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Pyroptosis is an inflammatory type of regulated cell death that is dependent on inflammasome activation and downstream proteases such as caspase-1 or caspase 4/5/11. The main executors are gasdermins, which have an inherent pore-forming function on the membrane and release inflammatory cytokines, such as interleukin (IL)-1β, IL-18 and high mobility group box 1. Emerging evidence demonstrates that pyroptosis is involved in the pathogenesis of various pulmonary diseases. In this review, we mainly discuss the biological mechanisms of pyroptosis, explore the relationship between pyroptosis and respiratory diseases, and discuss emerging therapeutic strategies for respiratory diseases.

Ruolin Mao,1,&ast; Zilong Liu,1,&ast; Yunfeng Zhao,2,&ast; Chunlin Du,3,&ast; Jintao Zhou,4,&ast; Qian Wang,5,&ast; Jinchang Lu,3 Lei Gao,1 Bo Cui,1 Yuan Ma,1 Tieying Sun,6 Lei Zhu,1,7 Zhihong Chen1 1Department of Respiratory and Critical Care Medicine, Zhongshan Hospital, Fudan University. Shanghai Institute of Respiratory Disease, Shanghai, People’s Republic of China; 2Department of Respiratory Disease, Punan Hospital, Pudong New Area, Shanghai, People’s Republic of China; 3Department of Respiratory and Critical Care Medicine, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai, People’s Republic of China; 4Department of Respiratory and Critical Care Medicine, Taicang Hospital Affiliated with Soochow University, Taicang, Jiangsu, People’s Republic of China; 5Department of Respiratory Medicine, Jing’an District Zhabei Central Hospital, Shanghai, People’s Republic of China; 6Department of Respiratory and Critical Care Medicine, Beijing Hospital, National Center of Gerontology, Beijing, People’s Republic of China; 7Department of Respiratory and Critical Care Medicine, Beijing Tsinghua Changgung Hospital, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhihong Chen;Tieying Sun Tel +86-21-64041990-2445; +86-10-85132266Fax +86-21-64187165; +86-10-65132969Email chen.zhihong@zs-hospital.sh.cn; suntieying@126.comBackground: Early diagnosis and proper management of a large number of chronic obstructive pulmonary disease (COPD) patients are great challenges for the Chinese health care system. Although tiered medical services have been promoted by the Chinese government since 2015, they have not been ideally implemented for COPD diagnosis and management.Patients and Methods: We designed a cross-sectional study. Eligible COPD patients (n = 648) and physicians (n = 161) were consecutively recruited from 8 hospitals in different tiers in China. COPD characteristics and treatments were compared among hospitals in different tiers. Multivariate logistic regression was performed to identify risk factors associated with airflow limitation, symptoms and acute exacerbation.Results: The PFT rate at first diagnosis was 99%, 69.4% and 29.9% in teaching, second-tier and community hospitals (P < 0.001). Only approximately 10.9%, 1.7% and 9.6% and 21.8%, 6.9% and 32% of COPD patients received influenza or pneumococcal vaccines (P < 0.001). The proportion of patients who did not use inhaled drugs or had irregular inhalation was 2%, 24.6% and 78.8% (P < 0.001). Education level (RR-1 = − 41.26%, P = 0.007), FEV1%pred (RR-1 = − 2.76%, P < 0.001), and influenza vaccination in the last year (RR-1 = − 64.53%, P = 0.006) were all negatively correlated with COPD acute exacerbation (AE). COPD duration (RR-1 = 131.73%, P = 0.009), AE (RR-1 = 151.39%, P < 0.001), and COPD Assessment Test (CAT) scores (RR-1 = 3.82%, P = 0.019) were all positively correlated with COPD airflow limitation severity.Conclusion: Differences exist in the diagnosis, treatment and management of COPD among different tiers of hospitals in China. Teaching hospitals can manage COPD patients relatively well. There are still some gaps compared with developed countries.Keywords: stable chronic obstructive pulmonary disease, tiered medical system, airflow limitation, symptoms, acute exacerbation

