Pirfenidone and nintedanib exert additive antifibrotic effects by the SPP1-AKT pathway in macrophages and fibroblasts.

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive disease with high mortality rates. It has been shown that pirfenidone (PFD) and nintedanib (Ofev) can slow down the decline in lung function of IPF patients, but their efficacy remains suboptimal. Some studies have suggested that the combination of PFD and Ofev may yield promising results. However, there is a lack of research on the combined application of these two medications in the treatment of IPF. A mouse model of bleomycin-induced (BLM) pulmonary fibrosis was established to investigate the impact of combination therapy on pulmonary fibrosis of mice. The findings demonstrated a significant reduction in lung tissue damage in mice treated with the combination therapy. Subsequent transcriptome analysis identified the differential gene secreted phosphoprotein 1 (SPP1), which was found to be associated with macrophages and fibroblasts based on multiple immunofluorescence staining results. Analysis of a phosphorylated protein microarray indicated that SPP1 plays a regulatory role in macrophages and fibroblasts via the AKT pathway. Consequently, the regulation of macrophages and fibroblasts in pulmonary fibrosis by the combination of PFD and Ofev is mediated by SPP1 through the AKT pathway, potentially offering a novel therapeutic option for IPF patients. Further investigation into the targeting of SPP1 for the treatment of pulmonary fibrosis is warranted.

Combined effect of ozone and household air pollution on COPD in people aged less than 50 years old.

OBJECTIVES: Air pollution has been suggested as an important risk factor for chronic obstructive pulmonary disease (COPD); however, evidence of interactive effects on COPD between different factors was sparse, especially for young adults. We aimed to assess the combined effects of ambient ozone (O3) and household air pollution on COPD in young individuals. METHODS: We conducted a population-based study of residents aged 15-50 years in the low-income and middle-income regions of western China. We used multivariable logistic regression models to examine the associations between long-term ozone exposure and COPD in young individuals. RESULTS: A total of 6537 young cases were identified among the participants, with a COPD prevalence rate of 7.8 (95% CI 7.2% to 8.5%), and most young COPD individuals were asymptomatic. Exposure to household air pollution was associated with COPD in young patients after adjustment for other confounding factors (OR 1.82, 95% CI 1.41 to 2.37). We also found positive associations of COPD with O3 per IQR increase of 20 ppb (OR 1.92, 95% CI 1.59 to 2.32). The individual effects of household air pollution and O3 were 1.68 (95% CI 1.18 to 2.46) and 1.55 (95% CI 0.99 to 2.43), respectively, while their joint effect was 3.28 (95% CI 2.35 to 4.69) with the relative excess risk due to interaction of 1.05 (95% CI 0.33 to 1.78). CONCLUSIONS: This study concludes that exposure to ambient O3 and household air pollution might be important risk factors for COPD among young adults, and simultaneous exposure to high levels of the two pollutants may intensify their individual effects.

Airflow obstruction and small airway dysfunction following pulmonary tuberculosis: a cross-sectional survey.

OBJECTIVES: Pulmonary function impairment and chronic respiratory symptoms after tuberculosis are relatively common in low-income and middle-income countries. We aimed to estimate the impact of post-tuberculosis (post-TB) on pulmonary function. METHODS: This large cross-sectional, population-based study included subjects aged 15 years or older with technically acceptable postbronchodilator spirometry measurements. Post-TB was diagnosed on the basis of radiological evidence and/or medical history. Airflow obstruction was defined as a postbronchodilator forced expiratory volume in 1 s/forced vital capacity ratio below the lower limit of normal of Global Lung Function Initiative (GLI) lung function equations. Small airway dysfunction was diagnosed if at least two of the following indicators were less than 65% of predicted: maximal mid-expiratory flow, forced expiratory flow (FEF) 50% or FEF 75%. RESULTS: In this population sample (N=8680, mean age: 40.1 years), 610 (7.0% (95% CI 6.5 to 7.6) participants were post-TB. Post-TB subjects had more frequent respiratory symptoms (46.8% vs 28.3%). Among post-TB subjects, 130 (21.3% (95% CI 18.1 to 24.8)) had airflow obstruction; OR of airflow obstruction was significantly associated with post-TB after adjustment for other confounding factors (OR 1.31, 95% CI 1.05 to 1.62). Post-TB was also associated with small airway dysfunction (OR 1.28, 95% CI1.07 to 1.53), which was present in 297 (48.9% (95% CI 33.9 to 53.0)) post-TB subjects. CONCLUSIONS: Our findings support existing knowledge that post-TB is positively associated with pulmonary function impairment and make for frequent respiratory symptoms. Post-TB should be considered as a potentially important cause of airflow obstruction and respiratory symptoms in patients originating from countries with a high burden of tuberculosis.

