Publications by authors named "Pixin Ran"

118 Publications

Platelet-derived growth factor-BB induces pulmonary venous smooth muscle cells proliferation by upregulating calcium sensing receptor under hypoxic conditions.

Cytotechnology 2021 Apr 27;73(2):189-201. Epub 2021 Feb 27.

Guangzhou Institute for Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, The First Affiliated Hospital of Guangzhou Medical University, 151 Yanjiang Road, Guangzhou, 510120 China.

Pulmonary hypertension (PH) is characterized by pulmonary vascular remodeling, which exists in both pulmonary arteries and pulmonary veins. Pulmonary vascular remodeling stems from excessive proliferation of pulmonary vascular myocytes. Platelet-derived growth factor-BB (PDGF-BB) is a vital vascular regulator whose level increases in PH human lungs. Although the mechanisms by which pulmonary arterial smooth muscle cells respond to PDGF-BB have been studied extensively, the effects of PDGF-BB on pulmonary venous smooth muscle cells (PVSMCs) remain unknown. We herein examined the involvement of calcium sensing receptor (CaSR) in PDGF-BB-induced PVSMCs proliferation under hypoxic conditions. In PVSMCs isolated from rat intrapulmonary veins, PDGF-BB increased the cell number and DNA synthesis under normoxic and hypoxic conditions, which was accompanied by upregulated CaSR expression. The influences of PDGF-BB on proliferation and CaSR expression in hypoxic PVSMCs were greater than that in normoxic PVSMCs. In hypoxic PVSMCs superfused with Ca-free solution, restoration of extracellular Ca induced an increase of [Ca], which was significantly smaller than that in PDGF-BB-treated hypoxic PVSMCs. The positive CaSR modulator spermine enhanced, whereas the negative CaSR modulator NPS2143 attenuated, the extracellular Ca-induced [Ca] increase in PDGF-BB-treated hypoxic PVSMCs. Furthermore, the spermine enhanced, whereas the NPS2143 inhibited, PDGF-BB-induced proliferation in hypoxic PVSMCs. Silencing CaSR with siRNA attenuated the extracellular Ca-induced [Ca] increase in PDGF-BB-treated hypoxic PVSMCs and inhibited PDGF-BB-induced proliferation in hypoxic PVSMCs. In conclusion, these results demonstrated that CaSR mediating PDGF-BB-induced excessive PVSMCs proliferation is an important mechanism involved in the initiation and progression of PVSMCs proliferation under hypoxic conditions.
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http://dx.doi.org/10.1007/s10616-021-00456-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035351PMC
April 2021

Pulmonary tuberculosis as a risk factor for chronic obstructive pulmonary disease: a systematic review and meta-analysis.

Ann Transl Med 2021 Mar;9(5):390

State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.

Background: Prior pulmonary tuberculosis (TB) can cause permanent changes in lung anatomy and is associated with lung function loss. However, it remains unclear whether pulmonary function impairment owing to TB is associated with airflow obstruction, the hallmark of chronic obstructive pulmonary disease (COPD). The aim of this systematic review and meta-analysis was to assess the association and quantify the magnitudes of association between pulmonary TB and COPD, and to evaluate the prevalence of COPD in patients with prior pulmonary TB.

Methods: We searched the PubMed, Embase, and Web of Science databases for studies published from inception to January 1, 2020. Pooled effect sizes were calculated according to a random effects model or fixed effect model depending on heterogeneity. Specific subgroups (different diagnostic criteria, smoking status, income level) were examined.

Results: A total of 23 articles were included in this study. Compared with controls, patients with pulmonary TB had an odds ratios (ORs) of 2.59 [95% confidence interval (CI): 2.12-3.15; P<0.001] for developing COPD. In jackknife sensitivity analyses, the increased risk of prior pulmonary TB remained consistent for COPD; when the meta-analysis was repeated and one study was omitted each time, the ORs and corresponding 95% CIs were greater than 2. Funnel plots of ORs with Egger's linear regression (t=2.00, P=0.058) and Begg's rank correlation (Z=0.75, P=0.455) showing no significant publication bias. Subgroup analysis showed that the same conclusion was still present in never smokers (ORs 2.41; 95% CI: 1.74-3.32; P<0.001), patients with pulmonary TB diagnosed using chest X-ray (ORs 2.47; 95% CI: 1.23-4.97; P<0.001), and low- and middle-income country (LMIC) settings (ORs 2.70; 95% CI: 2.08-3.51; P<0.001). The pooled prevalence of COPD in patients with prior pulmonary TB was 21% (95% CI: 16-25%; P<0.001).

Conclusions: Individuals with prior pulmonary TB have an increased risk and high prevalence of COPD. Future studies identifying the underlying mechanisms for TB-associated COPD and therapeutic strategies are required.
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http://dx.doi.org/10.21037/atm-20-4576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033376PMC
March 2021

Analysis of pathological changes in the epithelium in COVID-19 patient airways.

ERJ Open Res 2021 Apr 6;7(2). Epub 2021 Apr 6.

State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.

https://bit.ly/2M2NcdO.
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http://dx.doi.org/10.1183/23120541.00690-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898030PMC
April 2021

NOX4-Derived ROS Promotes Collagen I Deposition in Bronchial Smooth Muscle Cells by Activating Noncanonical p38MAPK/Akt-Mediated TGF- Signaling.

Oxid Med Cell Longev 2021 19;2021:6668971. Epub 2021 Mar 19.

Department of Pulmonary and Critical Care Medicine, General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, China.

Background: Airway smooth muscle (ASM) remodeling is a hallmark in chronic obstructive pulmonary disease (COPD). NADPH oxidase 4- (NOX4-) mediated reactive oxygen species (ROS) production plays a crucial role in cell differentiation and extracellular matrix (ECM) synthesis in ASM remodeling. However, the precise mechanisms underpinning its pathogenic roles remain elusive.

Methods: The expression of NOX4 and TGF- in the airway of the lung was measured in COPD patients and the control group. Cigarette smoke- (CS-) induced emphysema mice were generated, and the alteration of -SMA, NOX4, TGF-, and collagen I was accessed. The changes of the expression of ECM markers, NOX4, components of TGF-/Smad, and MAPK/Akt signaling in human bronchial smooth muscle cells (HBSMCs) were ascertained for delineating mechanisms of NOX4-mediated ROS production on cell differentiation and remodeling in human ASM cells.

Results: An increased abundance of NOX4 and TGF- proteins in the epithelial cells and ASM of lung was observed in COPD patients compared with the control group. Additionally, an increased abundance expression of NOX4 and -SMA was observed in the lungs of the CS-induced emphysema mouse model. TGF- displayed abilities to increase the oxidative burden and collagen I production, along with enhanced phosphorylation of ERK, p38MAPK, and p-Akt473 in HBSMCs. These effects of TGF- could be inhibited by the ROS scavenger N-acetylcysteine (NAC), siRNA-mediated knockdown of Smad3 and NOX4, and pharmacological inhibitors SB203580 (p38MAPK inhibitor) and LY294002 (Akt inhibitor).

Conclusions: NOX4-mediated ROS production alters TGF--induced cell differentiation and collagen I protein synthesis in HBSMCs in part through the p38MAPK/Akt signaling pathway in a Smad-dependent manner.
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http://dx.doi.org/10.1155/2021/6668971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007363PMC
March 2021

Exposure to SARS-CoV-2 generates T-cell memory in the absence of a detectable viral infection.