Jingjing Liu,1– 3 Guoqing Fan,1– 3 Ningning Tao,4 Feifei Feng,5 Chao Meng,1– 3 Tieying Sun1,2 1Department of Respiratory Medicine and Critical Care, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 2Graduate School of Peking Union Medical College, Beijing, People’s Republic of China; 3The MOH Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Beijing, People’s Republic of China; 4Department of Respiratory & Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, People’s Republic of China; 5Department of Respiratory & Critical Care Medicine, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People’s Republic of ChinaCorrespondence: Tieying Sun, Department of Respiratory Medicine and Critical Care, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China, Tel +15153169108, Email suntieying@126.comPurpose: Idiopathic pulmonary fibrosis is a chronic and irreversible fibrotic interstitial pneumonia of unknown etiology and therapeutic strategies are limited. Emerging evidence suggests that the continuous activation of the central nucleotide-binding oligomerization-, leucine-rich repeat-, and pyrin domain-containing protein 3 (NLRP3) inflammasome is involved in the pathogenesis of pulmonary fibrosis. Ginsenoside Rb1 (G-Rb1) is the most abundant component in the traditional Chinese herb ginseng and has anti-inflammatory and anti-fibrotic activities. The purpose of this study was to explore whether G-Rb1 exerts anti-inflammatory and anti-fibrotic activities in vivo and in vitro by suppressing the activation of the NLRP3 inflammasome and NF-κB pathway.Methods: Forty-eight male C57BL/6 mice were randomly divided into four groups (n=12/group) as follows: control, bleomycin (BLM), BLM/G-Rb1, and G-Rb1. A pulmonary fibrosis model was developed via an intratracheal injection of BLM. Six mice from each group were euthanized on days 3 and 21. The degree of pulmonary fibrosis was examined by histological evaluation and assessing α-smooth muscle actin levels. THP-1 cells were differentiated into macrophages, and stimulated by lipopolysaccharide and adenosine triphosphate. Activation of the NLRP3 inflammasome and NF-κB pathway was determined by Western blotting. Interleukin-1 beta and interleukin-18 levels were measured by ELISA. MRC-5 cells were cultured in the conditioned medium of the treated macrophages, after which markers of myofibroblasts were determined by Western blotting.Results: G-Rb1 ameliorated BLM-induced pulmonary inflammation and fibrosis in mice, and suppressed NLRP3 inflammasome activation and the NF-κB pathway in lung tissues. Moreover, interleukin-1 beta secreted after NLRP3 inflammasome activation in macrophages promoted fibroblast differentiation. G-Rb1 inhibited lipopolysaccharide- and adenosine triphosphate-induced NLRP3 inflammasome activation in macrophages and disturbed the crosstalk between macrophages and fibroblasts.Conclusion: G-Rb1 ameliorates BLM-induced pulmonary inflammation and fibrosis by suppressing NLRP3 inflammasome activation and the NF-κB pathway. Hence, G-Rb1 is a potential novel therapeutic drug for idiopathic pulmonary fibrosis.Keywords: G-Rb1, pulmonary fibrosis, NLRP3 inflammasome, macrophages

In this paper, we described 2 cases with COVID-19 pneumonia, who developed pulmonary emphysema, bullae, and pneumothorax during therapy. In a 48-year-old man with mechanical ventilation, parts of ground glass opacities and consolidations transformed into emphysema and giant bulla, and bilateral pneumothorax were also observed. In a 35-year-old man, localized emphysema and pulmonary bullae were seen in subpleural area in bilateral upper lobes, where no previous lesions were presented. In conclusion, pulmonary emphysema, bullae, and pneumothorax could be complications of COVID-19. On one hand, surgical emphysema in ventilated COVID-19 patients was observed as in SARS patients. On the other hand, more serious destruction of lung parenchyma was found in COVID-19 patients.

BackgroundClinical practice guidelines or recommendations often require timely and regular updating as new evidence emerges, because this can alter the risk-benefit trade-off. The scientific process of developing and updating guidelines accompanied by adequate implementation can improve outcomes. To promote better management of patients receiving vancomycin therapy, we updated the guideline for the therapeutic drug monitoring (TDM) of vancomycin published in 2015.MethodsOur updated recommendations complied with standards for developing trustworthy guidelines, including timeliness and rigor of the updating process, as well as the use of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. We also followed the methodology handbook published by the National Institute for Health and Clinical Excellence and the Spanish National Health System.ResultsWe partially updated the 2015 guideline. Apart from adults, the updated guideline also focuses on pediatric patients and neonates requiring intravenous vancomycin therapy. The guideline recommendations involve a broadened range of patients requiring TDM, modified index of TDM (both 24-hour area under the curve and trough concentration), addition regarding the necessity and timing of repeated TDM, and initial dose for specific subpopulations. Overall, 1 recommendation was deleted and 3 recommendations were modified. Eleven new recommendations were added, and no recommendation was made for 2 clinical questions.ConclusionsWe updated an evidence-based guideline regarding the TDM of vancomycin using a rigorous and multidisciplinary approach. The updated guideline provides more comprehensive recommendations to inform rational and optimized vancomycin use and is thus of greater applicability.

