Jin-Fu Xu

Carbon Monoxide Activates Autophagy via Mitochondrial Reactive Oxygen Species Formation

Autophagy, an autodigestive process that degrades cellular organelles and protein, plays an important role in maintaining cellular homeostasis during environmental stress. Carbon monoxide (CO), a toxic gas and candidate therapeutic molecule, confers cytoprotection in animal models of acute lung injury. The mechanisms underlying CO-dependent lung cell protection and the role of autophagy in this process remain unclear. Here, we demonstrate that CO exposure time-dependently increased the expression and activation of the autophagic protein, microtubule-associated protein-1 light chain-3B (LC3B) in mouse lung, and in cultured human alveolar (A549) or human bronchial epithelial cells. Furthermore, CO increased autophagosome formation in epithelial cells by electron microscopy and green fluorescent protein (GFP)-LC3 puncta assays. Recent studies indicate that reactive oxygen species (ROS) play an important role in the activation of autophagy. CO up-regulated mitochondria-dependent generation of ROS in epithelial cells, as assayed by MitoSOX fluorescence. Furthermore, CO-dependent induction of LC3B expression was inhibited by N-acetyl-L-cysteine and the mitochondria-targeting antioxidant, Mito-TEMPO. These data suggest that CO promotes the autophagic process through mitochondrial ROS generation. We investigated the relationships between autophagic proteins and CO-dependent cytoprotection using a model of hyperoxic stress. CO protected against hyperoxia-induced cell death, and inhibited hyperoxia-associated ROS production. The ability of CO to protect against hyperoxia-induced cell death and caspase-3 activation was compromised in epithelial cells infected with LC3B-small interfering (si)RNA, indicating a role for autophagic proteins. These studies uncover a new mechanism for the protective action of CO, in support of potential therapeutic application of this gas.

Short-term Exposure to Ambient Fine Particulate Matter Increases Hospitalizations and Mortality in COPD: A Systematic Review and Meta-analysis

BACKGROUND Many epidemiologic studies have documented variable relationships between ambient particulate matter (PM) and COPD hospitalizations and mortality in cities worldwide. METHODS Comprehensive and systematic searches were performed in the electronic reference databases (PubMed, EMBASE, Google Scholar, Ovid, and Web of Science) with specific search terms and selection criteria for relevant studies. Summary ORs and 95% CIs were calculated to evaluate the relationship between short-term exposure to PM with aerodynamic diameters ≤ 2.5 μm (PM2.5) and COPD hospitalizations and mortality. The sources of heterogeneity and the effect of potential confounders were explored using subgroup analyses. Study findings were analyzed using a random effects model and a fixed effects model in COPD hospitalizations and mortality, respectively. RESULTS The search yielded 12 studies suitable for meta-analysis of hospitalizations and six studies suitable for the mortality meta-analysis until April 15, 2015. A 10-μg/m(3) increase in daily PM2.5 (lag days 0-7) was associated with a 3.1% (95% CI, 1.6%-4.6%) increase in COPD hospitalizations and a 2.5% (95% CI, 1.5%-3.5%) increase in COPD mortality. Significant publication bias was not found in studies focusing on the relationship between short-term PM2.5 exposure and COPD hospitalizations and mortality. CONCLUSIONS Our combined analysis indicated that short-term exposure to a 10-μg/m(3) increment of ambient PM2.5 is associated with increased COPD hospitalizations and mortality. Further study is needed to elucidate to what extent this relationship is causal, together with other factors, and to elucidate the mechanism by which PM2.5 induces activation of cellular processes promoting COPD exacerbations.