Nat Commun 2021 03 19;12(1):1724. Epub 2021 Mar 19.

State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China.

T-cell immunity is important for recovery from COVID-19 and provides heightened immunity for re-infection. However, little is known about the SARS-CoV-2-specific T-cell immunity in virus-exposed individuals. Here we report virus-specific CD4 and CD8 T-cell memory in recovered COVID-19 patients and close contacts. We also demonstrate the size and quality of the memory T-cell pool of COVID-19 patients are larger and better than those of close contacts. However, the proliferation capacity, size and quality of T-cell responses in close contacts are readily distinguishable from healthy donors, suggesting close contacts are able to gain T-cell immunity against SARS-CoV-2 despite lacking a detectable infection. Additionally, asymptomatic and symptomatic COVID-19 patients contain similar levels of SARS-CoV-2-specific T-cell memory. Overall, this study demonstrates the versatility and potential of memory T cells from COVID-19 patients and close contacts, which may be important for host protection.
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http://dx.doi.org/10.1038/s41467-021-22036-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979809PMC
March 2021

Association of change in air quality with hospital admission for acute exacerbation of chronic obstructive pulmonary disease in Guangdong, China: A province-wide ecological study.

Ecotoxicol Environ Saf 2021 Jan 11;208:111590. Epub 2020 Nov 11.

State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China. Electronic address:

Aims: To assess possible effect of air quality improvements, we investigated the temporal change in hospital admissions for acute exacerbations of chronic obstructive pulmonary disease (AECOPD) associated with pollutant concentrations.

Methods: We collected daily concentrations of particulate matter (i.e., PM, PM and PM), sulfur dioxide (SO), nitrogen dioxide (NO), carbon monoxide (CO), ozone (O), and admissions for AECOPD for 21 cities in Guangdong from 2013 to 2017. We examined the association of air pollution with AECOPD admissions using two-stage time-series analysis, and estimated the annual attributable fractions, numbers, and direct hospitalization costs of AECOPD admissions with principal component analysis.

Results: From 2013-2017, mean daily concentrations of SO, PM and PM declined by nearly 40%, 30%, and 26% respectively. As the average daily 8 h O concentration increased considerably, the number of days exceeding WHO target (i.e.,100 μg/m³) increased from 103 in 2015-152 in 2017. For each interquartile range increase in pollutant concentration, the relative risks of AECOPD admission at lag 0-3 were 1.093 (95% CI 1.06-1.13) for PM, 1.092 (95% CI 1.08-1.11) for O, and 1.092 (95% CI 1.05-1.14) for SO. Attributable fractions of AECOPD admission advanced by air pollution declined from 9.5% in 2013 to 4.9% in 2016, then increased to 6.0% in 2017. A similar declining trend was observed for direct AECOPD hospitalization costs.

Conclusion: Declined attributable hospital admissions for AECOPD may be associated with the reduction in concentrations of PM, PM and SO in Guangdong, while O has emerged as an important risk factor. Summarizes the main finding of the work: Reduction in PM may result in declined attributable hospitalizations for AECOPD, while O has emerged as an important risk factor following an intervention.
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http://dx.doi.org/10.1016/j.ecoenv.2020.111590DOI Listing
January 2021

Using Mobile Health Technology to Deliver a Community-Based Closed-Loop Management System for Chronic Obstructive Pulmonary Disease Patients in Remote Areas of China: Development and Prospective Observational Study.

JMIR Mhealth Uhealth 2020 11 25;8(11):e15978. Epub 2020 Nov 25.

State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Diseases, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.

Background: Mobile health (mHealth) technology is an increasingly recognized and effective method for disease management and has the potential to intervene in pulmonary function, exacerbation risk, and psychological status of patients with chronic obstructive pulmonary disease (COPD).

Objective: This study aimed to investigate the feasibility of an mHealth-based COPD management system designed for Chinese remote areas with many potential COPD patients but limited medical resources.

Methods: The system was implemented based on a tailored closed-loop care pathway that breaks the heavy management tasks into detailed pieces to be quantified and executed by computers. Low-cost COPD evaluation and questionnaire-based psychological intervention are the 2 main characteristics of the pathway. A 6-month prospective observational study at the community level was performed to evaluate the effect of the system. Primary outcomes included changes in peak expiratory flow values, quality of life measured using the COPD assessment test scale, and psychological condition. Acute exacerbations, compliance, and adverse events were also measured during the study. Compliance was defined as the ratio of the actual frequency of self-monitoring records to the prescribed number.

Results: A total of 56 patients was enrolled; 39 patients completed the 6-month study. There was no significant difference in the mean peak expiratory flow value before and after the 6-month period (366.1, SD 106.7 versus 313.1, SD 116.6; P=.11). Psychological condition significantly improved after 6 months, especially for depression, as measured using the Patient Health Questionnaire-9 scale (median 6.0, IQR 3.0-9.0 versus median 4.0, IQR 0.0-6.0; P=.001). The COPD assessment test score after 6 months of intervention was also lower than that at the baseline, and the difference was significant (median 4.0, IQR 1.0-6.0 versus median 3.0, IQR 0.0-6.0; P=.003). The median overall compliance was 91.1% (IQR 67%-100%). In terms of acute exacerbation, 110 exacerbations were detected and confirmed by health care providers (per 6 months, median 2.0, IQR 1.0-5.0). Moreover, 72 adverse events occurred during the study, including 1 death, 19 hospitalizations, and 52 clinic visits due to persistent respiratory symptoms.

Conclusions: We designed and validated a feasible mHealth-based method to manage COPD in remote Chinese areas with limited medical resources. The proposed closed-loop care pathway was effective at the community level. Proper education and frequent communication with health care providers may encourage patients' acceptance and use of smartphones to support COPD self-management. In addition, WeChat might play an important role in improving patient compliance and psychological distress. Further research might explore the effect of such systems on a larger scale and at a higher evidence level.
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http://dx.doi.org/10.2196/15978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725649PMC
November 2020

Prevalence and Population Attributable Risk for Chronic Airflow Obstruction in a Large Multinational Study.

Am J Respir Crit Care Med 2020 Nov 10. Epub 2020 Nov 10.

Department of Respiratory Medicine, Maastricht University Medical Center, Maastricht, Netherlands.

The Global Burden of Disease programme identified smoking, and ambient and household air pollution as the main drivers of death and disability from Chronic Obstructive Pulmonary Disease (COPD). To estimate the attributable risk of chronic airflow obstruction (CAO), a quantifiable characteristic of COPD, due to several risk factors. The Burden of Obstructive Lung Disease study is a cross-sectional study of adults, aged≥40, in a globally distributed sample of 41 urban and rural sites. Based on data from 28,459 participants, we estimated the prevalence of CAO, defined as a post-bronchodilator one-second forced expiratory volume to forced vital capacity ratio < lower limit of normal, and the relative risks associated with different risk factors. Local RR were estimated using a Bayesian hierarchical model borrowing information from across sites. From these RR and the prevalence of risk factors, we estimated local Population Attributable Risks (PAR). Mean prevalence of CAO was 11.2% in men and 8.6% in women. Mean PAR for smoking was 5.1% in men and 2.2% in women. The next most influential risk factors were poor education levels, working in a dusty job for ≥10 years, low body mass index (BMI), and a history of tuberculosis. The risk of CAO attributable to the different risk factors varied across sites. While smoking remains the most important risk factor for CAO, in some areas poor education, low BMI and passive smoking are of greater importance. Dusty occupations and tuberculosis are important risk factors at some sites.
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http://dx.doi.org/10.1164/rccm.202005-1990OCDOI Listing
November 2020

Association of hospital admission for bronchiectasis with air pollution: A province-wide time-series study in southern China.