Rationale It remains unknown whether long-term ozone exposure can impair lung function. Objectives To investigate the associations between long-term ozone exposure and adult lung function in China. Methods Lung function results and diagnosis of small airways dysfunction (SAD) were collected from a cross-sectional study, China Pulmonary Health Study (N=50,991). We used multivariate linear and logistic regression models to examine the associations of long-term ozone exposure with lung function parameters and SAD, respectively, adjusting for demographic characteristics, individual risk factors, and longitudinal trend. We then performed a stratification analysis by chronic obstructive pulmonary disease (COPD). Measurements and main results We observed each 1-standard deviation (SD, 4.9 ppb) increase in warm-season ozone concentrations was associated with a 14.2 mL/s [95% confidence interval (CI): 8.8, 19.6] decrease in forced expiratory flow at 75th percentile of vital capacity and a 29.5 mL/s (95% CI: 19.6, 39.5) decrease in mean forced expiratory flow between the 25th and 75th percentile of vital capacity. The odds ratio of SAD was 1.09 (95% CI: 1.06, 1.11) for a 1-SD increase in warm-season ozone concentrations. Meanwhile, we observed a significant association with a decreased ratio of expiratory volume in 1 second to forced vital capacity (FEV1/FVC) but not with FEV1 or FVC. The association estimates were greater in the COPD group than in the non-COPD group. Conclusion We found independent associations of long-term ozone exposure with impaired small airways function and higher SAD risks, while the associations with airflow obstruction were weak. COPD patients appear to be more vulnerable.

Mingming Pan, Hongsheng Zhang, Tieying SunDepartment of Respiratory and Critical Care Medicine, Beijing Hospital, National Center of Gerontology, Beijing, People’s Republic of ChinaPurpose: Sensitively assessing bronchial reversibility by spirometry is difficult in patients with serious airflow limitation and the elderly. Some patients cannot exhale for ≥6 s to achieve FVC testing criteria. The aim of this study was to assess if FEV3 could be a more sensitive and an acceptable surrogate for evaluating bronchial reversibility in such patients.Patients and methods: Subjects who had undergone pulmonary function examination in Beijing hospital from July 2003 to April 2015 were included in the study. Patients with FEV1

Lower respiratory tract infection due to Pseudomonas aeruginosa has become increasingly challenging, resulting in a worse morbidity and mortality. Airway remodeling is a common phenomenon in this process, to which epithelial-mesenchymal transition (EMT) may contribute as an important promoter. Previous studies showed that epithelium-specific integrin αvβ6-mediated EMT was involved in pulmonary fibrosis via transforming growth factor-β1 (TGF-β1) signaling, but whether integrin αvβ6 plays a role in the P. aeruginosa-associated airway remodeling remains unknown. BEAS-2B cells were incubated with lipopolysaccharide (LPS) from P. aeruginosa in the presence or the absence of integrin αvβ6-blocking antibodies. Morphologic changes were observed by an inverted microscopy. The EMT markers were detected using Western blotting and immunofluorescence. The activation of TGF-β1-Smad2/3 signaling pathway was assessed. Furthermore, matrix metalloproteinase (MMP)-2 and -9 in the medium were measured using ELISA. P. aeruginosa's LPS decreased the expression of the epithelial marker E-cadherin and promoted the mesenchymal markers, vimentin and α-smooth muscle actin in BEAS-2B cells. The expression of integrin αvβ6 was significantly increased during EMT process. Blocking integrin αvβ6 could attenuate P. aeruginosa's LPS-induced EMT markers' expression via TGF-β1-Smad2/3 signaling pathway. Furthermore, blocking integrin αvβ6 could prevent morphologic changes and oversecretion of MMP-2 and -9. Integrin αvβ6 mediates epithelial-mesenchymal transition in human bronchial epithelial cells induced by lipopolysaccharides of P. aeruginosa via TGF-β1-Smad2/3 signaling pathway and might be a promising therapeutic target for P. aeruginosa-associated airway remodeling.

With undetermined etiology and limited treatment option, idiopathic pulmonary fibrosis (IPF) an age related disease is extremely lethal. Persistent injury of epithelial cells, abnormal activation of fibroblasts/myofibroblasts, and superabundant deposition of extracellular matrix protein pathologically characterize IPF. Redox imbalance is reported to play a vital role in both IPF development and senescence. This study aim to investigate whether and how Liproxstatin-1 (Lip-1), a strong lipid autoxidation inhibitor, regulates bleomycin (BLM) induced pulmonary fibrosis both in vivo and in vitro. It’s demonstrated that Lip-1 exerted a potent anti-fibrotic function in BLM-induced mice pulmonary fibrosis via alleviating inflammatory, reshaping redox equilibrium, and ameliorating collagen deposition. Lip-1 reduced the level of reactive oxygen species (ROS) and methane dicarboxylic aldehyde (MDA), promoted the expression of glutathione (GSH), catalase (CAT), and total superoxide dismutase (T-SOD) after BLM treatment. Moreover, in vitro experiments verified that Lip-1 protected A549 cells from BLM-induced injury and fibrosis. Lip-1 seemed to attenuate BLM-induced fibrosis by targeting ROS/p53/α-SMA signaling both in vivo and in vitro. In summary, this study demonstrates that Lip-1 administration performs a protective role in against pulmonary fibrosis and lights up the potential of Lip-1 treatment for patient with IPF in future.

