Impact of Using Pre- and Postbronchodilator Spirometry Reference Values in a Chinese Population.

Rationale: Spirometry reference equations that are derived from a large, nationally representative general population are warranted in China, and the impact of using prebronchodilator (pre-BD) and post-BD spirometry reference values has yet to be assessed in Chinese populations. Objectives: To present the pre-BD and post-BD spirometry reference values for Chinese adults using the China Pulmonary Health (CPH) Study. Methods: A reference population of 17,969 healthy, nonsmoking participants in the CPH Study was used to calculate the pre- and post-BD reference values for FEV1, FVC, and FEV1/FVC ratio. Pre- and post-BD reference values were applied to the entire CPH population (N = 50,991) to illustrate the divergence between the use of different references in determining disease prevalence and severity grading. Measurements and Main Results: The prevalences of airflow limitation were 5.36% using the pre-BD reference and 8.02% using the post-BD reference. Individuals who had a post-BD FEV1/FVC ratio lower than the post-BD reference value but higher than the pre-BD reference value were found to have significantly higher rates of self-reported respiratory symptoms and significantly lower values on spirometry indicators than those whose post-BD FEV1/FVC ratio was greater than the post-BD reference value. An additional 3.51% of participants were identified as having grade II-IV chronic obstructive pulmonary disease using the post-BD FEV1 predicted values. Conclusions: This study generated and applied pre- and post-BD spirometry reference values in a nationally representative Chinese adult population. Post-BD reference values may serve as an additional criterion in identifying individuals at risk for obstructive pulmonary diseases, and their diagnostic and prognostic values should be further investigated.

Single-cell transcriptomics reveals e-cigarette vapor-induced airway epithelial remodeling and injury.

BACKGROUND: In recent years, e-cigarettes have been used as alternatives among adult smokers. However, the impact of e-cigarette use on human bronchial epithelial (HBE) cells remains controversial. METHODS: We collected primary HBE cells of healthy nonsmokers and chronic obstructive pulmonary disease (COPD) smokers, and analyzed the impact of e- cigarette vapor extract (ECE) or cigarette smoke extract (CSE) on HBE cell differentiation and injury by single-cell RNA sequencing, immunostaining, HE staining, qPCR and ELISA. We obtained serum and sputum from healthy non- smokers, smokers and e-cigarette users, and analyzed cell injury markers and mucin proteins. RESULTS: ECE treatment led to a distinct differentiation program of ciliated cells and unique patterns of their cell-cell communications compared with CSE. ECE treatment caused increased Notch signaling strength in a ciliated cell subpopulation, and HBE cell remodeling and injury including hypoplasia of ciliated cells and club cells, and shorter cilia. ECE-induced hypoplasia of ciliated cells and shorter cilia were ameliorated by the Notch signaling inhibition. CONCLUSIONS: This study reveals distinct characteristics in e-cigarette vapor-induced airway epithelial remodeling, pointing to Notch signaling pathway as a potential targeted intervention for e-cigarette vapor-caused ciliated cell differentiation defects and cilia injury. In addition, a decrease in SCGB1A1 proteins is associated with e- cigarette users, indicating a potential lung injury marker for e-cigarette users.

Clinical characterization and outcomes of impulse oscillometry-defined bronchodilator response: an ECOPD cohort-based study.

BACKGROUND: The clinical significance of the impulse oscillometry-defined small airway bronchodilator response (IOS-BDR) is not well-known. Accordingly, this study investigated the clinical characteristics of IOS-BDR and explored the association between lung function decline, acute respiratory exacerbations, and IOS-BDR. METHODS: Participants were recruited from an Early Chronic Obstructive Pulmonary Disease (ECOPD) cohort subset and were followed up for two years with visits at baseline, 12 months, and 24 months. Chronic obstructive pulmonary disease (COPD) was defined as a post-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio < 0.70. IOS-BDR was defined as meeting any one of the following criteria: an absolute change in respiratory system resistance at 5 Hz ≤ - 0.137 kPa/L/s, an absolute change in respiratory system reactance at 5 Hz ≥ 0.055 kPa/L/s, or an absolute change in reactance area ≤ - 0.390 kPa/L. The association between IOS-BDR and a decline in lung function was explored with linear mixed-effects model. The association between IOS-BDR and the risk of acute respiratory exacerbations at the two-year follow-up was analyzed with the logistic regression model. RESULTS: This study involved 466 participants (92 participants with IOS-BDR and 374 participants without IOS-BDR). Participants with IOS-BDR had higher COPD assessment test and modified Medical Research Council dyspnea scale scores, more severe emphysema, air trapping, and rapid decline in FVC than those without IOS-BDR over 2-year follow-up. IOS-BDR was not associated with the risk of acute respiratory exacerbations at the 2-year follow-up. CONCLUSIONS: The participants with IOS-BDR had more respiratory symptoms, radiographic structural changes, and had an increase in decline in lung function than those without IOS-BDR. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR1900024643. Registered on 19 July, 2019.