Evaluation of PCR in Bronchoalveolar Lavage Fluid for Diagnosis of Pneumocystis jirovecii Pneumonia: A Bivariate Meta-Analysis and Systematic Review

Background As a promising tool, PCR in bronchoalveolar lavage fluid (BALF) has not been accepted as a diagnostic criterion for PJP. Objective We undertook a systematic review of published studies to evaluate the diagnostic accuracy of PCR assays in BALF for PJP. Methods Eligible studies from PubMed, Embase and Web of Science reporting PCR assays in BALF for diagnosing PJP were identified. A bivariate meta-analysis of the method’s sensitivity, specificity, and positive and negative likelihood ratios with a 95% confidence interval (CI) were analyzed. The post-test probability was performed to evaluate clinical usefulness. A summary receiver operating characteristics (SROC) curve was used to evaluate overall performance. Subgroup analyses were carried out to analysis the potential heterogeneity. Results Sixteen studies published between 1994 and 2012 were included. The summary sensitivity and specificity values (95% CI) of PCR in BALF for diagnosis of PJP were 98.3% (91.3%–99.7%) and 91.0% (82.7%–95.5%), respectively. The positive and negative likelihood ratios were 10.894 (5.569–21.309) and 0.018 (0.003–0.099), respectively. In a setting of 20% prevalence of PJP, the probability of PJP would be over 3-fold if the BALF-PCR test was positive, and the probability of PJP would be less than 0.5% if it was negative. The area under the SROC curve was 0.98 (0.97–0.99). Conclusions The method of PCR in BALF shows high sensitivity and good specificity for the diagnosis of PJP. However, clinical practice for the diagnosis of PJP should consider the consistent respiratory symptoms, radiographic changes and laboratory findings of the suspected patients.

Effects of long-term use of macrolides in patients with non-cystic fibrosis bronchiectasis: a meta-analysis of randomized controlled trials

BackgroundThe purpose of this study was to evaluate the clinical benefits and safety of the long-term use of macrolides in patients with non-cystic fibrosis (non-CF) bronchiectasis.MethodsEmbase, Pubmed, the Cochrane Library and Web of Science databases were searched from inception up to March 2014. The primary outcome was the improvement of exacerbations of bronchiectasis. Secondary endpoints included changes of microbiology, lung function, quality of life, sputum volume, adverse events and macrolide resistance.ResultsThe literature search yielded 139 studies, ten of which containing 601 patients were included in this meta-analysis. Macrolides showed a statistically-significant improvement in reducing acute exacerbations per patient during follow-up treatment (RR = 0.55, 95% CI: 0.47, 0.64, P < 0.001), increasing the number of patients free from exacerbations (OR = 2.81, 95% CI: 1.85, 4.26, P < 0.001), and prolonging time to a first exacerbation (HR = 0.38, 95% CI: 0.28, 0.53, P < 0.001). Macrolides maintenance treatment was superior to control with respect to attenuating FEV1 decline (p = 0.02), improving sputum volume (p = 0.009) and SGRQ total scores (p = 0.02), but showed a higher risk of adverse events, especially diarrhea (OR = 5.36; 95% CI: 2.06, 13.98, P = 0.0006). Eradication of pathogens was improved in the macrolide group (OR = 1.76, 95% CI: 0.91, 3.41, P = 0.09), while pathogen resistance caused by macrolides dramatically increased (OR = 16.83, 95% CI: 7.26, 38.99, P < 0.001). The new appearance of a microbiologic profile or participant withdrawal due to adverse events showed no significant differences between the two groups.ConclusionIn patients with non-CF bronchiectasis, macrolide maintenance treatment can effectively reduce frequency of exacerbations, attenuate lung function decline, decrease sputum volume, improve quality of life, but may be accompanied with increased adverse events (especially diarrhea) and pathogen resistance.