Background: Exacerbations are important events when managing chronic obstructive pulmonary disease (COPD) because they negatively impact disease progression. Inhaled corticosteroid (ICS) usage in patients with COPD is controversial. Therefore, we reviewed the benefits and risks of regular ICS treatment in patients with COPD regarding hospitalized acute exacerbation.Methods: This retrospective multicenter study—conducted in 18 medical centers across China—included 1,862 participants from 34 hospitals in northern China. Baseline characteristics, comorbidities, and administered medicines in the last year were matched using 1:1 propensity score-matching. We reviewed electronic patient medical records to ascertain symptoms, tests, in-hospital treatment, and prognosis. Subsequently, we reviewed computed tomography imaging results and pathogen identification tests.Results: Patients who used ICS in the past year presented more severe respiratory symptoms during acute exacerbations of COPD but less frequent right heart failure or consciousness disturbance. More antibiotics were used during hospitalization, resulting in higher costs; however, their prognosis was not different from patients who did not use ICS. Additionally, although ICS usage could increase gram-negative bacilli in sputum smears, it did not increase the probability of pulmonary infection.Conclusions: ICS use could protect patients from right heart failure, without detrimentally affecting prognosis during hospitalized exacerbations. Therefore, the risk of cardiovascular disease should be taken into consideration when making decisions regarding the potential administration of ICS in patients with COPD.

Summary 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 FEV1 and FEV1/forced vital capacity [FVC] ratio before bronchodilator inhalation), and post-small airway dysfunction (defined as having normal FEV1 and FEV1/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 (PM2·5) 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/m2. 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 PM2·5, and increase of BMI by 5 kg/m2 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 PM2·5 exposure and increase of BMI by 5 kg/m2. 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.

Unexplained chronic cough (UCC) affects millions of patients worldwide. New therapeutic approaches to this condition are urgently needed, since current treatment options provide only symptomatic relief. Cough reflex hypersensitivity has been shown to play an important role in the pathogenesis of UCC. The transient receptor potential vanilloid type 1 (TRPV1) is present on peripheral terminals of airway sensory nerves and modulation of its activity represents a potential target for the pharmacological treatment of UCC. The aim of this study was to explore the efficacy and the possible mechanism of SB705498, a TRPV1 antagonist, for cough in a capsaicin-induced cough animal model (i.e. guinea pigs). Induction of cough by capsaicin was successfully implemented in the guinea pigs, and the animals that met the inclusion criteria were randomly divided into four treatment groups: (1) Saline inhalation group (NSInh group, N = 10, negative control group), (2) Codeine phosphate intraperitoneal injection group (CPInp group, N = 10, positive control group), (3) SB705498 inhalation group (SBInh group, N = 10), (4) SB705498 intragastric administration group (SBIng group, N = 10). After treatment with above compounds, the capsaicin-induced cough experiment was performed again. The cough numbers and the cough incubation periods were recorded to evaluate the antitussive effect of SB705498. Enzyme-linked immunosorbent assay (ELISA) testing and Immunohistochemistry (IHC) staining for substance P (SP), calcitonin gene related peptide (CGRP) and neurokinin A (NKA) expression in lung and brain tissues were performed as an indication of neurogenic inflammation. Hematoxylin-Eosin (H&E) staining was used to observe the pathology morphology of lung and brain tissues. When the CPInp, SBInh and SBIng groups were compared to the NSInh group, the cough numbers were significantly reduced (p < .001), while the cough incubation periods were significantly prolonged (P < .001). In addition, the expression of SP, CGRP and NKA in lung and brain tissue was reduced (P < .05). None of the animals in the four groups exhibited lung and brain parenchymal inflammation. The results from this study showed that SB705498 had a significant antitussive effect, could reduce the neurogenic inflammation by reducing the expression of SP, CGRP and NKA in a capsaicin-induced cough model of guinea pigs. The results further indicated that TRPV1 played an important role in UCC and SB705498 might be a promising therapeutic agent for UCC.

Glucocorticoids play a key role in treatment of inflammatory lung diseases including both airway and parenchymal lung diseases. RNA viral infections are major causes of chronic lung disease exacerbations and can determine glucocorticoid resistance. The antibacterial peptide LL-37, the only member of human cathelicidin family, also functions as antiviral-activity enhancer. However, whether it can alleviate the glucocorticoid resistance caused by RNA viruses remains unclear. Here, we used type I (BEAS-2B) and type II (A549) lung epithelial cells to assess the effect of LL-37 on dsRNA-induced glucocorticoid resistance. We verified that LL-37 and polyinosinic-polycytidylic acid (poly I:C, a mimic of viral dsRNA) interact and enter both cell lines. Co-treatment with LL-37 and poly I:C increased glucocorticoid-induced expression of promyelocytic leukemia zinc finger (PLZF), an anti-inflammatory protein, compared to poly I:C alone. Pre-treatment with LL-37 also restored transactivation of the glucocorticoid response element (GRE). Moreover, LL-37 rescued poly I:C-induced glucocorticoid resistance by increasing phosphorylation and nuclear translocation of glucocorticoid receptor. Importantly, LL-37 downregulated poly I:C-induced Erk and Akt signaling pathways in lung epithelial cells. Finally, we verified our data in vivo, showing that mCRAMP, the mouse LL-37 ortholog, can alleviate poly I:C-induced glucocorticoid insensitivity in a murine asthma model. In summary, this study showed that LL-37 restored glucocorticoid sensitivity impaired by dsRNA possibly by inhibiting Akt pathway, in addition to Erk1/2 pathway. These findings suggest LL-37 as a therapeutic agent for treatment of viral infections in inflammatory pulmonary diseases.