Int J Hyg Environ Health 2021 Jan 3;231:113654. Epub 2020 Nov 3.

State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong Province, China. Electronic address:

The relation of acute fluctuations of air pollution to hospital admission for bronchiectasis remained uncertain, and large-scale studies were needed. We collected daily concentrations of particulate matter (PM), sulfur dioxide (SO), nitrogen dioxide (NO), carbon monoxide (CO), ozone (O), and daily hospitalizations for bronchiectasis for 21 cities across Guangdong Province from 2013 through 2017. We examined their association using two-stage time-series analysis. Our analysis was stratified by specific sub-diagnosis, sex and age group to assess potential effect modifications. Relative risks of hospitalization for bronchiectasis were 1.060 (95%CI 1.014-1.108) for PM at lag0-6, 1.067 (95%CI 1.020-1.116) for PM at lag0-6, 1.038 (95%CI 1.005-1.073) for PM at lag0-6, 1.058 (95%CI 1.015-1.103) for SO at lag0-4, 1.057 (95%CI 1.030-1.084) for NO at lag0 and 1.055 (95%CI 1.025-1.085) for CO at lag0-6 per interquartile range increase of air pollution. Specifically, acute fluctuations of air pollution might be a risk factor for bronchiectasis patients with lower respiratory infection but not with hemoptysis. Patients aged ≥65 years, and female patients appeared to be particularly susceptible to air pollution. Acute fluctuations of air pollution, particularly PM may increase the risk of hospital admission for bronchiectasis exacerbations, especially for the patients complicated with lower respiratory infection. This study strengthens the importance of reducing adverse impact on respiratory health of air pollution to protect vulnerable populations.
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http://dx.doi.org/10.1016/j.ijheh.2020.113654DOI Listing
January 2021

PM2.5 Induces the Expression of Inflammatory Cytokines via the Wnt5a/Ror2 Pathway in Human Bronchial Epithelial Cells.

Int J Chron Obstruct Pulmon Dis 2020 23;15:2653-2662. Epub 2020 Oct 23.

State Key Laboratory of Respiratory Diseases, National Clinical Research Center for Respiratory Diseases, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, People's Republic of China.

Background And Purpose: Recently, fine particulate matter (PM2.5) was identified as the main exposure risk for COPD, and inflammation is central to the development of COPD. In this study, we investigated whether PM2.5 can induce the secretion of interleukin-6 (IL-6), IL-8 and IL-1β in human bronchial epithelial cells (HBECs) in vitro via the wingless-related integration site 5A (Wnt5a)/receptor tyrosine kinase-like orphan receptor 2 (Ror2) signaling.

Methods: The expression of Wnt5a and Ror2 was assessed by immunohistochemistry in motor vehicle exhaust (MVE)-induced Sprague-Dawley rats. HBECs were transfected with small interfering RNA (siRNA) targeting Wnt5a or Ror2 and subsequently stimulated with PM2.5.The secretion of IL-6, IL-8 and IL-1β was assessed by ELISAs, and the expression of Wnt5a/Ror2 signaling were assessed by RT-PCR and Western blotting.

Results: Both Wnt5a and Ror2 protein were increased in the lung of MVE-induced rats. HBECs exposed to PM2.5 for 24 h significantly upregulated Wnt5a and Ror2 expression and subsequently promoted the nuclear translocation of NF-κB, which increased the production of IL-1β, IL-6 and IL-8. Wnt5a siRNA prevented these outcomes. Wnt5a antagonist (BOX5) also prevented inflammatory effects. Furthermore, Ror2 siRNA blocked the NF-κB activity and inhibited the release of IL-6, IL-8 and IL-1β from PM2.5-exposed HBECs.

Conclusion: PM2.5 induces the secretion of IL-6, IL-8 and IL-1β in HBECs via the Wnt5a/Ror2 signaling, demonstrating a novel mechanism for PM2.5-associated airway inflammation.
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http://dx.doi.org/10.2147/COPD.S270762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591099PMC
October 2020

Chronic exposure to ambient particulate matter induces gut microbial dysbiosis in a rat COPD model.

Respir Res 2020 Oct 19;21(1):271. Epub 2020 Oct 19.

State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510000, P.R. China.

Background: The role of the microbiota in the pathogenesis of chronic obstructive pulmonary disease (COPD) following exposure to ambient particulate matter (PM) is largely unknown.

Methods: Fifty-four male Sprague-Dawley rats were exposed to clean air, biomass fuel (BMF), or motor vehicle exhaust (MVE) for 4, 12, and 24 weeks. We performed pulmonary inflammation evaluation, morphometric measurements, and lung function analysis in rat lung at three different times points during exposure. Lung and gut microbial composition was assessed by 16S rRNA pyrosequencing. Serum lipopolysaccharide levels were measured and short-chain fatty acids in colon contents were quantified.

Results: After a 24-week PM exposure, rats exhibited pulmonary inflammation and pathological changes characteristic of COPD. The control and PM exposure (BMF and MVE) groups showed similar microbial diversity and composition in rat lung. However, the gut microbiota after 24 weeks PM exposure was characterized by decreased microbial richness and diversity, distinct overall microbial composition, lower levels of short-chain fatty acids, and higher serum lipopolysaccharide.

Conclusion: Chronic exposure to ambient particulate matter induces gut microbial dysbiosis and metabolite shifts in a rat model of chronic obstructive pulmonary disease.
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http://dx.doi.org/10.1186/s12931-020-01529-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574574PMC
October 2020

Association of diurnal temperature range with daily hospitalization for exacerbation of chronic respiratory diseases in 21 cities, China.

Respir Res 2020 Sep 29;21(1):251. Epub 2020 Sep 29.

State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China.

Background: The association between diurnal temperature range (DTR) and hospitalization for exacerbation of chronic respiratory diseases (CRD) was rarely reported.

Objectives: To examine the association between DTR and daily hospital admissions for exacerbation of CRD and find out the potential effect of modifications on this association.

Method: Data on daily hospitalization for exacerbation of chronic obstructive pulmonary disease (COPD), asthma and bronchiectasis and meteorology measures from 2013 through 2017 were obtained from 21 cities in South China. After controlling the effects of daily mean temperature, relative humidity (RH), particulate matter < 2.5 μm diameter (PM) and other confounding factors, a standard generalized additive model (GAM) with a quasi-Poisson distribution was performed to evaluate the relationships between DTR and daily hospital admissions of CRD in a two-stage strategy. Subgroup analysis was performed to find potential modifications, including seasonality and population characteristics.

Result: Elevated risk of hospitalization for exacerbation of CRD (RR = 1.09 [95%CI: 1.08 to 1.11]) was associated with the increase in DTR (the 75th percentile versus the 25th percentile of DTR at lag0-6). The effects of DTR on hospital admissions for CRD were strong at low DTR in the hot season and high DTR in the cold season. The RR (the 75th percentile versus the 25th percentile of DTR at lag0-6) of hospitalization was 1.11 (95%CI: 1.08 to 1.12) for exacerbations of COPD and 1.09 (95%CI: 1.05 to 1.13) for asthma. The adverse effect of DTR on hospitalization for bronchiectasis was only observed in female patients (RR = 1.06 [95%CI: 1.03 to 1.10]).