Chronic exposure to ampicillin alters lung microbial composition in laboratory rat.

PURPOSE: High-throughput sequencing technologies have revealed that the lungs contain a variety of low biomass microbiota associated with various lung diseases. Rat model is an important tool to understand the possible causal relationship between pulmonary microbiota and diseases. Antibiotic exposure can alter the microbiota, however, a direct influence of long-term ampicillin exposure on commensal bacteria of healthy lungs has not been investigated, which could be useful in the study of the relation between microbiome and long-term lung diseases, especially in animal model-making of lung diseases. METHODS: The rats were aerosolized ampicillin of different concentrations for five months, and then the effect on the lung microbiota was investigated using 16S rRNA gene sequencing. RESULTS: The ampicillin treatment by a certain concentration (LA5, 0.2 ml of 5 mg/ml ampicillin) administration leads to profound changes in the rat lung microbiota but not in the low critical ampicillin concentration (LA01 and LA1, 0.1 and 1 mg/ml ampicillin), when compared to the untreated group (LC). The genus Acidobacteria_Gp16 dominated the ampicillin treated lung microbiota while the genera Brucella, Acinetobacter, Acidobacteria_Gp14, Sphingomonas, and Tumebacillus dominated the untreated lung microbiota. The predicted KEGG pathway analysis profile revealed some difference in the ampicillin treated group. CONCLUSIONS: The study demonstrated the effects of different concentrations of ampicillin treatment on lung microbiota of rats in a relatively long term. It could serve as a basis for the clinical use of antibiotic and the use of ampicillin to control certain bacteria in the animal model-making of respiratory diseases such as chronic obstructive pulmonary disease.

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.

Clinical characteristics of airway impairment assessed by impulse oscillometry in patients with chronic obstructive pulmonary disease: findings from the ECOPD study in China.

BACKGROUND: The role of airway impairment assessed by impulse oscillometry (IOS) in patients with chronic obstructive pulmonary disease (COPD) remains unclear. Therefore, this study aimed to analyze the proportion and clinical characteristics of airway impairment assessed by IOS across COPD severities, and explore whether airway impairment is a subtype of COPD. METHODS: This study was based on cross-sectional data from the ECOPD cohort in Guangdong, China. Subjects were consecutively recruited from July 2019 to August 2021. They filled out questionnaires and underwent lung function tests, IOS and computed tomography (CT). COPD was defined as post-bronchodilator forced expiratory volume in one second/forced vital capacity < lower limit of normal (LLN). Meanwhile, airway impairment was defined as IOS parameters > upper limit of normal or < LLN. On the one hand, Poisson regression was employed to analyze the associations between acute exacerbations of COPD (AECOPD) in the previous year and airway impairment. On the other hand, logistic regression was used to assess differences in CT imaging between patients with IOS parameters' abnormalities and patients with normal IOS parameters. RESULTS: 768 COPD subjects were finally enrolled in the study. The proportion of airway impairment assessed by R5, R20, R5-R20, X5, AX, and Fres was 59.8%, 29.7%, 62.5%, 52.9%, 60.9% and 67.3%, respectively. Airway impairment assessed by IOS parameters (R5, R5-R20, X5, AX, and Fres) in patients with COPD was present across all severities of COPD, particularly in GOLD 3-4 patients. Compared with patients with normal IOS parameters, patients with IOS parameters' abnormalities had more respiratory symptoms, more severe airway obstruction and imaging structural abnormalities. Patients with IOS parameters' abnormalities assessed by R5 [risk ratio (RR): 1.58, 95% confidential interval (CI): 1.13-2.19, P = 0.007], R5-R20 [RR: 1.73, 95%CI: 1.22-2.45, P = 0.002], X5 [RR: 2.11, 95%CI: 1.51-2.95, P < 0.001], AX [RR: 2.20, 95%CI: 1.53-3.16, P < 0.001], and Fres [RR: 2.13, 95%CI: 1.44-3.15, P < 0.001] had a higher risk of AECOPD in the previous year than patients with normal IOS parameters. CONCLUSIONS: Airway impairment assessed by IOS may be a subtype of COPD. Future studies are warranted to identify the underlying mechanisms and longitudinal progression of airway impairment.