Long-Term Ozone Exposure and Small Airway Dysfunction: The China Pulmonary Health (CPH) Study.

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 airway dysfunction (SAD) were collected from a cross-sectional study, the China Pulmonary Health Study (N = 50,991). We used multivariable 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 trends. We then performed a stratification analysis by chronic obstructive pulmonary disease (COPD). Measurements and Main Results: We observed that each 1 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 ml/s] decrease in forced expiratory flow at the 75th percentile of vital capacity and a 29.5 ml/s (95% CI, 19.6-39.5 ml/s) 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 decreased FEV1/FVC but not with FEV1 or FVC. The association estimates were greater in the COPD group than in the non-COPD group. Conclusions: We found independent associations of long-term ozone exposure with impaired small airway function and higher SAD risks, while the associations with airflow obstruction were weak. Patients with COPD appear to be more vulnerable.

Associations of residential greenness with lung function and chronic obstructive pulmonary disease in China.

BACKGROUND: Studies on the association of greenness with respiratory health are scarce in developing countries, and previous studies in China have focused on only one or two indicators of lung function. OBJECTIVE: The study aims to evaluate the associations of residential greenness with full-spectrum lung function indicators and prevalence of chronic obstructive pulmonary disease (COPD). METHODS: This nationwide cross-sectional survey included 50,991 participants from the China Pulmonary Health study. Lung function indicators included four categories: indicators of obstructive ventilatory dysfunction (FEV1, FVC and FEV1/FVC); an indicator of large-airway dysfunction (PEF); indicators of small-airway dysfunction (FEF25-75% and FEV3/FEV6); and other indicators. Residential greenness was assessed by the Normalized Difference Vegetation Index (NDVI). Multivariable linear regression models and logistic regression models were used to analyze associations of greenness with lung function and COPD prevalence. RESULTS: Within the 500 m buffer, an interquartile range (IQR) increase in NDVI was associated with higher FEV1 (24.76 mL), FVC (16.52 mL), FEV1/FVC (0.38), FEF50% (56.34 mL/s), FEF75% (33.43 mL/s), FEF25-75% (60.73 mL/s), FEV3 (18.59 mL), and FEV6 (21.85 mL). However, NDVI was associated with lower PEF. In addition, NDVI was significantly associated with 10% lower odds of COPD. The stratified analyses found that the associations were only significant in middle-young people, females, and nonsmokers. The associations were influenced by geographic regions. CONCLUSIONS: Residential greenness was associated with better lung function and lower odds of COPD in China. These findings provide a scientific basis for healthy community planning.

Development and Validation of a Screening Questionnaire of COPD from a Large Epidemiological Study in China.