Conclusion: Our study provided additional evidence for the association between DTR and daily hospitalization for exacerbation of CRD, and these associations are especially stronger in COPD patients and in the cold season than the hot season. Preventive measures to reduce the adverse impacts of DTR were needed for CRD patients.
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http://dx.doi.org/10.1186/s12931-020-01517-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526384PMC
September 2020

Improved night shift schedule related to the mortality of critically ill patients with Corona Virus Disease 2019.

Sleep Med 2020 11 17;75:354-360. Epub 2020 Aug 17.

State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China. Electronic address:

Purpose: To determine the relationship between the improved night shift schedule and the mortality of critically ill patients with Corona Virus Disease 2019 (COVID-19).

Methods: According to the time of the implementation of the new night shift schedule, we divided all patients into two groups: initial period group and recent period group. The clinical electronic medical records, nursing records, laboratory findings, and radiological examinations for all patients with laboratory confirmed Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection were reviewed. Cox proportional hazard ratio (HR) models were used to determine the risk factors associated with in hospital death.

Results: A total of 75 patients were included in this study. Initial period group includes 45 patients and recent period group includes 30 patients. The difference in mortality between the two groups was significant, 77.8% and 36.7%, respectively. Leukocytosis at admission and admitted to hospital before the new night shift schedule were associated with increased odds of death.

Conclusions: Shift arrangement of medical staff are associated with the mortality of critically ill patients with COVID-19. The new night shift schedule might improve the continuity of treatment, thereby improving the overall quality of medical work and reducing the mortality of critically ill patients.
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http://dx.doi.org/10.1016/j.sleep.2020.08.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429562PMC
November 2020

Symptomless multi-variable apnea prediction index assesses adverse outcomes in patients with Corona Virus Disease 2019.

Sleep Med 2020 11 4;75:294-300. Epub 2020 Sep 4.

State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China. Electronic address:

Purpose: To explore the relationship between symptomless multi-Variable apnea prediction (sMVAP) index and adverse outcomes of patients with Corona Virus Disease 2019 (COVID-19).

Methods: According to the sMVAP quartiles, we divided all patients into four groups. The clinical electronic medical records, nursing records, laboratory findings, and radiological examinations for all patients with laboratory confirmed Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection were reviewed. Cox proportional hazard ratio (HR) models were used to determine the risk factors associated with in hospital death.

Results: A total of 97 patients were included in this study. The "Quartile 4" group 's ICU transfer rate was significantly higher than the "Quartile 1" group. Coronary heart disease, high d-dimer and sMVAP at admission were associated with increased odds of death.

Conclusions: Using the sMVAP index for obstructive sleep apnea hypopnea syndrome (OSAHS) risk assessment, and then predicting the adverse outcomes of COVID-19 patients, is an effective method. Therefore, the use of sMVAP index for OSAHS screening for inpatients with COVID-19 should be vigorously promoted, and high-risk patients should be effectively managed.
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http://dx.doi.org/10.1016/j.sleep.2020.08.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7472977PMC
November 2020

High-dose N-acetylcysteine for long-term, regular treatment of early-stage chronic obstructive pulmonary disease (GOLD I-II): study protocol for a multicenter, double-blinded, parallel-group, randomized controlled trial in China.

Trials 2020 Sep 11;21(1):780. Epub 2020 Sep 11.

State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, 151 Yanjiang Xi Road, Guangzhou, Guangdong, China.

Introduction: The presence of increased oxidative stress and airway inflammation has been proven in subjects with chronic obstructive pulmonary disease (COPD). Several studies have demonstrated that drugs with antioxidant and anti-inflammatory properties such as N-acetylcysteine (NAC) can reduce the rate of exacerbations in patients with COPD. However, the beneficial effects of NAC in early-stage COPD are minimally discussed. We are investigating whether high-dose NAC has therapeutic effects in Chinese patients with early-stage COPD.

Method And Analysis: A randomized, double-blinded, placebo-controlled, parallel-group, multicenter clinical trial is evaluating the efficacy and safety of NAC for the long-term treatment of patients with early-stage COPD at 24 centers in China. Subjects aged 40-80 years and recruited by physicians or researchers with special training will be randomized to either NAC 600 mg twice daily group or matching placebo group for 2 years. Measurements will include forced expiratory volume in 1 s (FEV), the number of COPD exacerbations, health-related quality, and pharmacoeconomic analysis.

Discussion: Currently, there are no randomized controlled trials with high-dose N-acetylcysteine (600 mg twice daily) for patients with mild-to-moderate COPD (GOLD I-II). We designed this multicenter randomized controlled trial (RCT) to assess the effectiveness, safety, and cost-effectiveness of long-term treatment with high-dose N-acetylcysteine. The results of this trial may guide clinical practice and change the standard of early COPD management.

Trial Registration: Chinese Clinical Trial Registry ChiCTR-IIR-17012604 . Registered on 07 September 2017.
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http://dx.doi.org/10.1186/s13063-020-04701-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488567PMC
September 2020

LncRNA RP11-86H7.1 promotes airway inflammation induced by TRAPM2.5 by acting as a ceRNA of miRNA-9-5p to regulate NFKB1 in HBECS.

Sci Rep 2020 07 14;10(1):11587. Epub 2020 Jul 14.

State Key Laboratory of Respiratory Diseases, National Clinical Research Center for Respiratory Diseases, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, 195 Dongfeng Xi Road, Guangzhou, 510182, Guangdong, China.

Traffic-related air pollution particulate matter 2.5 (TRAPM2.5), is involved in chronic obstructive pulmonary disease (COPD), which is characterized by airway inflammation. Specifically, these harmful particles or gases can increase chronic airway inflammation. Some recent studies have shown that lncRNAs are closely related to COPD and participate in the regulation of airway inflammation. However, the precise mechanisms remain unknown. In the present study, we investigated the effect of TRAPM2.5 on airway inflammation in human bronchial epithelial cells (HBECs) and the underlying mechanisms mediated by a lncRNA. After exposure to TRAPM2.5, the novel lncRNA RP11-86H7.1 was markedly upregulated in HBECs. Functional assays indicated that the lncRNA RP11-86H7.1 was required for the TRAPM2.5-induced expression of inflammatory factors in HBECs. A mechanistic study demonstrated that lncRNA RP11-86H7.1 might participate in TRAPM2.5-induced inflammatory responses by activating the NF-κB signaling pathway. Moreover, the lncRNA RP11-86H7.1 can promote the inflammatory response by acting as a competing endogenous RNA of miR-9-5p, reversing the inhibitory effect of its target gene NFKB1, and sustaining NF-κB activation. In summary, our study elucidates the pro-inflammatory roles of the lncRNA RP11-86H7.1-miR-9-5p-NFKB1 regulatory network in airway inflammation induced by TRAPM2.5 and indicates that the components of this network might serve as novel diagnostic biomarkers and potential therapeutic targets.
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http://dx.doi.org/10.1038/s41598-020-68327-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360621PMC
July 2020

Clinical characteristics of COVID-19 infection in chronic obstructive pulmonary disease: a multicenter, retrospective, observational study.

J Thorac Dis 2020 May;12(5):1811-1823

Huangshi Central Hospital of Edong Healthcare Group, Affiliated Hospital of Hubei Polytechnic University, Huangshi, China.