Mycolyl-arabinogalactan-peptidoglycan (mAGP) is the major content of the mycobacterium cell wall structure and essential for mycobacterial survival. Peptidoglycan (PG) plays an important role in maintenance of cell division, cell wall integrity and pathogenesis. Mycobacterium smegmatis MSMEG_6281, a peptidoglycan amidase, is vital for mycobacterial cell division. However, the effects of MSMEG_6281on cell wall integrity and mycobacterial virulence remain unknown. In the current study, we demonstrate that MSMEG_6281gene knockout in M.smegmatis alters the microbiological characteristics. Our results revealed that MSMEG_6281gene knockout bacteria (M. sm-ΔM_6281) lost their acid-fastness, increased their sensitivity to lipophilic compounds and presented an abnormal morphology. Our results revealed that MSMEG_6281was related to maintaining the cell wall integrity. Furthermore, we investigated the effects of MSMEG_6281 inactivation on mycobacterial virulence using mice models infected by different M.smegmatis strains. MSMEG_6281 inactivation in the M sm-ΔM_6281 infected group caused less mycobacterial colonization, reduced pathological signs, decreased the anti-microbial enzymes production including iNOS and β-defensins in mouse lungs. Moreover, IL-1β and TLR2 expression were significantly down-regulated, while the production of IFN-γ and TNF-α was up-regulated. These findings indicated the diversity of host immune responses induced by different strains of M.smegmatis, suggesting that MSMEG_6281 inactivation impact mycobacterial virulence. In conclusion, the MSMEG_6281 protein plays important roles in maintaining cell wall integrity and mycobacterial virulence.

Background: Chronic obstructive pulmonary disease (COPD) is a major public health problem in China. Because of regional diversity in the geography and financial resources of various regions in China, data on the prevalence and risk factors of COPD in high altitude Chinese populations, including Tibetans, are limited. Methods: This prospective cross-sectional study of six urban and rural Tibetan regions in China was performed using stratified-cluster random sampling. A revised questionnaire was used to interview every participant, who all underwent chest radiography and pre- and post-bronchodilator pulmonary function testing. The diagnostic criteria used for COPD was based on the Global Initiative for Chronic Obstructive Lung Disease. Findings: The study was composed of a representative sample of 3,741 participants aged 15-83 years who had satisfactory spirograms. The overall prevalence of COPD was 4*9% (95% confidence interval [CI]: 4*2%-5*6%). The difference between men and women (4*9% [3*9%-5*9%] vs 5*0% [4*0%-5*9%]; P=0*922) was not significant, but a higher prevalence of COPD was found in participants aged =40 years (8*0% [6*7%-9*2%]) than in those aged 15-39 years (2*3% [1*6%-2*9%], P

Summary Background Ceftriaxone with or without a macrolide antibiotic is a recommended treatment for patients with community-acquired pneumonia requiring hospital admission and intravenous antibiotic treatment. We aimed to assess the efficacy and safety of ceftaroline fosamil compared with ceftriaxone in the treatment of Asian patients admitted to hospital with community-acquired pneumonia. Methods In this international, randomised, controlled, double-blind, phase 3, non-inferiority with nested superiority trial, adult Asian patients with Pneumonia Outcomes Research Team (PORT) risk class III–IV acute community-acquired pneumonia were randomly assigned (1:1) to receive intravenous ceftaroline fosamil (600 mg every 12 h) or ceftriaxone (2 g every 24 h) for 5–7 days. Patients were randomly assigned via centralised telephone and web-based system; patients and treating clinicians were masked to treatment allocation. Investigators who did study assessments remained masked to treatment allocation until completion of the study. The primary endpoint was clinical cure at the test-of-cure visit (8–15 days after last dose of study drug) in the clinically evaluable population. Non-inferiority of ceftaroline fosamil was defined as a lower limit of the two-sided 95% CI for the difference in the proportion of patients clinically cured of −10% or higher; if non-inferiority was achieved, superiority was to be concluded if the lower limit of the 95% CI was greater than 0%. This trial is registered with ClinicalTrials.gov, number NCT01371838. Findings Between Dec 13, 2011, and April 26, 2013, 847 patients were enrolled at 64 centres in China, India, South Korea, Taiwan, and Vietnam, of whom 771 were randomly assigned and 764 received study treatment. In the clinically evaluable population (n=498) 217 (84%) of 258 patients in the ceftaroline fosamil group and 178 (74%) of 240 patients in the ceftriaxone group were clinically cured at the test-of-cure visit (difference 9·9%, 95% CI 2·8–17·1). The superiority of ceftaroline fosamil was consistent across all preplanned patient subgroup analyses (split by age 65 years, age 75 years, sex, PORT risk class, and previous antibiotic use) apart from patients younger than 65 years. The frequency of adverse events was similar between treatment groups and the safety results for ceftaroline fosamil were consistent with the cephalosporin class and previous clinical trial data. Interpretation Ceftaroline fosamil 600 mg given every 12 h was superior to ceftriaxone 2 g given every 24 h for the treatment of Asian patients with PORT III–IV community-acquired pneumonia. These data suggest that ceftaroline fosamil should be regarded as an alternative to ceftriaxone in empirical treatment regimens for this patient population. Funding AstraZeneca.