Chronic exposure to biomass ambient particulate matter triggers alveolar macrophage polarization and activation in the rat lung.

The role of alveolar macrophages (AMs) in chronic obstructive pulmonary disease is unclear. We characterized the function of AMs in rats chronically exposed to biomass fuel smoke (BMF) and studied the signal pathways that regulate AMs polarization. One hundred and eighty male Sprague-Dawley rats were divided into BMF group and clean air control (CON) group. After BMF smoke exposure for 4 days, 1 month and 6 months, the cytokine secretion and function of AMs were determined by flow cytometry, quantitative polymerase chain reaction, Western blotting and immunofluorescence. Bone marrow-derived macrophages were cultured and exposed to particulate matter (PM) from the smoke. Exposure initially promoted pro-inflammatory factors, but pro-inflammatory macrophages shared features of anti-inflammatory macrophages. Consistent with IL-4 upregulated in bronchoalveolar lavage fluid, p-Stat6 and peroxisome proliferator-activated receptor γ (PPARγ) in AMs elevated at 4 days of exposure. After 6 months of exposure, CD206, TGF-ß1 and p-Smad3 were significantly higher than the control groups. PPARγ reversed the M1 phenotype induced by PM in vitro and drove the macrophages into the M2 phenotype. Altogether, the study demonstrates the dynamic phenotype and functional changes in AMs during exposure to BMF smoke.

The association between small airway dysfunction and aging: a cross-sectional analysis from the ECOPD cohort.

BACKGROUND: Aging has been evidenced to bring about some structural and functional lung changes, especially in COPD. However, whether aging affects SAD, a possible precursor of COPD, has not been well characterized. OBJECTIVE: We aimed to comprehensively assess the relationship between aging and SAD from computed tomography, impulse oscillometry, and spirometry perspectives in Chinese. METHODS: We included 1859 participants from ECOPD, and used a linear-by-linear association test for evaluating the prevalence of SAD across various age subgroups, and multivariate regression models for determining the impact of age on the risk and severity of SAD. We then repeated the analyses in these subjects stratified by airflow limitation. RESULTS: The prevalence of SAD increases over aging regardless of definitional methods. After adjustment for other confounding factors, per 10-yrs increase in age was significantly associated with the risk of CT-defined SAD (OR 2.57, 95% CI 2.13 to 3.10) and the increase in the severity of air trapping (ß 2.09, 95% CI - 0.06 to 4.25 for LAA-856), airway reactance (ß - 0.02, 95% CI - 0.04 to - 0.01 for X5; ß 0.30, 95% CI 0.13 to 0.47 for AX; ß 1.75, 95% CI 0.85 to 2.66 for Fres), as well as the decrease in expiratory flow rates (ß - 3.95, 95% CI - 6.19 to - 1.71 for MMEF%predicted; ß - 5.42, 95% CI - 7.88 to - 2.95 for FEF50%predicted) for SAD. All these associations were generally maintained in SAD defined by IOS or spirometry. After stratification of airflow limitation, we further found that the effect of age on LAA-856 was the most significant among almost all subgroups. CONCLUSIONS: Aging is significantly associated with the prevalence, increased risk, as well as worse severity of SAD. CT may be a more optimal measure to assess aging-related SAD. The molecular mechanisms for the role of aging in SAD need to be explored in the future. Trial registration Chinese Clinical Trial Registry ChiCTR1900024643. Registered on 19 July 2019.

Impaired AT2 to AT1 cell transition in PM2.5-induced mouse model of chronic obstructive pulmonary disease.