Background: Coronavirus disease 2019 (COVID-19) has been a global pandemic disease, with more than 4 million cases and nearly 300,000 deaths. Little is known about COVID-19 in patients with chronic obstructive pulmonary disease (COPD). We aimed to evaluate the influence of preexisting COPD on the progress and outcomes of COVID-19.

Methods: This was a multicenter, retrospective, observational study. We enrolled 1,048 patients aged 40 years and above, including 50 patients with COPD and 998 patients without COPD, and with COVID-19 confirmed via high-throughput sequencing or real-time reverse transcription-polymerase chain reaction, between December 11, 2019 and February 20, 2020. We collected data of demographics, pathologic test results, radiologic imaging, and treatments. The primary outcomes were composite endpoints determined by admission to an intensive care unit, the use of mechanical ventilation, or death.

Results: Compared with patients who had COVID-19 but not COPD, those with COPD had higher rates of fatigue (56.0% 40.2%), dyspnea (66.0% 26.3%), diarrhea (16.0% 3.6%), and unconsciousness (8.0% 1.7%) and a significantly higher proportion of increased activated partial thromboplastin time (23.5% 5.2%) and D-dimer (65.9% 29.3%), as well as ground-glass opacities (77.6% 60.3%), local patchy shadowing (61.2% 41.4%), and interstitial abnormalities (51.0% 19.8%) on chest computed tomography. Patients with COPD were more likely to develop bacterial or fungal coinfection (20.0% 5.9%), acute respiratory distress syndrome (ARDS) (20.0% 7.3%), septic shock (14.0% 2.3%), or acute renal failure (12.0% 1.3%). Patients with COPD and COVID-19 had a higher risk of reaching the composite endpoints [hazard ratio (HR): 2.17, 95% confidence interval (CI): 1.40-3.38; P=0.001] or death (HR: 2.28, 95% CI: 1.15-4.51; P=0.019), after adjustment.

Conclusions: In this study, patients with COPD who developed COVID-19 showed a higher risk of admission to the intensive care unit, mechanical ventilation, or death.
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http://dx.doi.org/10.21037/jtd-20-1914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330323PMC
May 2020

Prevalence and risk factors of small airway dysfunction, and association with smoking, in China: findings from a national cross-sectional study.

Lancet Respir Med 2020 11 26;8(11):1081-1093. Epub 2020 Jun 26.

State Key Laboratory of Biotherapy of China and Department of Respiratory and Critical Care Medicine, West China Hospital of Sichuan University, Chengdu, China.

Background: Small airway dysfunction is a common but neglected respiratory abnormality. Little is known about its prevalence, risk factors, and prognostic factors in China or anywhere else in the world. We aimed to estimate the prevalence of small airway dysfunction using spirometry before and after bronchodilation, both overall and in specific population subgroups; assess its association with a range of lifestyle and environmental factors (particularly smoking); and estimate the burden of small airway dysfunction in China.

Methods: From June, 2012, to May, 2015, the nationally representative China Pulmonary Health study invited 57 779 adults to participate using a multistage stratified sampling method from ten provinces (or equivalent), and 50 479 patients with valid lung function testing results were included in the analysis. We diagnosed small airway dysfunction on the basis of at least two of the following three indicators of lung function being less than 65% of predicted: maximal mid-expiratory flow, forced expiratory flow (FEF) 50%, and FEF 75%. Small airway dysfunction was further categorised into pre-small airway dysfunction (defined as having normal FEV and FEV/forced vital capacity [FVC] ratio before bronchodilator inhalation), and post-small airway dysfunction (defined as having normal FEV and FEV/FVC ratio both before and after bronchodilator inhalation). Logistic regression yielded adjusted odds ratios (ORs) for small airway dysfunction associated with smoking and other lifestyle and environmental factors. We further estimated the total number of cases of small airway dysfunction in China by applying present study findings to national census data.

Findings: Overall the prevalence of small airway dysfunction was 43·5% (95% CI 40·7-46·3), pre-small airway dysfunction was 25·5% (23·6-27·5), and post-small airway dysfunction was 11·3% (10·3-12·5). After multifactor regression analysis, the risk of small airway dysfunction was significantly associated with age, gender, urbanisation, education level, cigarette smoking, passive smoking, biomass use, exposure to high particulate matter with a diameter less than 2·5 μm (PM) concentrations, history of chronic cough during childhood, history of childhood pneumonia or bronchitis, parental history of respiratory diseases, and increase of body-mass index (BMI) by 5 kg/m. The ORs for small airway dysfunction and pre-small airway dysfunction were similar, whereas larger effect sizes were generally seen for post-small airway dysfunction than for either small airway dysfunction or pre-small airway dysfunction. For post-small airway dysfunction, cigarette smoking, exposure to PM, and increase of BMI by 5 kg/m were significantly associated with increased risk, among preventable risk factors. There was also a dose-response association between cigarette smoking and post-small airway dysfunction among men, but not among women. We estimate that, in 2015, 426 (95% CI 411-468) million adults had small airway dysfunction, 253 (238-278) million had pre-small airway dysfunction, and 111 (104-126) million had post-small airway dysfunction in China.

Interpretation: In China, spirometry-defined small airway dysfunction is highly prevalent, with cigarette smoking being a major modifiable risk factor, along with PM exposure and increase of BMI by 5 kg/m. Our findings emphasise the urgent need to develop and implement effective primary and secondary prevention strategies to reduce the burden of this condition in the general population.

Funding: Ministry of Science and Technology of China; National Natural Science Foundation of China; National Health Commission of China.
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http://dx.doi.org/10.1016/S2213-2600(20)30155-7DOI Listing
November 2020

Prognostic Role of NT-proBNP for in-Hospital and 1-Year Mortality in Patients with Acute Exacerbations of COPD.

Int J Chron Obstruct Pulmon Dis 2020 8;15:57-67. Epub 2020 Jan 8.

Guangzhou Institute of Respiratory Disease, State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, People's Republic of China.

Background And Objective: The association between N-terminal pro B-type natriuretic peptide (NT-proBNP) concentrations and in-hospital and 1-year mortality in acute exacerbations of chronic obstructive pulmonary disease (AECOPD) patients is largely unknown. Our objective was to explore the usefulness of NT-proBNP concentrations in AECOPD patients as a prognostic marker for in-hospital and 1-year mortality.

Methods: NT-proBNP levels were measured in patients upon admission and laboratory and clinical data were also recorded. The cut-point for the NT-proBNP concentration level for in-hospital death was obtained using the receiver operating characteristic (ROC) curve. Univariate and multivariate logistic regression and Cox regression were used in the analyses of factors of in-hospital and 1-year mortality.