Background Small airways dysfunction (SAD) is common but neglected respiratory abnormality. However, little is known about its prevalence, risk factors, and prognosis in the general population of China. Methods The nationally representative China Pulmonary Health study included more than 50 000 adults during 2012–15 using multistage stratified cluster sampling method, with valid spirometry measurements. Ten Chinese provinces, autonomous regions, and municipalities in mainland China were selected from six geographical regions, and all assessments were done in community health centres. SAD was defined as two of the three measures (ie, maximal mid-expiratory flow, forced expiratory flow 50%, and forced expiratory flow 75%) having below 65% of the predicted pre-bronchodilator values. Early-stage SAD was defined as SAD with normal forced expiratory volume in 1 sec (FEV1), forced vital capacity (FVC), peak expiratory flow, and FEV1/FVC, whereas pre-SAD was defined as early-stage SAD before bronchodilator inhalation, and pre-SAD plus post-SAD as early-stage SAD before and after bronchodilator inhalation. Logistic regression yielded adjusted odds ratios (aORs) for SAD associated with lifestyle and environmental factors. We estimated the total number of SAD in China using data from the present study and national census. Findings Overall the prevalence of SAD, pre-SAD, and pre-SAD plus post-SAD was 43·5%, 21·4%, and 10·8%, respectively. The risk of SAD, especially pre-SAD plus post-SAD, was significantly associated with several factors, including cigarette smoking (aOR 1·16, 95% CI 1·04–1·28), exposure to particulate matter 2·5 (1·27 [1·12–1·44] at 50–74 μg/m3, and 1·48 [1·30–1·69] at ≥75 μg/m3), adiposity (1·37 [1·26–1·48] per 5 kg/m2 higher body-mass index) and parental history of respiratory diseases (1·11, 1·02–1·21). In 2015, an estimated 426 million (95% CI 411–467), 211 million (191–242), and 104 million (94–126) adults had SAD, pre-SAD, and pre-SAD plus post-SAD, respectively, in China. Interpretation In China, spirometry-defined SAD is highly prevalent, with cigarette smoking, air pollution, and adiposity being major modifiable risk factors. Our findings highlight the need for early screening of SAD to reduce the health burden associated with chronic lung diseases in general populations. Funding National Natural Science Foundation of China, National Key R&D Program of China, and the Special Research Foundation for Public Welfare of Health, Ministry of Health of China.

Epigallocatechin gallate (EGCG) is the main component of green tea extracts that inhibits the growth of Mycobacterial smegmatis mc(2)155, and the mechanism is not clear. This study showed the effects of EGCG on the growth of mc(2)155. The content and the structure of EGCG in LB medium with mc(2)155 were identified by HPLC and LC/MS. Transmission electron microscopy was utilised to identify the cell envelope structure. As a result, the optional inhibition concentration was determined to be 20 μg mL(-1). Most of EGCG was transferred into its isomeride in LB medium, but the inhibition effects against mc(2)155 had yet been maintained. The changes of cell envelope structure were showed after EGCG treatment for 18 h. The cell wall appeared to have a less electron-translucent zone, turn rougher and thicker. The results show that EGCG impacts the integrity of mycobacterial cell wall and is likely be a better prophylactic agent against tuberculosis.