OBJECTIVE: We aimed to establish an easy-to-use screening questionnaire with risk factors and suspected symptoms of COPD for primary health care settings. METHODS: Based on a nationwide epidemiological study of pulmonary health among adults in mainland China (China Pulmonary Health, CPH study) between 2012 and 2015, participants ≥40 years who completed the questionnaire and spirometry tests were recruited and randomly divided into development set and validation set by the ratio of 2:1. Parameters including sex, age, BMI, residence, education, smoking status, smoking pack-years, biomass exposure, parental history of respiratory diseases and daily respiratory symptoms were initially selected for the development of scoring system. Receiver operating characteristic (ROC) curve, area under curve (AUC), positive and negative predictive values were calculated in development set and validation set. RESULTS: After random split by 2:1 ratio, 22443 individuals were assigned to development set and 11221 to validation set. Ten variables were significantly associated with COPD independently in development set after a stepwise selection by multivariable logistic model and used to develop scoring system. The scoring system yielded good discrimination, as measured by AUC of 0.7737, and in the validation set, the AUC was 0.7711. When applying a cutoff point of ≥16, the sensitivity in development set was 0.69 (0.67 - 0.71); specificity 0.72 (0.71 - 0.73), PPV 0.25 (0.24 - 0.26) and NPV 0.94 (0.94 - 0.95). CONCLUSION: We developed and validated a comprehensive screening questionnaire, COPD-CPHS, with good discrimination. The score system still needs to be validated by large cohort in the future.Supplemental data for this article is available online at https://doi.org/10.1080/15412555.2022.2042504 .

Liproxstatin-1 alleviates bleomycin-induced alveolar epithelial cells injury and mice pulmonary fibrosis via attenuating inflammation, reshaping redox equilibrium, and suppressing ROS/p53/α-SMA pathway.

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.

Evidence-based Guideline for Therapeutic Drug Monitoring of Vancomycin: 2020 Update by the Division of Therapeutic Drug Monitoring, Chinese Pharmacological Society.

BACKGROUND: Clinical 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. METHODS: Our 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. RESULTS: We 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. CONCLUSIONS: We 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.

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

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.

Prevalence and risk factors of chronic obstructive pulmonary disease in China (the China Pulmonary Health [CPH] study): a national cross-sectional study.

BACKGROUND: Although exposure to cigarette smoking and air pollution is common, the current prevalence of chronic obstructive pulmonary disease (COPD) is unknown in the Chinese adult population. We conducted the China Pulmonary Health (CPH) study to assess the prevalence and risk factors of COPD in China. METHODS: The CPH study is a cross-sectional study in a nationally representative sample of adults aged 20 years or older from ten provinces, autonomous regions, and municipalities in mainland China. All participants underwent a post-bronchodilator pulmonary function test. COPD was diagnosed according to 2017 Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria. FINDINGS: Between June, 2012, and May, 2015, 57 779 individuals were invited to participate, of whom 50 991 (21 446 men and 29 545 women) had reliable post-bronchodilator results and were included in the final analysis. The overall prevalence of spirometry-defined COPD was 8·6% (95% CI 7·5-9·9), accounting for 99·9 (95% CI 76·3-135·7) million people with COPD in China. Prevalence was higher in men (11·9%, 95% CI 10·2-13·8) than in women (5·4%, 4·6-6·2; p<0·0001 for sex difference) and in people aged 40 years or older (13·7%, 12·1-15·5) than in those aged 20-39 years (2·1%, 1·4-3·2; p<0·0001 for age difference). Only 12·0% (95% CI 8·1-17·4) of people with COPD reported a previous pulmonary function test. Risk factors for COPD included smoking exposure of 20 pack-years or more (odds ratio [OR] 1·95, 95% CI 1·53-2·47), exposure to annual mean particulate matter with a diameter less than 2·5 µm of 50-74 µg/m3 (1·85, 1·23-2·77) or 75 µg/m3 or higher (2·00, 1·36-2·92), underweight (body-mass index <18·5 kg/m2; 1·43, 1·03-1·97), sometimes childhood chronic cough (1·48, 1·14-1·93) or frequent cough (2·57, 2·01-3·29), and parental history of respiratory diseases (1·40, 1·23-1·60). A lower risk of COPD was associated with middle or high school education (OR 0·76, 95% CI 0·64-0·90) and college or higher education (0·47, 0·33-0·66). INTERPRETATION: Spirometry-defined COPD is highly prevalent in the Chinese adult population. Cigarette smoking, ambient air pollution, underweight, childhood chronic cough, parental history of respiratory diseases, and low education are major risk factors for COPD. Prevention and early detection of COPD using spirometry should be a public health priority in China to reduce COPD-related morbidity and mortality. FUNDING: Ministry of Health and Ministry of Science and Technology of China.