Results: A total of 429 patients were enrolled. Twenty-nine patients died during hospitalization and 59 patients died during the 1-year follow-up. Patients who died in-hospital compared with those in-hospital survivors were older (80.14±6.56 vs 75.93±9.45 years, p=0.003), had a higher percentage of congestive heart failure (65.52% vs 33.75%, p<0.001), had higher NT-proBNP levels (5767.00 (1372.50-12,887.00) vs 236.25 (80.03-1074.75) ng/L, p<0.001), higher neutrophil counts (10.52±5.82 vs 7.70±4.31, p=0.016), higher D-dimer levels (1231.62±1921.29 vs 490.11±830.19, p=0.048), higher blood urea nitrogen levels (9.91±6.33 vs 6.51±4.01 mmol/L, p=0.001), a lower body mass index (19.49±3.57 vs 22.19±4.76, p=0.003), and higher hemoglobin levels (122.34±25.36 vs 130.57±19.63, p=0.034). The area under the ROC curve (AUC) for NT-proBNP concentration was 0.88 (95% confidence interval [CI], 0.84-0.93). NT-proBNP concentrations ≥551.35 ng/L were an independent prognostic factor for both in-hospital and 1-year mortality after adjustment for relative risk (RR) (RR=29.54, 95% CI 3.04-286.63, p=0.004 for the multivariate logistic regression analysis) and hazard ratio (HR) (HR=4.47, 95% CI, 2.38-8.41, p <0.001 for the multivariate cox regression analysis).

Conclusion: NT-proBNP was a strong and independent predictor of in-hospital and 1-year mortality in AECOPD patients.
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http://dx.doi.org/10.2147/COPD.S231808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6955621PMC
February 2021

A novel function of calcium sensing receptor in chronic hypoxia-induced pulmonary venous smooth muscle cells proliferation.

Hypertens Res 2020 04 18;43(4):271-280. Epub 2019 Dec 18.

Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.

Chronic hypoxia (CH) causes remodeling not only in pulmonary arteries but also in pulmonary veins. Pulmonary vascular remodeling stems from increased pulmonary vascular myocyte proliferation. However, the pathogenesis of CH-induced proliferation of pulmonary venous smooth muscle cells (PVSMCs) remains unknown. The present study aimed to explore the mechanisms by which CH affects PVSMCs proliferation. PVSMCs were isolated from rat distal pulmonary veins and exposed to CH (4% O for 60 h). The expression of calcium sensing receptor (CaSR) was determined by immunofluorescence, real-time quantitative PCR and Western blotting. Cell proliferation was assessed by cell counting, CCK-8 assay, and BrdU incorporation. Apoptosis analysis was examined by flow cytometry. In rat distal PVSMCs, CH increased the cell number and cell viability and enhanced DNA synthesis, which is accompanied by upregulated mRNA and protein expression levels of CaSR. Two negative CaSR modulators (NPS2143, NPS2390) not only attenuated CH-induced CaSR upregulation but also inhibited CH-induced increases in cell number, cell viability and the proliferation index of PVSMCs, whereas two positive modulators (spermine, R568) not only amplified CH-induced CaSR upregulation but also intensified CH-induced increases in cell number, cell viability and the proliferation index of PVSMCs. Silencing CaSR with siRNA similarly attenuated the CH-induced enhancement of cell number, cell viability and DNA synthesis in PVSMCs. Neither CH nor downregulation of CaSR with siRNA had an effect on apoptosis in PVSMCs. These results suggest that CaSR mediating excessive proliferation is a new pathogenic mechanism involved in the initiation and progression of distal PVSMCs proliferation under CH conditions.
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http://dx.doi.org/10.1038/s41440-019-0373-9DOI Listing
April 2020

Co-delivery of allergen epitope fragments and R848 inhibits food allergy by inducing tolerogenic dendritic cells and regulatory T cells.

Int J Nanomedicine 2019 30;14:7053-7064. Epub 2019 Aug 30.

Research Center of Allergy & Immunology, Department of Medicine, Shenzhen University, Shenzhen 518055, People's Republic of China.

Background: Food allergy (FA) is a significant public health problem. The therapeutic efficacy for FA is unsatisfactory currently. The breakdown of intestinal immune tolerance is associated with the pathogenesis of FA. Therefore, it is of great significance to develop novel therapeutic methods to restore immune tolerance in treating FA.

Methods: We proposed an oral administration strategy to treat FA by co-delivering food allergen epitope fragment (peptide: IK) and adjuvant R848 (TLR7 ligand) in the mPEG-PDLLA nanoparticles (PPLA-IK/R848 NPs). The generation of tolerogenic dendritic cells (DCs) and regulatory T cells (Tregs) induced by PPLA-IK/R848 NPs were evaluated in vitro and in vivo. The therapeutic effects of PPLA-IK/R848 NPs were also assessed in an OVA-induced FA model.

Results: PPLA-IK/R848 NPs could efficiently deliver IK to DCs to drive DCs into the tolerogenic phenotypes and promote the differentiation of Tregs in vitro and in vivo, significantly inhibited FA responses through the recovery of intestinal immune tolerance.

Conclusion: Oral administration of PPLA-IK/R848 NPs could efficiently deliver IK and R848 to intestinal DCs and stimulate DCs into allergen tolerogenic phenotype. These tolerogenic DCs could promote the differentiation of Tregs, which significantly protected mice from food allergic responses. This study provided an efficient formulation to alleviate FA through the recovery of immune tolerance.
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http://dx.doi.org/10.2147/IJN.S215415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6722440PMC
November 2019

Regulating Bcl2L12 expression in mast cells inhibits food allergy.

Theranostics 2019 9;9(17):4982-4992. Epub 2019 Jul 9.

Research Center of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, China.

: Mast cells play a crucial role in allergic diseases. Yet, the regulation of mast cell bioactivities is not fully understood. This study aims to elucidate the role of B cell lymphoma 2 like protein 12 (Bcl2L12), one of the anti-apoptosis proteins, in regulating mast cell apoptosis. : A food allergy (FA) mouse model was developed to establish mast cell over population in the intestinal tissue. Either compound 48/80 (C48/80) or specific antigens were used to activate mast cells in the intestinal mucosa. : After treating with C48/80, apoptosis was induced in mast cells of the intestine of naive control mice, but not in FA mice. The expression of Fas ligand (FasL) was lower in the mast cells of FA mice. Interleukin (IL)-5 was responsible for the suppression of FasL by upregulating the expression of Bcl2L12 in mast cells. Bcl2L12 prevented c-Myc, the major transcription factor of FasL, from binding the FasL promoter to inhibit the expression of FasL in mast cells. Inhibition of Bcl2L12 restored the apoptosis machinery of mast cells in the FA mouse intestine. : The apoptosis machinery in mast cells is impaired in an allergic environment. Inhibition of Bcl2L12 restores the apoptosis machinery in mast cells in the FA mouse intestine.
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http://dx.doi.org/10.7150/thno.34001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691383PMC
August 2020

IgE binding activities and in silico epitope prediction of Der f 32 in Dermatophagoides farinae.

Immunol Lett 2019 09 2;213:46-54. Epub 2019 Aug 2.

