Search

Recently, the rs41291957 polymorphism in the promoter region of miR-143/145 has been repeatedly investigated for its contribution to cancer susceptibility. However, the results remain conflicting rather than conclusive, which calls for further investigations. Therefore, we here conducted a case-control study and meta-analysis to explore the association between rs41291957 and cancer risk. In the case-control study, a total of 2277 cancer patients (lung, liver, gastric and colorectal cancers) and 800 normal controls were recruited, the genotyping of rs41291957 was performed with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and Sanger sequencing. In the meta-analysis, 5 previously published studies and our present study were included, the STATA 14.0 software was applied to conduct all statistical analyses. The results of case-control study showed that rs41291957 was significantly associated with the risk of gastric cancer, colon cancer, rectal cancer, and colorectal cancer in Hubei Han Chinese population. The results of meta-analysis demonstrated that rs41291957 was significantly associated with overall cancer risk, especially colorectal cancer risk and lung cancer risk. Collectively, the rs41291957 polymorphism of miR-143/145 may be a plausible susceptible locus for cancer risk, which should be validated in future studies with larger samples in different ethnic populations.

Previous studies have repeatedly investigated the effects of MALAT1 gene rs3200401 and MEG3 gene rs7158663 on cancer risk. However, their results remain conflicting rather than conclusive. Therefore, we here performed a case-control study and a followed meta-analysis to examine their contribution to the risk of lung, colorectal, gastric and liver cancer. 550 lung cancer patients, 787 colorectal cancer patients, 460 gastric cancer patients, 480 liver cancer patients and 800 normal controls were included. The genotyping of rs3200401 and rs7158663 was applied with Sanger sequencing technology. Our case-control study revealed that in Hubei Chinese population, rs3200401 was significantly associated with the risk of gastric cancer but not lung, colorectal, or liver cancer, rs7158663 was significantly associated with the risk of gastric and colorectal cancer but not lung or liver cancer. The followed meta-analysis, combining the data of previous studies and present study, showed that rs3200401 was significantly associated with the risk of gastric and colorectal cancer in the pooled population but not liver cancer in Chinese population, rs7158663 was significantly associated with the risk of lung, colorectal and gastric but not liver cancer in Chinese population. Collectively, MALAT1 gene rs3200401 may be a susceptive factor for the development of colorectal and gastric cancer, and MEG3 gene rs7158663 may be a susceptive factor for the development of lung, colorectal and gastric cancer. However, the findings should be validated in future studies with larger sample sizes of different ethnic populations.

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive fatal interstitial lung disease characterized by abnormal transition and proliferation of fibroblasts. The uncontrolled transition of fibroblasts, commonly known as myofibroblasts, are the principal source of the enormous extracellular matrix (ECM) depositing in lung parenchyma, leading to gradual failure of gas exchange and mortality of the patients. However, up to now, rare effective therapeutic strategies have been developed to blockade fibroblast-to-myofibroblast transition (FMT) in IPF. Method: We illustrated that the lungs originated from IPF patients and mice with pulmonary fibrosis are characterized by the overexpression of sushi-repeat-containing protein, X-linked 2 (SRPX2). Further functionality studies identified the pivotal role of SRPX2 in FMT. Mechanistically, SRPX2 was involved in a TGFβR1/SMAD3/SRPX2/AP1/SMAD7 positive feedback loop. Specifically, SRPX2 was upregulated by TGF-β1 in a TGFβR1/SMAD3-dependent manner, after which SRPX2 in turn repressed the expression of AP1, subsequently minimized SMAD7 expression, through which it reduced the formation of inhibitory complex with TGFβR1 and enhanced SMAD signaling pathway to promote FMT and exacerbate pulmonary fibrosis. Notably, intratracheal administration of siRNA-loaded liposomes could effectively suppress the expression of Srpx2 in the lung and remarkably protect mice against BLM-induced pulmonary fibrosis, concomitant with a significant reduction of FMT. Results: Accordingly, these data indicate that Srpx2 plays an essential role in the pathogenesis of pulmonary fibrosis and suggests the strategy aiming at silencing Srpx2 could be a promising therapeutic approach against pulmonary fibrosis in clinical settings.