Lack of MSMEG_6281, a peptidoglycan amidase, affects cell wall integrity and virulence of Mycobacterium smegmatis.

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 ß-defensins in mouse lungs. Moreover, IL-1ß 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.

The research of the possible mechanism and the treatment for capsaicin-induced cough.

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.

[A preliminary study of the distribution and the characteristics of nonspecific pulmonary function].

OBJECTIVE: To investigate the manifestations, pulmonary function test (PFT) characteristics and imaging features of patients with nonspecific pulmonary function (NSPF). METHODS: All the data from the same PFT apparatus in Beijing Hospital were collected from January 2003 to December 2012. NSPF was defined as normal FEV1/FVC and TLC, but decreased FEV1 or FVC or both. Patients with complete clinical data from January 2012 to June 2012 were enrolled into this analysis. The NSPF group was compared with the normal group, the obstructive group, the restrictive group and the mixed group. RESULTS: There were totally 14 771 cases of PFT on this apparatus during 10 year period, and those with NSPF were 2759 (18.68%). From January 2012 to June 2012, 341 patients were enrolled into this study with a sex ratio of 1.37:1, and an average age of 66±12 years. Compared with the normal group, the NSPF group had a significantly higher rate of small airway abnormalities and elevated RV/TLC. Multiple logistic regression analysis showed that statistical differences were found in TLC%pred (OR=0.668, P<0.01, 95%CI 0.563-0.791), FEF25-75%pred (OR=0.963, P<0.01, 95%CI 0.939-0.988), RV%pred (OR=1.144, P<0.01, 95%CI 1.075-1.217), and RV/TLC (OR=1.31, P<0.01, 95%CI 1.15-1.492). Compared with the obstructive group, the NSPF group had a significantly lower rate of small airway abnormalities. Multiple logistic regression analysis showed that female gender(OR=15.283, P<0.001, 95%CI 3.526-66.248), TLC%pred (OR=0.961, P=0.02, 95%CI 0.928-0.994), and FEF50%%pred (OR=1.189, P<0.001, 95%CI 1.103-1.281) were significantly different between the 2 groups. Respiratory symptoms were more common in the NSPF group. Airway diseases were diagnosed in more cases of the NSPF group when compared to the normal group, but in fewer cases when compared to the obstructive group. Clinical manifestations and imaging features of the NSPF cases were not specific. CONCLUSIONS: NSPF is a common clinical condition which mainly affects the small airway function with some degree of restrictive dysfunction. NSPF has limited predictive value for diagnosis because the manifestations and imaging features are not specific.

Angiotensin-Converting Enzyme 2 Attenuates Bleomycin-Induced Lung Fibrosis in Mice.

BACKGROUND: Local renin-angiotensin system (RAS) activation has been shown to play an important role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). It has been reported that angiotensin-converting enzyme 2 (ACE2) could inhibit RAS-mediated epithelial injury and fibrogenesis and that ACE2 deficiency could aggravate acute and chronic lung injury. Through research, it could be deduced that ACE2 could protect against pulmonary fibrosis as a therapeutic target. METHODS: Time-course analysis of the pathological characteristics of bleomycin-induced lung fibrosis was undertaken in a mouse model, and the effect of exogenous ACE2 on lung fibrosis was studied. Immunohistchemistry (IHC) staining and western blot (WB) testing for AGT and ACE2 were performed to evaluate the regulation of local RAS. TUNEL staining was used to observe epithelial apoptosis. Leukocyte common antigen (LCA) and pulmonary surfactant-associated protein A (SP-A) IHC staining and WB testing were performed to assess the inflammatory response and epithelial regeneration. Masson's staining and a hydroxyproline assay were performed to examine collagen deposition. IHC staining and WB testing for TGF-ß1 and α-SMA were performed to investigate the regulation of pro-fibrotic cytokines and the activation of fibroblasts. RESULTS: Exogenous ACE2 attenuated bleomycin-induced lung fibrosis by reversing the reduction of local ACE2 and by suppressing the elevation of AGT. ACE2 decreased the apoptosis index and LCA levels and ameliorated the dynamic change in SP-A level, thus protecting against epithelial injury. Reductions of TGF-ß1 and α-SMA were also found in ACE2-treated mice, indicating the inhibition of fibrogenesis. CONCLUSION: ACE2 attenuated bleomycin-induced lung fibrosis as an anti-inflammatory anti-apoptotic and anti-fibrotic agent, and it might be a promising therapeutic target for IPF.