BACKGROUND: Particular matter 2.5 (PM2.5) is one of the most important air pollutant, and it is positively associated with the development of chronic obstructive pulmonary disease (COPD). However, the precise underlying mechanisms through which PM2.5 promotes the development of COPD remains largely unknown. METHODS: Mouse alveolar destruction were determined by histological analysis of lung tissues and lung function test. Alveolar type II cells (AT2) to alveolar type I cells (AT1) transition in PM2.5-induced COPD mouse model was confirmed via immunofluorescence staining and qPCR analysis. The differentially expressed genes in PM2.5-induced COPD mouse model were identified by RNA-sequencing of alveolar epithelial organoids and generated by bioinformatics analysis. RESULTS: In this study, we found that 6 months exposure of PM2.5 induced a significantly decreased pulmonary compliance and resulted in pulmonary emphysema in mice. We showed that PM2.5 exposure significantly reduced the AT2 to AT1 cell transition in vitro and in vivo. In addition, we found a reduced expression of the intermediate AT2-AT1 cell process marker claudin 4 (CLDN4) at day 4 of differentiation in mouse alveolar organoids treated with PM2.5, suggesting that PM2.5 exposure inhibited AT2 cells from entering the transdifferentiation process. RNA-sequencing of mouse alveolar organoids showed that several key signaling pathways that involved in the AT2 to AT1 cell transition were significantly altered including the Wnt signaling, MAPK signaling and signaling pathways regulating pluripotency of stem cells following PM2.5 exposure. CONCLUSIONS: In summary, these data demonstrate a critical role of AT2 to AT1 cell transition in PM2.5-induced COPD mouse model and reveal the signaling pathways that potentially regulate AT2 to AT1 cell transition during this process. Our findings therefore advance the current knowledge of PM2.5-induced COPD and may lead to a novel therapeutic strategy to treat this disease.

Preserved ratio impaired spirometry is associated with small airway dysfunction and reduced total lung capacity.

BACKGROUND: Preserved ratio impaired spirometry (PRISm) refers to decreased forced expiratory volume in 1 s (FEV1) in the setting of preserved ratio. Little is known about the role of PRISm and its complex relation with small airway dysfunction (SAD) and lung volume. Therefore, we aimed to investigate the associations between PRISm and SAD and lung volume. METHODS: We conducted a cross-sectional community-dwelling study in China. Demographic data, standard respiratory epidemiology questionnaire, spirometry, impulse oscillometry (IOS) and computed tomography (CT) data were collected. PRISm was defined as post-bronchodilator FEV1/FVC ≥ 0.70 and FEV1 < 80% predicted. Spirometry-defined SAD was defined as at least two of three of the post-bronchodilator maximal mid-expiratory flow (MMEF), forced expiratory flow 50% (FEF50), and forced expiratory flow 75% (FEF75) less than 65% of predicted. IOS-defined SAD and CT-defined gas trapping were defined by the fact that the cutoff value of peripheral airway resistance R5-R20 > 0.07 kPa/L/s and LAA- 856>20%, respectively. Analysis of covariance and logistic regression were used to determine associations between PRISm and SAD and lung volume. We then repeated the analysis with a lower limit of normal definition of spirometry criteria and FVC definition of PRISm. Moreover, we also performed subgroup analyses in ever smoker, never smoker, subjects without airway reversibility or self-reported diagnosed asthma, and subjects with CT-measured total lung capacity ≥70% of predicted. RESULTS: The final analysis included 1439 subjects. PRISm had higher odds and more severity in spirometry-defined SAD (pre-bronchodilator: odds ratio [OR]: 5.99, 95% confidence interval [95%CI]: 3.87-9.27, P < 0.001; post-bronchodilator: OR: 14.05, 95%CI: 8.88-22.24, P < 0.001), IOS-defined SAD (OR: 2.89, 95%CI: 1.82-4.58, P < 0.001), and CT-air trapping (OR: 2.01, 95%CI: 1.08-3.72, P = 0.027) compared with healthy control after adjustment for confounding factors. CT-measured total lung capacity in PRISm was lower than that in healthy controls (4.15 ± 0.98 vs. 4.78 ± 1.05 L, P < 0.05), after adjustment. These results were robust in repeating analyses and subgroup analyses. CONCLUSION: Our finding revealed that PRISm was associated with SAD and reduced total lung capacity. Future studies to identify the underlying mechanisms and longitudinal progression of PRISm are warranted.

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.