State Key Laboratory of Respiratory Disease for Allergy at Shenzhen University, Shenzhen University School of Medicine, Shenzhen 518060, China; The Third Affiliated Hospital of Shenzhen University, Shenzhen 518020, China. Electronic address:

Dermatophagoides farinae is a common indoor allergen source that produces more than 30 allergens, which induces diverse allergic diseases such as allergic rhinitis, allergic asthma and atopic dermatitis. Der f 32 is an inorganic pyrophosphatase and an important allergen from Dermatophagoides farinae. In the present study, Der f 32 was cloned, expressed and purified in order to better understand its structure and immunogenicity. Immunoblotting analysis and ELISA showed 5 of 5 positive reactions to recombinant Der f 32 using serum from house dust mite (HDM)-allergic patients. We constructed homology modeling and predicted epitopes of Der f 32 via bioinformatic tools. The sequence and structural analysis indicated that Der f 32 belonged to the pyrophosphatase family and represented a special structure of external α-helices and internal antiparallel closed β-sheets. In addition, eight B-cell epitopes and four T-cell epitopes were predicted. B-cell epitopes were 24-31, 111-121, 135-140, 168-172, 200-207, 214-220, 237-243, and 268-274 and T-cell epitopes were 47-55, 78-90, 127-135 and 143-151. The B-cell epitopes were distributed completely on the surface of Der f 32 and were located largely in random coils of secondary structures. Hydrophobic and charged amino acids comprised more than 80% of the residues of B-cell epitopes and may participate in IgE binding. The T-cell epitopes were located primarily in the interior of Der f 32 and, to a certain extent avoided degradation by proteases. The structures of T-cell epitopes were surrounded by B-cell epitopes, and this arrangement may have important biological significance for maintaining the immunogenicity of allergens.
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http://dx.doi.org/10.1016/j.imlet.2019.07.006DOI Listing
September 2019

Prevalence, risk factors, and management of asthma in China: a national cross-sectional study.

Lancet 2019 08 20;394(10196):407-418. Epub 2019 Jun 20.

Department of Respiratory and Critical Care Medicine, Beijing Hospital, Beijing, China; National Center of Gerontology, Beijing Hospital, Beijing, China.

Background: Asthma is a common chronic airway disease worldwide. Despite its large population size, China has had no comprehensive study of the national prevalence, risk factors, and management of asthma. We therefore aimed to estimate the national prevalence of asthma in a representative sample of the Chinese population.

Methods: A representative sample of 57 779 adults aged 20 years or older was recruited for the national cross-sectional China Pulmonary Health (CPH) study using a multi-stage stratified sampling method with parameters derived from the 2010 census. Ten Chinese provinces, representative of all socioeconomic settings, from six geographical regions were selected, and all assessments were done in local health centres. Exclusion criteria were temporary residence, inability to take a spirometry test, hospital treatment of cardiovascular conditions or tuberculosis, and pregnancy and breastfeeding. Asthma was determined on the basis of a self-reported history of diagnosis by a physician or by wheezing symptoms in the preceding 12 months. All participants were assessed with a standard asthma questionnaire and were classed as having or not having airflow limitation through pulmonary function tests before and after the use of a bronchodilator (400 μg of salbutamol). Risk factors for asthma were examined by multivariable-adjusted analyses done in all participants for whom data on the variables of interest were available. Disease management was assessed by the self-reported history of physician diagnosis, treatments, and hospital visits in people with asthma.

Findings: Between June 22, 2012, and May 25, 2015, 57 779 participants were recruited into the CPH study. 50 991 (21 446 men and 29 545 women) completed the questionnaire survey and had reliable post-bronchodilator pulmonary function test results and were thus included in the final analysis. The overall prevalence of asthma in our sample was 4·2% (95% CI 3·1-5·6), representing 45·7 million Chinese adults. The prevalence of asthma with airflow limitation was 1·1% (0·9-1·4), representing 13·1 million adults. Cigarette smoking (odds ratio [OR] 1·89, 95% CI 1·26-2·84; p=0·004), allergic rhinitis (3·06, 2·26-4·15; p<0·0001), childhood pneumonia or bronchitis (2·43, 1·44-4·10; p=0·002), parental history of respiratory disease (1·44, 1·02-2·04; p=0·040), and low education attainment (p=0·045) were associated with prevalent asthma. In 2032 people with asthma, only 28·8% (95% CI 19·7-40·0) reported ever being diagnosed by a physician, 23·4% (13·9-36·6) had a previous pulmonary function test, and 5·6% (3·1-9·9) had been treated with inhaled corticosteroids. Furthermore, 15·5% (11·4-20·8) people with asthma reported at least one emergency room visit and 7·2% (4·9-10·5) at least one hospital admission due to exacerbation of respiratory symptoms within the preceding year.

Interpretation: Asthma is prevalent but largely undiagnosed and undertreated in China. It is crucial to increase the awareness of asthma and disseminate standardised treatment in clinical settings to reduce the disease burden.

Funding: National Key R&D Program of China, Ministry of Science and Technology of China; the Special Research Foundation for Public Welfare of Health, Ministry of Health of China; the Chinese National Research Program for Key Issues in Air Pollution Control; and the National Natural Science Foundation of China.
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http://dx.doi.org/10.1016/S0140-6736(19)31147-XDOI Listing
August 2019

Long Noncoding RNA COPDA1 Promotes Airway Smooth Muscle Cell Proliferation in Chronic Obstructive Pulmonary Disease.

Am J Respir Cell Mol Biol 2019 11;61(5):584-596

State Key Laboratory of Respiratory Diseases, National Clinical Research Center for Respiratory Diseases, Guanzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University Guangzhou, Guangdong, China.

Abnormal expression of long noncoding RNAs (lncRNAs) has been confirmed to be associated with many diseases, including chronic obstructive pulmonary disease (COPD). To gain better understanding of the mechanism of COPD, we investigated the lncRNA and mRNA profiles in the lung tissue of patients with COPD. According to the analysis, one of the significantly different lncRNAs, COPDA1, might participate in the occurrence and development of COPD. Lung tissues were collected from nonsmokers, smokers, or smokers with COPD for RNA sequencing. Bioinformatic analysis and cell experiments were used to define the function of COPDA1, and the effects of COPDA1 on intracellular Ca concentration and cell proliferation were examined after knockdown or overexpression of COPDA1. A number of variations of lncRNAs were found in the comparison of nonsmokers, smokers, and smokers with COPD. GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analyses indicated that smoking was involved in the activation of cytokines and the cell cycle, which is associated with COPD. According to the lncRNA-mRNA-coexpressing network and enrichment analysis, COPDAz1 and one of its target genes, (membrane-spanning 4-domains family, subfamily A) were investigated, and we discovered that the expression of was closely associated with lncRNA COPDA1 expression in human bronchial smooth muscle cells (HBSMCs). Further study showed that lncRNA COPDA1 upregulated the expression of to increase store-operated calcium entry in the HBSMCs, resulting in the promotion of the proliferation of smooth muscle cells as well as of airway remodeling. COPDA1 might be involved in the regulation of certain signaling pathways in COPD, might promote the proliferation of HBSMCs, and might also be involved in facilitating airway remodeling.
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http://dx.doi.org/10.1165/rcmb.2018-0269OCDOI Listing
November 2019

Benzo(a)pyrene facilitates dermatophagoides group 1 (Der f 1)-induced epithelial cytokine release through aryl hydrocarbon receptor in asthma.

Allergy 2019 09 19;74(9):1675-1690. Epub 2019 Jun 19.

The Affiliated Luohu Hospital of Shenzhen University, Shenzhen Luohu Hospital Group, Shenzhen, China.

Background: Environmental pollutants, which coexist with allergens, have been associated with the exacerbation of asthma. However, the underlying molecular mechanisms remain elusive. We sought to determine whether benzo(a)pyrene (BaP) co-exposure with dermatophagoides group 1 allergen (Der f 1) can potentiate Der f 1-induced asthma and its underlying mechanisms.

Methods: The effect of BaP was investigated in Der f 1-induced mouse model of asthma, including airway hyper-responsiveness, allergic inflammation, and epithelial-derived cytokines. The impact of BaP on Der f 1-induced airway epithelial cell oxidative stress (ROS) and cytokine release was further analyzed. The role of aryl hydrocarbon receptor (AhR) signaling in BaP-promoted Der f 1-induced ROS, cytokine production, and allergic inflammation was also investigated.

