inflammation induced by CS was demonstrated by histological changes, increased cell counts and pro-inflammatory cytokines in BALF, and NF-κB activation and high levels of total glutathione and NO, which were all reversed by AS-IV in a dose-dependent fashion. In conclusion, CS exposure induces rBD-2 expression in rat airways via a NF-κB-dependent pathway, and AS-IV attenuates CS-induced airway inflammation due to its anti-inflammatory and antioxidant properties, at least partly through NF-κB inactivation.

Effect of sildenafil on acrolein-induced airway inflammation and mucus production in rats.

Airway inflammation with mucus overproduction is a distinguishing pathophysiological feature of many chronic respiratory diseases. Phosphodiesterase (PDE) inhibitors have shown anti-inflammatory properties. In the present study, the effect of sildenafil, a potent inhibitor of PDE5 that selectively degrades cyclic guanosine 3',5'-monophosphate (cGMP), on acrolein-induced inflammation and mucus production in rat airways was examined. Rats were exposed to acrolein for 14 and 28 days. Sildenafil or distilled saline was administered intragastrically prior to acrolein exposure. Bronchoalveolar lavage fluid (BALF) was acquired for cell count and the detection of pro-inflammatory cytokine levels. Lung tissue was examined for cGMP content, nitric oxide (NO)-metabolite levels, histopathological lesion scores, goblet cell metaplasia and mucin production. The results suggested that sildenafil pretreatment reversed the significant decline of cGMP content in rat lungs induced by acrolein exposure, and suppressed the increase of lung NO metabolites, the BALF leukocyte influx and pro-inflammatory cytokine release. Moreover, sildenafil pretreatment reduced acrolein-induced Muc5ac mucin synthesis at both mRNA and protein levels, and attenuated airway inflammation, as well as epithelial hyperplasia and metaplasia. In conclusion, sildenafil could attenuate airway inflammation and mucus production in the rat model, possibly through the nitric oxide/cyclic guanosine 3',5'-monophosphate pathway, and, thus, might have a therapeutic potential for chronic airway diseases.

Plasma ghrelin levels and weight loss in Chinese Uygur patients with chronic obstructive pulmonary disease.

Ghrelin is an important orexigenic hormone that reduces fat oxidation and increases adiposity. This study investigated plasma ghrelin levels in Chinese Uygur patients with chronic obstructive pulmonary disease (COPD). Plasma ghrelin and anabolic and catabolic factors were measured in 38 patients and 24 control subjects. COPD patients were divided into two groups based on body mass index (BMI): underweight (BMI < 20 kg/m(2), n = 18) or normoweight (BMI > or = 20 kg/m(2), n = 20). Plasma ghrelin levels were found to be significantly higher in underweight than in normoweight patients or healthy controls. Circulating tumour necrosis factor-alpha and interleukin-6 concentrations were significantly higher in underweight than in normoweight patients, whereas insulin concentrations were significantly lower. Plasma ghrelin levels correlated negatively with forced expiratory volume in 1 s (FEV(1); r = 0.35), but did not significantly correlate with FEV(1)/forced vital capacity. Plasma ghrelin levels were elevated in underweight COPD patients and were associated with cachexia and abnormal pulmonary function.

Serum angiopoietin-like 4 is over-expressed in COPD patients: association with pulmonary function and inflammation.

OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is both a pulmonary and systematic disease, which will cause abnormal expression of some circulating factors. Angiopoietin-like protein 4 (ANGPTL4) has been reported to play important role in inflammatory responses and several diseases. However, whether it contributes to COPD is an open question. The aim of this study is to explore the potential relationship between ANGPTL4 and COPD. PATIENTS AND METHODS: In this study, circulating levels of ANGPTL4, C-reactive protein (CRP), adiponectin, tumor necrosis factor (TNF)-α, matrix metalloproteinase (MMP)-9 and monocyte chemotactic protein (MCP)-1 in 73 COPD patients and 40 healthy volunteers were investigated using multiplex enzyme-linked immunosorbent assay Kits. Then, we analyzed the correlations between ANGPTL4 with other inflammatory mediators and pulmonary function. RESULTS: Serum ANGPTL4 levels were significantly elevated in COPD patients compared with healthy controls (122.86 ± 38.59 ng/mL versus 99.03 ± 31.84 ng/mL, p = 0.001). Besides, serum ANGTPL4 levels were much higher in ever-smokers with COPD than in never-smokers with COPD (131.71 ± 32.92 ng/mL versus 113.25 ± 42.34 ng/mL, p = 0.03). More importantly, the concentrations of circulating ANGPLT4 correlated inversely with forced expiratory volume in 1 second (FEV1) % predicted, an index of lung function in COPD (r = -0.450, p < 0.001) and in all participants (r = -0.369, p < 0.001), while correlated positively with CRP (r = 0.312, p = 0.007 for COPD; r = 0.404, p < 0.001 for total subjects), adiponectin (r = 0.266, p = 0.004 for total subjects), and MMP-9 (r = 0.254, p = 0.03 for COPD). CONCLUSIONS: Our results suggest that circulating ANGPTL4 levels are up-regulated in COPD patients, and have correlations with pulmonary function and systematic inflammation in COPD, which provides a novel idea to further dig the pathogenic mechanisms of COPD, and justifies more studies to determine how ANGPTL4 contributes to COPD.