Background: The only human cathelicidin, LL-37, and the innate defense regulator peptide IDR-1, which have been proven to have antimicrobial activity, represent essential elements of immunity. Our previous study showed that the peptide LL-37 was protective in vitro to attenuate LTA-induced inflammatory effects. Methicillin-resistant staphylococcus aureus (MRSA) causes a multitude of serious and sometimes life-threatening diseases around the globe. However, the effect of LL-37 and IDR-1 in MRSA-induced pneumonia is unknown. In the present study, we explored the potential of LL-37 and IDR-1 in ameliorating MRSA-induced pneumonia in vivo. Methods: C57BL/6 mice were randomly divided into four groups and perfused intratracheally with PBS, peptide, MRSA and MRSA plus peptide, respectively. Pulmonary tissue pathology, ELISA and quantitative RT-PCR were employed. The relative signal pathways were further explored by western blot analysis. Results: Pathological analysis of the lung tissue sections demonstrated that, when compared with the MRSA-treated group, both the LL-37 and IDR-1 could ameliorate the MRSA-induced pneumonia. The phosphorylation of JNK and Akt were markedly decreased in the peptide plus MRSA-treated group compared with the MRSA-treated group. Furthermore, both of them also reduced TNF-α and IL-6 production in the bronchoalveolar lavage fluid (BALF) and serum in vivo. Conclusion: We report the first evidence of peptides inhibiting inflammation, decreasing the release of inflammatory cytokines and restoring pulmonary function in vivo. The antimicrobial peptide LL-37 and IDR-1 could ameliorate MRSA-induced pneumonia by exerting an anti-inflammatory property and attenuating pro-inflammatory cytokine release, thus providing support for the hypothesis that both innate and synthetic peptides could protect against MRSA in vivo.

To summarize the clinical characteristics of IgG4 related disease.A retrospective analysis of clinical manifestation, radiography and pathological information of patients diagnosed with IgG4 related disease in Beijing Hospital.Patients recruited in this study were 7 males and 7 females at the average age of (64.3±10.0) years old. Equal or greater than two organs were suffered in 10 patients. In these involved organs, pancreas was the most suffered organ with 10 times, bile duct and salivary gland was suffered 5 times respectively, lung was suffered 4 times and lacrimal gland was suffered 2 times. Laboratory examination of these 14 cases showed that 5 of these cases were with increased level of plasma IgG and all of the cases were with increased level of IgG4, 7 patients were with increased level of eosinophil count and 9 patients in 12 cases were with the increased level of IgE. All of the diagnosed patients were eusemia and 13 of them received the treatment of glucocorticoid. After usage of glucocorticoid, the clinical symptom and radiography findings were at great improvement, and the levels of IgG4 were decreased, but only two cases were down to normal level.IgG4 related disease is a kind of disease with various manifestation and multiple organs are commonly suffered. The increase of IgG, IgE levels and eosinophil count could be considered as diagnosis clues.

Sirtuin1 (SIRT1) is an NAD+‑dependent deacetylase that exhibits multiple biological functions, including cell differentiation inhibition, transcription regulation, cell cycle regulation and anti‑apoptosis. Lipopolysaccharides (LPS) are crucial virulence factors produced by Pseudomonas aeruginosa and serve an important role in adjusting the interactions between the host and the pathogen. However, the effect of SIRT1 in the regulation of LPS‑induced A459 human alveolar epithelial cells (AECs) oxidative stress remains unclear. The cellular reactive oxygen species (ROS) production was examined in A549 cells that were supplemented with LPS. Relative cell signaling pathway proteins were further investigated by western blot analysis. It was identified that LPS downregulated SIRT1 expression, however, upregulated ROS generation, which was associated with the increase of nuclear factor (NF)‑κB and acetyl‑NF‑κB. Activation of SIRT1 by resveratrol significantly reversed the effects of LPS on A549 cells. By contrast, inhibition of SIRT1 by nicotinamide had the opposite effects that enhance cell ROS production. Thus, the results indicated that SIRT1 serves an important role in the regulation of oxidative stress induced by LPS in human AECs.

Cancer-associated fibroblasts (CAFs) contribute to tumor progression through multiple pathways. However, the effect of CAFs on gene expression in lung cancer has been largely unknown. Here we systematically compared the gene expression changes in lung cancer cells induced by normal fibroblasts and CAFs.Wound healing and cell proliferation assays were used to identify the property of CAFs used in this study. We used cDNA microarray analysis to compare gene expression in lung cancer cells cultured with either conditioned medium (CM) from lung CAFs or normal lung fibroblasts, the result of which was confirmed by RT-PCR and Western blot analysis. Immunohistochemistry on tissue sections from lung cancers was conducted to further confirm the results of cDNA microarray analysis.The expression of many genes was upregulated in cancer cells by CAF CM, particularly cell adhesion molecules, integrins, and anti-apoptotic protein Bcl-2. Expression of integrins appeared to be upstream from Bcl-2. We identified transforming growth factor-β as a candidate factor that induced the expression of those genes in cancer cells. Immunohistochemical studies of clinical lung cancer tissues revealed that integrins and Bcl-2 were more highly expressed in the leading cells (LCs) than in the following cells, at the invasive front of cancer nests, which are adjacent to or in proximity to the stroma. Furthermore, the expression of integrins and Bcl-2 in LCs had a tendency to correlate with the clinical stage of cancer progression, including lymph node metastasis.Our results suggest that CAFs promote lung cancer progression partly through the direct regulation of gene expression in the LCs of invasive cancer nests.