Asthma and bronchiectasis exacerbation

Bronchiectasis and asthma are common respiratory diseases worldwide. However, the influence of asthma on bronchiectasis remains unclear. The objective of this study is to analyse the effects of asthma on bronchiectasis exacerbation. Data from inpatients diagnosed with bronchiectasis with or without asthma at Shanghai Pulmonary Hospital (Shanghai, China) between January 2013 and December 2014 were retrospectively collected and analysed. 249 patients with only bronchiectasis and 214 patients with both bronchiectasis and asthma were included in the study. Follow-up records were used to evaluate the effect of asthma on bronchiectasis exacerbation. The variables found to be independently associated with bronchiectasis exacerbations were age (OR 1.07, 95% CI 1.03–1.11; p<0.001), duration of symptoms (OR 1.06, 95% CI 1.03–1.09; p<0.001), the presence of asthma (OR 2.6, 95% CI 1.15–5.88; p=0.021), forced expiratory volume in 1 s <50% predicted (OR 4.03, 95% CI 1.75–9.26; p=0.001), isolation of Pseudomonas aeruginosa in sputum (OR 2.41, 95% CI 1.00–5.79; p=0.05) and lung lesion extension to more than two lobes (OR 2.73, 95% CI 1.16–6.45; p=0.022). The existence of asthma was associated with an independent increase in risk of bronchiectasis exacerbation. The existence of asthma was associated with an independent increase in risk of bronchiectasis exacerbation http://ow.ly/XFSWS

Evaluation of a new cryptococcal antigen lateral flow immunoassay in serum, cerebrospinal fluid and urine for the diagnosis of cryptococcosis: a meta-analysis and systematic review.

Background A new lateral flow immunoassay (LFA) for the detection of cryptococcal antigen was developed. Objective We aimed to systematically review all relevant studies to evaluate the diagnostic accuracy of the cryptococcal antigen LFA on serum, CSF and urine specimens. Methods We searched public databases including PubMed, Web of Science, Elsevier Science Direct and Cochrane Library for the English-language literature published up to September 2014. We conducted meta-analyses of sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR) and diagnostic odds ratios (DOR) and SROC of LFA in serum and CSF, respectively. The sensitivity of LFA in urine was also analyzed. Subgroup analyses were carried out to analyze the potential heterogeneity. Results 12 studies were included in this study. The pooled sensitivity and specificity values of LFA in serum were 97.6% (95% CI, 95.6% to 98.9%) and 98.1% (95% CI, 97.4% to 98.6%), respectively. The average PLR of LFA in serum was 43.787 (95% CI, 22.60–84.81) and the NLR was 0.03 (95% CI, 0.01–0.09). The pooled DOR was 2180.30 (95% CI, 868.92–5471.00) and the AUC was 0.9968. The pooled sensitivity and specificity values of LFA in CSF were 98.9% (95% CI, 97.9% to 99.5%) and 98.9% (95% CI, 98.0% to 99.5%), respectively. The average PLR of LFA in serum was 48.83 (95% CI, 21.59–110.40) and the NLR was 0.02 (95% CI, 0.01–0.04). The pooled DOR was 2931.10 (95% CI, 1149.20–7475.90) and the AUC was 0.9974. The pooled sensitivity value of LFA in urine was 85.0% (95% CI, 78.7% to 90.1%) Conclusions The study demonstrates a very high accuracy of LFA in serum and CSF for the diagnosis of cryptococcosis in patients at risk. LFA in urine can be a promising sample screening tool for early diagnosis of cryptococcosis.

The existence of bronchiectasis predicts worse prognosis in patients with COPD

Bronchiectasis is prevalent in patients with COPD. The objective of this study was to assess the clinical characteristics and prognostic value of bronchiectasis in patients with COPD in China. Data from patients diagnosed with COPD at the Shanghai Pulmonary Hospital between January 2009 and December 2013 were retrospectively collected and analyzed. SPSS statistical software was used to analyze the data. Data from 896 patients with COPD were analyzed. Bronchiectasis was present in 311 patients. The isolation of pseudomonas aeruginosa (PA) from sputum was the variable most significantly associated with the presence of bronchiectasis in patients with COPD (hazard ratio (HR), 2.93; 95% confidence interval (CI), 1.35–6.37; P = 0.007). During follow-up (median of 21 months; interquartile range: 10-39 months), there were 75 deaths, of which 39 were in the bronchiectasis group. The presence of bronchiectasis (HR, 1.77; 95% CI, 1.02–3.08; P = 0.043) was associated with an increase in all-cause mortality in patients with COPD. These results suggest that bronchiectasis in patients with COPD was associated with the isolation of PA from the sputum. Bronchiectasis was an independent risk factor for all-cause mortality in patients with COPD.