[Desmosine plasma levels and exacerbation risk assessment of chronic obstructive pulmonary disease].

OBJECTIVE: To explore the relationship between desmosine plasma levels and exacerbation risk in patients with chronic obstructive pulmonary disease (COPD). METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

[Clinical characteristics and influencing factors of nosocomial candidemia].

OBJECTIVE: To retrospectively explore the clinical features and risk factors of nosocomially acquired candidemia. METHODS: 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. RESULTS: 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 score>24 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). CONCLUSIONS: 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.

[Analysis of clinical feature of IgG4 related disease].

OBJECTIVE: To summarize the clinical characteristics of IgG4 related disease. METHODS: A retrospective analysis of clinical manifestation, radiography and pathological information of patients diagnosed with IgG4 related disease in Beijing Hospital. RESULTS: 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. CONCLUSIONS: 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.

[Clinical characteristic and outcomes of lung cancer patients with venous thromboembolism].

OBJECTIVE: To explore the clinical characteristics and outcomes of lung cancer patients with venous thromboembolism (VTE). METHODS: The clinical data of 80 lung cancer patients with VTE hospitalized from January 2003 to April 2013 at our hospital were reviewed. The clinical factors of age, gender, clinical manifestations, pathological type, clinical stage, performance status and therapeutic regimen were recorded and analyzed. And the pulmonary thromboembolism (PTE) patients with deep venous thrombosis (DVT) were enrolled into PTE group. The occurrences, clinical manifestations and prognosis of VTE were evaluated. RESULTS: A total of 80 patients were enrolled. There were 40 males and 40 females with a mean age of (65.8 ± 11.3) years. Adenocarcimoma was identified in 58 (72.5%) patients and advanced lung cancer in 71 (88.8%) patients. Among 37 (46.3%) patients with histodifferentiation results, 89.2% (33/37) of them were moderately and/or poorly differentiated. In 32 (40.0%) patients on chemotherapy, 71.9% (23/32) of them received a platinum-based regimen. There were 35 (43.8%) pulmonary thromboembolism embolism (PTE) and 45 (56.2%) DVT patients. Among PTE patents, 14 (40.0%) were identified incidentally. Dyspnea and swollen of limb were the most common symptoms. Only 20.0% (16/80) patients received VTE prophylaxis. After a definite diagnosis of cancer, 73.8%, 77.5%, 82.5% and 85.0% of patients experienced an event within 3, 6, 9 and 12 months respectively. Up to April 2014, among 53 deceased patients, 77.4% (41/53) died from lung cancer, 9.3% (5/53) PTE while 13.2% (7/53) due to other causes. The cumulative mortality rates within 3, 6, 9 and 12 months after VTE event were 49.1%, 67.9%, 77.4% and 79.2% respectively. CONCLUSIONS: Adenocarcimoma, advanced lung cancer, poor histodifferentiation and platinum-based chemotherapy regimen are the risk factors of VTE in lung cancer patients. Most events of VTE occur within 3-6 months after a diagnosis of lung cancer while most mortality cases within 1 year after VTE events.

[A retrospective clinicopathological study of aspiration pneumonia in the elderly].