We use the molecular dynamics to study the migration of He atom, dimer and trimer in Ti. The migration features of these three He species are shown in this paper. It is observed that the Arrhenius relation can well describe their diffusion. However, the diffusion is significant anisotropic. This anisotropy is represented by that the prefactor of the diffusion coefficients are quite different for these He species diffusing in different directions, but the activation energies are the same. Another counterintuitive observation is that He-dimer migrate more quickly than single He atom does. The results emphasize the importance of dynamics simulations in predicting diffusion behavior of He in metals.

To retrospectively explore the clinical features and risk factors of nosocomially acquired candidemia.Retrospective analyses were conducted for general information, underlying diseases, risk factors, clinical features and laboratory tests of blood culture Candida-positive cases at Beijing Hospital from January 1, 2006 to December 31, 2011. Comparisons were made with regards to the clinical features, prognostic factors, risk factors of candidemia pathogen distribution between dead and survival groups and Candida albicans vs non-Candida albicans groups. Statistical analysis was performed with SPSS 19.0.A total of 30 Candida albicans and 35 non-candida albicans cases were recruited. Their mean age was (76±14) years and total in-hospital fatality rate 58.5% (38/65). The acute physiology and chronic health evaluation II (APACHE II) score, ratio of APACHE II score24 points, ratio of shock, primary diagnosis time (from onset to reporting time of positive outcome of blood culture) and ratio of serum albumin≤30 g/L of death group were (28.7±8.6) score, 55.3% (21/38), 71.1% (27/38), (138.7±50.4) h, 47.4% (18/38) respectively. And the values were significantly higher than those of survival group, i.e. (20.1±8.0) score, 29.6% (8/27), 44.4% (12/27), (127.2±50.2) h and 22.2% (6/27) respectively. Multivariate Logistic regression analysis showed that shock (OR=4.821, P=0.030), primary diagnosis time (OR=1.594, P=0.027) and APACHE II score (OR=1.096, P=0.032) were independent risk factors for death. However continuous blood purification therapy was an independent protective factor (OR=0.014, P=0.004). And diabetes was an independent risk factors for non-Candida albicans infection (OR=4.426, P=0.016).Advanced age, more underlying diseases, severe clinical conditions and high fatality rate are the major clinical characteristics of candidemia. Shock, APACHE II score and primary diagnosis time are independent risk factors for death. Continuous blood purification therapy is a protective factor. And diabetes is an independent risk factor for non-Candida albicans candidemia.

To explore the relationship between desmosine plasma levels and exacerbation risk in patients with chronic obstructive pulmonary disease (COPD).COPD patients and normal subjects were recruited from Beijing Hospital during March 2013 to March 2014. COPD patients were divided into COPD low risk and COPD high risk groups according to the criteria of Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy. The plasma concentrations of desmosine were measured by enzyme-linked immunosorbent assay (ELISA) for exploring the inter-group difference in desmosine levels.Sixty-three COPD patients (COPD low risk group, n = 30; COPD high risk group, n = 33) and 50 normal subjects (24 healthy non-smokers, 26 healthy smokers) were recruited. The plasma desmosine concentrations in healthy non-smokers, healthy smokers, low risk and high risk COPD patients were (200 ± 159), (191 ± 105), (197 ± 118) and (131 ± 47) ng/L respectively. The plasma concentration of desmosine was significantly lower in COPD high risk group than healthy non-smokers (mean difference -70, 95%CI: -128--11, P = 0.021), healthy smokers (mean difference -60, 95%CI: -118--3, P = 0.039) and COPD low risk group (mean difference -67, 95%CI: -122--12, P = 0.018). The plasma concentration of desmosine was negatively correlated with exacerbation frequency (r = -0.409, P = 0.002), mMRC scores (r = -0.447, P = 0.010) and emphysema severity (r = -0.386, P = 0.047) in COPD patients. No significant correlation existed between desmosine plasma levels and forced expiratory volume in one second (FEV1%pred) in COPD patients (r = 0.225, P = 0.084).The plasma levels of desmosine are lower in high risk COPD patients than those in normal subjects or low risk COPD patients. And it is negatively correlated with exacerbation frequency in COPD patients.

Epigallocatechin gallate (EGCG) is the main component of green tea extracts that inhibits the growth of Mycobacterial smegmatis mc2155, and the mechanism is not clear. This study showed the effects of EGCG on the growth of mc2155. The content and the structure of EGCG in LB medium with mc2155 were identified by HPLC and LC/MS. Transmission electron microscopy was utilised to identify the cell envelope structure. As a result, the optional inhibition concentration was determined to be 20 μg mL− 1. Most of EGCG was transferred into its isomeride in LB medium, but the inhibition effects against mc2155 had yet been maintained. The changes of cell envelope structure were showed after EGCG treatment for 18 h. The cell wall appeared to have a less electron-translucent zone, turn rougher and thicker. The results show that EGCG impacts the integrity of mycobacterial cell wall and is likely be a better prophylactic agent against tuberculosis.