Results: Compared with Der f 1, BaP co-exposure with Der f 1 led to airway hyper-responsiveness and increased lung inflammation in mouse model of asthma. Increased expression of TSLP, IL-33, and IL-25 was also found in the airways of these mice. Moreover, BaP co-exposure with Der f 1 activated AhR signaling with increased expression of AhR and CYP1A1 and promoted airway epithelial ROS generation and TSLP and IL-33, but not IL-25, expression. Interestingly, AhR antagonist CH223191 or cells with AhR knockdown abrogated the increased expression of ROS, TSLP, and IL-33. Furthermore, ROS inhibitor N-acetyl-L-cysteine (NAC) also suppressed BaP co-exposure-induced expression of epithelial TSLP, IL-33, and IL-25. Finally, AhR antagonist CH223191 and NAC inhibited BaP co-exposure with Der f 1-induced lung inflammation.

Conclusions: Our findings suggest that BaP facilitates Der f 1-induced epithelial cytokine release through the AhR-ROS axis.
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http://dx.doi.org/10.1111/all.13784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6790621PMC
September 2019

Tiotropium discontinuation in patients with early-stage COPD: a prospective observational cohort study.

ERJ Open Res 2019 Feb 18;5(1). Epub 2019 Feb 18.

The State Key Laboratory of Respiratory Disease, National Clinical Researcher Center for Respiratory Diseases, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.

Background: Tiotropium improves lung function and ameliorates the annual decline in forced expiratory volume in 1 s (FEV) after bronchodilator use in patients with mild to moderate chronic obstructive pulmonary disease (COPD). However, whether these benefits persist in patients with early-stage COPD after tiotropium discontinuation is unknown.

Methods: In this prospective cohort observational follow-up study, patients who had completed the Tiotropium in Early-Stage COPD (Tie-COPD) trial were followed for a maximum of 3 years, continuing or discontinuing treatment according to their willingness. The outcomes measured were spirometry parameters, COPD exacerbations, COPD Assessment Test (CAT) scores, Clinical COPD Questionnaire (CCQ) scores, modified Medical Research Council (mMRC) scores and the use of respiratory medications.

Results: Out of 376 patients, 262 (126 in the post-placebo group and 136 in the post-tiotropium group) completed the maximum 3-year follow-up after the study medication was withdrawn. After discontinuation, the decrease in FEV and forced vital capacity (FVC) did not differ significantly between the two groups, and neither did their annual decline. In addition, the frequency of acute COPD exacerbations and the mMRC scores were similar between the two groups after medication withdrawal. Both the mean CAT and CCQ scores were significantly lower in the post-tiotropium group than in the post-placebo group (p<0.05 for all comparisons) at the 1-year follow-up after withdrawal, but they were not different at the next follow-up.

Conclusion: Withdrawal of tiotropium treatment in early-stage COPD resulted in difference reduction of both FEV and FVC, indicating that treatment should be continued.
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http://dx.doi.org/10.1183/23120541.00175-2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378343PMC
February 2019

TRPC channels mediated calcium entry is required for proliferation of human airway smooth muscle cells induced by nicotine-nAChR.

Biochimie 2019 Mar 11;158:139-148. Epub 2018 Dec 11.

Respiratory Medicine, Hunan Provincial People's Hospital, No. 61 Jiefang Xi Road, Changsha, 410219, Hunan, PR China; Institute of Respiratory Medicine, Changsha Medical College, No. 1501 Leifeng Road, Changsha, 410219, Hunan, PR China. Electronic address:

The present study was designed to explore the role of transient receptor potential canonical 3 (TRPC3) in nicotine-induced chronic obstructive pulmonary disease (COPD) and its underlying mechanism. In this study, the expression and localization of α5 nicotinic acetylcholine receptor (α5-nAchR) in lung tissues were determined by western blotting and immunohistochemistry. The quantitative real-time PCR (qRT-PCR) analysis was performed to examine the mRNA expression levels of α5-nAchR and TRPC3 in human airway smooth muscle cells (HASMCs). Cell viability was assessed by CCK-8 assay. Proliferation was detected by cell counting and EdU immunofluorescent staining. Fluorescence calcium imaging was carried out to measure cytosolic Ca ([Ca]cyt) concentration. The results showed that the α5-nAchR and TRPC3 expressions were significantly up-regulated in lung tissues of COPD smokers. Nicotine promoted HASMC proliferation, which was accompanied by elevated α5-nAchR and TRPC3 expressions, basal [Ca]cyt, store-operated calcium entry (SOCE) and the rate of Mn quenching in HASMCs. Further investigation indicated that nicotine-induced Ca response and TRPC3 up-regulation was reversibly blocked by small interfering RNA (siRNA) suppression of α5-nAChR. The knockdown of TRPC3 blunted Ca response and HASMC proliferation induced by nicotine. In conclusion, nicotine-induced HASMC proliferation was mediated by TRPC3-dependent calcium entry via α5-nAchR, which provided a potential target for treatment of COPD.
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http://dx.doi.org/10.1016/j.biochi.2018.12.004DOI Listing
March 2019

Identification of ceRNA network based on a RNA-seq shows prognostic lncRNA biomarkers in human lung adenocarcinoma.

Oncol Lett 2018 Nov 21;16(5):5697-5708. Epub 2018 Aug 21.

Oncology Department, Gansu Provincial Hospital of Traditional Chinese Medicine, Lanzhou, Gansu 730050, P.R. China.

Previous studies have emphasized the significant functions of long non-coding RNAs (lncRNAs) as competing endogenous RNAs (ceRNAs) in tumor biology. However, the functions of certain cancer lncRNAs in the lncRNA-related ceRNA network in lung adenocarcinoma (LUAD) are unknown. A systematic and integrative survey of RNA-seq data from The Cancer Genome Atlas (TCGA) was performed to identify candidate lncRNAs for the prognosis of LUAD. In total, 20,502 genes that contain 181 lncRNAs were evaluated in a cohort of 570 LUAD cases. Initially, 6,280 differentially expressed genes (fold-change >2, P<0.05) were obtained using R package, which includes 75 lncRNAs. Next, by univariate regression and multivariate Cox proportional hazards analysis, 32 genes were associated with survival in LUAD. Using these 29 mRNAs and 3 lncRNAs, a prognosis index (PI) was calculated to accurately estimate the survival in LUAD: PI=∑exp × HRrisk gene. Furthermore, the 32-gene signature was an independent prognostic indicator for LUAD (HR >1; P<0.05, by multivariate analysis). Weighted gene co-expression network analysis (WGCNA) of three risk lncRNAs-FAM138B, NHEG1 and TLX1NB-was performed, based on the P-values of the associated genes, and the top 27 miRNAs that bound to these lncRNAs were predicted by Miranda as target miRNAs. Next, these target miRNAs were transferred to the TarBase, miRTarBase, miRecards and starBase v2.0 databases to obtain their target genes. According to the previous miRNA-mRNA and miRNA-lncRNA data, three lncRNA-miRNA-mRNA ceRNA networks were established, based on the 29 prognostic mRNAs, forming a regulatory network in LUAD. The present study provided insight into the lncRNA-related ceRNA network in LUAD and has identified potential diagnostic and prognostic biomarkers.
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http://dx.doi.org/10.3892/ol.2018.9336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6176255PMC
November 2018