OBJECTIVE: To explore the clinicopathological characteristics of aspiration pneumonia in the elderly. METHODS: The clinical data of 30 cases of autopsy-proven aspiration pneumonia in Beijing Hospital from 1973 to 2002 were reviewed. The patients consisted of 28 males and 2 females, aged from 63 to 103 [mean (83 ± 9)] years. RESULTS: Only 15 cases were clinically diagnosed as aspiration pneumonia before death. Concomitant diseases were severe and complex, mostly coronary disease, cerebrovascular disease, hypertension, COPD, and diabetes mellitus. All the patients suffered from at least 3 concomitant diseases. Long-term bedridden and nasogastric feeding was seen in 11 and 17 patients respectively. The clinical presentation and chest X-ray of aspiration pneumonia in the elderly were nonspecific and variable. Mixed infections were common . The main bacteria isolated were Gram-negative bacilli, in particular Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Escherichia coli and Candida albicans. By pathology, macrophages with foreign bodies were found in all the 30 cases and multiple small abscesses were found in 14 cases. The lesions were adjacent to the bronchioles and in the lung tissue around the bronchioles, mostly multi-lobar and bilateral. Unilateral or bilateral pleural effusion developed in 20 patients. The accordance between radiological and pathological diagnosis of aspiration pneumonia was very poor. The foci of infection detected by X-ray were proven by autopsy in 13 patients, while pleural effusions in X-ray were proven by autopsy in 15 patients. CONCLUSIONS: Multi-concomitant diseases, mixed infection and extra-pulmonary presentations were common in elderly patients with aspiration pneumonia. Multiple small abscesses were the pathological characteristics of aspiration pneumonia in the aged. A definite clinical diagnosis of aspiration pneumonia was difficult. Recurrent silent microaspiration was a feature of aspiration in the elderly. The assessment of risk factor of aspiration played an important role in the clinical diagnosis of aspiration pneumonia.

Heterogeneities and impact profiles of early chronic obstructive pulmonary disease status: findings from the China Pulmonary Health Study.

Background: The prevalence, epidemiological and clinical heterogeneities, and impact profiles of individuals with preserved ratio impaired spirometry (PRISm), pre-COPD, young COPD, and mild COPD in general Chinese population were not known yet. Methods: Data were obtained from the China Pulmonary Health study (2012-2015), a nationally representative cross-sectional survey that recruited 50,991 adults aged 20 years or older. Definitions of the four early disease status were consistent with the latest publications and the Global Initiative for Chronic Obstructive Lung Disease criteria. Findings: The age-standardised prevalences of PRISm, pre-COPD, young COPD, and mild COPD were 5.5% (95% confidence interval, 4.3-6.9), 7.2% (5.9-8.8), 1.1% (0.7-1.8), and 3.1% (2.5-3.8), respectively. In summary, mild COPD was under more direct or established impact factor exposures, such as older age, male gender, lower education level, lower family income, biomass use, air pollution, and more accumulative cigarette exposures; young COPD and pre-COPD experienced more personal and parents' events in earlier lives, such as history of bronchitis or pneumonia in childhood, frequent chronic cough in childhood, parental history of respiratory diseases, passive smoke exposure in childhood, and mother exposed to passive smoke while pregnant; pre-COPD coexisted with heavier symptoms and comorbidities burdens; young COPD exhibited worse airway obstruction; and most of the four early disease status harbored small airway dysfunction. Overall, older age, male gender, lower education level, living in the urban area, occupational exposure, frequent chronic cough in childhood, more accumulated cigarette exposure, comorbid with cardiovascular disease and gastroesophageal reflux disease were all associated with increased presence of the four early COPD status; different impact profiles were additionally observed with distinct entities. Over the four categories, less than 10% had ever taken pulmonary function test; less than 1% reported a previously diagnosed COPD; and no more than 13% had received pharmaceutical treatment. Interpretation: Significant heterogeneities in prevalence, epidemiological and clinical features, and impact profiles were noted under varied defining criteria of early COPD; a unified and validated definition for an early disease stage is warranted. Closer attention, better management, and further research need to be administrated to these population. Funding: Chinese Academy of Medical Sciences Institute of Respiratory Medicine Grant for Young Scholars (No. 2023-ZF-9); China International Medical Foundation (No. Z-2017-24-2301); Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (No. 2021-I2M-1-049); National High Level Hospital Clinical Research Funding (No. 2022-NHLHCRF-LX-01); Major Program of National Natural Science Foundation of China (No. 82090011).