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

Rationale: The Global Burden of Disease program identified smoking and ambient and household air pollution as the main drivers of death and disability from chronic obstructive pulmonary disease (COPD). Objectives: To estimate the attributable risk of chronic airflow obstruction (CAO), a quantifiable characteristic of COPD, due to several risk factors. Methods: 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 postbronchodilator FEV1-to-FVC ratio less than the lower limit of normal, and the relative risks associated with different risk factors. Local relative risks were estimated using a Bayesian hierarchical model borrowing information from across sites. From these relative risks and the prevalence of risk factors, we estimated local population attributable risks. Measurements and Main Results: The mean prevalence of CAO was 11.2% in men and 8.6% in women. The mean population attributable risk 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, and a history of tuberculosis. The risk of CAO attributable to the different risk factors varied across sites. Conclusions: Although smoking remains the most important risk factor for CAO, in some areas, poor education, low body mass index, and passive smoking are of greater importance. Dusty occupations and tuberculosis are important risk factors at some sites.

Validity of a portable spirometer in the communities of China.

BACKGROUND: The lack of simple and affordable spirometry has led to the missed and delayed diagnoses of chronic respiratory diseases in communities. The PUS201P is a portable spirometry developed to solve this problem. OBJECTIVE: We aimed to verify the consistency of the PUS201P spirometer with conventional Jaeger spirometer. METHODS: In this cross-sectional study, we randomly recruited 202 subjects aged > 40 years. Testing with the portable spirometry and conventional spirometry were performed on all participants. We compared forced expiratory volume in one second (FEV1), forced vital capacity (FVC), FEV1/FVC measured by the PUS201P device with the conventional spirometer. Pearson correlation coefficient and Interclass Correlation Coefficient (ICC) were assessed to confirm the consistency of the measures from two instruments. Bland-Altman graph was created to assess the agreement of the measures from two devices. RESULTS: 202 participants were included in this study. The ICC on FEV1, FVC, FEV1/FVC measured by the portable spirometer and the conventional spirometer were 0.95 (95% confidence interval [CI]: 0.94-0.96), 0.92 (95% CI: 0.90-0.94], 0.93 (95% CI: 0.91-0.95), respectively. The Bland-Altman plots showed that the mean difference between the measures from two spirometers are always located in the 95% limits of agreement. CONCLUSIONS: Our results support that the measures from the portable spirometer and the conventional spirometer have a good agreement and reproducibility. And the portable spirometer is a reliable tool to screen and diagnose chronic airway diseases in the primary care settings.

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 .

Chronic hypoxia promoted pulmonary arterial smooth muscle cells proliferation through upregulated calcium-sensing receptorcanonical transient receptor potential 1/6 pathway.

OBJECTIVES: Although both calcium-sensing receptor (CaSR) and canonical transient receptor potential (TRPC) proteins contribute to chronic hypoxia (CH)-induced pulmonary arterial smooth muscle cells (PASMCs) proliferation, the relationship between CaSR and TRPC in hypoxic PASMCs proliferation remains poorly understood. The goal of this study was to identify that CH promotes PASMCs proliferation through CaSR-TRPC pathway. METHODS: Rat PASMCs were isolated and treated with CH. Cell proliferation was assessed by cell counting, CCK-8 assay, and EdU incorporation. CaSR and TRPC expressions were determined by qPCR and Western blotting. Store-operated Ca2+ entry (SOCE) was assessed by extracellular Ca2+ restoration. RESULTS: In PASMCs, CH enhanced the cell number, cell viability and DNA synthesis, which is accompanied by upregulated expression of CaSR, TRPC1 and TRPC6. Negative CaSR modulators (NPS2143, NPS2390) inhibited, whereas positive modulators (spermine, R568) enhanced, the CH-induced increases in cell number, cell viability and DNA synthesis in PASMCs. Knockdown of CaSR by siRNA inhibited the CH-induced upregulation of TRPC1 and TRPC6 and enhancement of SOCE and attenuated the CH-induced enhancements of cell number, cell viability and DNA synthesis in PASMCs. However, neither siTRPC1 nor siTRPC6 had an effect on the CH-induced CaSR upregulation, although both significantly attenuated the CH-induced enhancements of cell number, cell viability and DNA synthesis in PASMCs. CONCLUSION: These results demonstrate that upregulated CaSR-TRPC1/6 pathway mediating PASMCs proliferation is an important pathogenic mechanism under hypoxic conditions.