Efficacy and safety of long-term inhaled antibiotic for patients with noncystic fibrosis bronchiectasis: a meta-analysis.

The evidence supported the use of nebulized antibiotics in non‐cystic fibrosis (non‐CF) bronchiectasis is indefinite. A meta‐analysis was performed to determine the efficacy and safety of long‐term inhaled antibiotics for patients with non‐CF bronchiectasis.

Creation of Lung-Targeted Dexamethasone Immunoliposome and Its Therapeutic Effect on Bleomycin-Induced Lung Injury in Rats

Objective Acute lung injury (ALI), is a major cause of morbidity and mortality, which is routinely treated with the administration of systemic glucocorticoids. The current study investigated the distribution and therapeutic effect of a dexamethasone(DXM)-loaded immunoliposome (NLP) functionalized with pulmonary surfactant protein A (SP-A) antibody (SPA-DXM-NLP) in an animal model. Methods DXM-NLP was prepared using film dispersion combined with extrusion techniques. SP-A antibody was used as the lung targeting agent. Tissue distribution of SPA-DXM-NLP was investigated in liver, spleen, kidney and lung tissue. The efficacy of SPA-DXM-NLP against lung injury was assessed in a rat model of bleomycin-induced acute lung injury. Results The SPA-DXM-NLP complex was successfully synthesized and the particles were stable at 4°C. Pulmonary dexamethasone levels were 40 times higher with SPA-DXM-NLP than conventional dexamethasone injection. Administration of SPA-DXM-NLP significantly attenuated lung injury and inflammation, decreased incidence of infection, and increased survival in animal models. Conclusions The administration of SPA-DXM-NLP to animal models resulted in increased levels of DXM in the lungs, indicating active targeting. The efficacy against ALI of the immunoliposomes was shown to be superior to conventional dexamethasone administration. These results demonstrate the potential of actively targeted glucocorticoid therapy in the treatment of lung disease in clinical practice.

Corticosteroids for the treatment of human infection with influenza virus: a systematic review and meta-analysis

Administration of corticosteroids to patients affected by influenza virus, especially pandemic avian influenza virus, although relatively common, remains controversial. A systematic review and meta-analysis was performed to assess the impact of corticosteroid treatment on outcomes of patients with influenza virus infection. The PubMed, EMBASE, Web of Science and Cochrane Library databases were searched up to February, 2015. Studies comparing corticosteroid treatment with no corticosteroid treatment in patients with influenza virus infection were included. The primary outcomes assessed were the association of mortality and nosocomial infection with corticosteroid treatment. Two authors independently extracted the data. ORs and weighted mean differences (WMDs) were used to describe dichotomous data and continuous data, respectively. Nineteen studies with 4916 patients were included in this meta-analysis. The results showed that corticosteroid treatment was significantly associated with mortality (OR 1.98, 95% CI 1.62-2.43, p < 0.00001) and nosocomial infection (OR 3.16, 95% CI 2.09-4.78, p < 0.00001). The durations of mechanical ventilation (WMD 3.82, 95% CI 1.49-6.15, p 0.001) and intensive-care unit stay (WMD 4.78, 95% CI 2.27-7.29, p 0.0002) were both markedly longer in the corticosteroid treatment group than in the control group. These findings suggest that routine steroid use may not be ideal for influenza virus infection. However, these results are derived from observational studies, with some important biases. They should be examined in future sufficiently powered randomized trials.