Gut microbiota dysbiosis contributes to the development of chronic obstructive pulmonary disease.

BACKGROUND: Dysbiosis of the gut microbiome is involved in the pathogenesis of various diseases, but the contribution of gut microbes to the progression of chronic obstructive pulmonary disease (COPD) is still poorly understood. METHODS: We carried out 16S rRNA gene sequencing and short-chain fatty acid analyses in stool samples from a cohort of 73 healthy controls, 67 patients with COPD of GOLD stages I and II severity, and 32 patients with COPD of GOLD stages III and IV severity. Fecal microbiota from the three groups were then inoculated into recipient mice for a total of 14 times in 28 days to induce pulmonary changes. Furthermore, fecal microbiota from the three groups were inoculated into mice exposed to smoke from biomass fuel to induce COPD-like changes. RESULTS: We observed that the gut microbiome of COPD patients varied from that of healthy controls and was characterized by a distinct overall microbial diversity and composition, a Prevotella-dominated gut enterotype and lower levels of short-chain fatty acids. After 28 days of fecal transplantation from COPD patients, recipient mice exhibited elevated lung inflammation. Moreover, when mice were under both fecal transplantation and biomass fuel smoke exposure for a total of 20 weeks, accelerated declines in lung function, severe emphysematous changes, airway remodeling and mucus hypersecretion were observed. CONCLUSION: These data demonstrate that altered gut microbiota in COPD patients is associated with disease progression in mice model.

Effects of high-frequency temperature variabilities on the morbidity of chronic obstructive pulmonary disease: Evidence in 21 cities of Guangdong, South China.

BACKGROUND: While temperature changes have been confirmed as one of the contributory factors affecting human health, the association between high-frequency temperature variability (HFTV, i.e., temperature variation at short time scales such as 1, 2, and 5 days) and the hospitalization of chronic obstructive pulmonary disease (COPD) was rarely reported. OBJECTIVES: To evaluate the associations between high-frequency temperature variabilities (i.e., at 1, 2, and 5-day scales) and daily COPD hospitalization. METHODS: We collected daily records of COPD hospitalization and meteorological variables from 2013 to 2017 in 21 cities of Guangdong Province, South China. A quasi-Poisson regression with a distributed lag nonlinear model was first employed to quantify the effects of two HFTV measures, i.e., the day-to-day (DTD) temperature change and the intraday-interday temperature variability (IITV), on COPD morbidity for each city. Second, we used multivariate meta-analysis to pool the city-specific estimates, and stratified analyses were performed by age and sex to identify vulnerable groups. Then, the meta-regression with city-level characteristics was employed to detect the potential sources of the differences among 21 cities. RESULTS: A monotonic increasing curve of the overall exposure-response association was observed, suggesting that positive HFTV (i.e., increased DTD and IITV) will significantly increase the risk of COPD admission. Negative DTD was associated with reduced COPD morbidity while positive DTD elevated the COPD risk. An interquartile range (IQR) increase in DTD was associated with a 24% (95% CI: 12-38%) increase in COPD admissions. An IQR increase in IITV0-1 was associated with 18% (95% CI: 7-27%) increase in COPD admissions. Males and people aged 0-64 years appeared to be more vulnerable to the DTD effect than others. Potential sources of the disparity among different cities include urbanization level, sex structure, industry structure, gross domestic product (GDP), health care services, and air quality. CONCLUSIONS: The increases of DTD and IITV have significant adverse impacts on COPD hospitalization. As climate change intensifies, precautions need to be taken to mitigate the impacts of high-frequency temperature changes.

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.

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., PM2.5, PM10 and PMcoarse), sulfur dioxide (SO2), nitrogen dioxide (NO2), carbon monoxide (CO), ozone (O3), 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 SO2, PM10 and PM2.5 declined by nearly 40%, 30%, and 26% respectively. As the average daily 8 h O3 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 PM2.5, 1.092 (95% CI 1.08-1.11) for O3, and 1.092 (95% CI 1.05-1.14) for SO2. 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 PM2.5, PM10 and SO2 in Guangdong, while O3 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 O3 has emerged as an important risk factor following an intervention.

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.

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

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.