Jie Xia,1– 4,* Lina Sun,5,* Suqin Xu,1– 4 Qiu Xiang,1– 4 Jianping Zhao,1– 4 Weining Xiong,1– 4 Yongjian Xu,1– 4 Shuyuan Chu1– 4,6 1Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences & Technology, Wuhan, People’s Republic of China; 2Wuhan Clinical Medical Research Center for Chronic Airway Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences & Technology, Wuhan, People’s Republic of China; 3Key Laboratory of Pulmonary Diseases of Health Ministry, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences & Technology, Wuhan, People’s Republic of China; 4Key Site of National Clinical Research Center for Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences & Technology, Wuhan, People’s Republic of China; 5Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, Beijing, People’s Republic of China; 6Laboratory of Respiratory Disease, Affiliated Hospital of Guilin Medical University, Guilin, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shuyuan Chu; Jie XiaDepartment of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences & Technology, Wuhan, People’s Republic of ChinaTel +8613978345180; +8627-83665520Email emilyyuanchu@163.com; xiajhzu1215@126.comPurpose: Patients with chronic obstructive pulmonary disease (COPD) would have a poor prognosis if they were not continuously managed according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines. We aim to develop a model to classify whether COPD patients have been continuously managed according to GOLD in the previous year.Methods: The Managed group were COPD patients from a prospectivecohort from November 2017 to November 2019, who have been continuously managed according to GOLD for 1 year. The Control group were COPD patients who were not continuously managed according to GOLD. They were from a retrospective cohort from October 2016 to October 2017 in the same hospitals as the Managed group. A synthetic minority over-sampling technique (SMOTE) algorithm was used to up-sample the Managed group in a training dataset. Features for classification were selected using a support vector machine recursive feature elimination (SVM-RFE) algorithm. The classification model was developed using LibSVM, and its performance was assessed on the testing dataset.Results: The final analysis included 15 subjects in the Managed group and 191 in the Control group. SVM-RFE selects nine features including smoking history, post-bronchodilator (post-)FVC before management, and those after 1-year follow-up (BMI, moderate and severe AECOPD frequency in previous 12 months, mMRC score, post-FEV1, post-FEV1%pred, post-FVC, and post-FEV1/FVC). For our model, positive predictive value is 66.7%, F1 score is 0.978, and AUC is 0.987.Conclusion: SVM classifier combined with SVM-REF feature selection algorithm could achieve good classification between COPD patients who are or are not continuously managed. This model could be applied in clinical practice to help doctors make decisions and enhance COPD patients’ compliance with standard treatment.Keywords: COPD, GOLD, continuous management, support vector machine

Coronavirus disease 2019 (COVID-19) emerged in December 2019 and has spread globally. Diabetics are at increased risk of infections caused by a variety of pathogens including viruses. The present research aims to describe clinical characteristics and outcomes of COVID-19 patients with diabetes.A retrospective multicenter study of COVID-19 patients with diabetes was conducted in four hospitals in Wuhan, Shanghai, and Anhui Province. Reverse transcription polymerase chain reaction or next-generation sequencing was carried out to confirm the existence of severe acute respiratory syndrome coronavirus 2 from respiratory specimens.A total of 54 diabetics (10.36%) were recruited from among 521 COVID-19 patients, with a median age of 63 (interquartile range, 52-70) years. Among them, 51 had been previously diagnosed with diabetes and 3 had been newly diagnosed based on glycosylated hemoglobin over 6.5%. For COVID-19, 47 of the 54 patients had an exposure history. Fever (47/54, 87.04%), dry cough (36/54, 66.67%), and expectoration (21/53, 39.62%) were among the top three symptoms. Lung infiltration was bilateral (46/52, 88.46%) and multilobe (47/52, 90.38%), and ground-glass opacity (36/37, 97.30%) was the most common pattern in radiological images. Moreover, COVID-19 patients with diabetes were prone to be classified as severe or critical cases (46.30%, 25/54) and had complications such as acute lung injury, acute respiratory distress syndrome, and acute kidney injury. The proportions of intensive care unit (ICU) admissions and deaths among the COVID-19 diabetics were 14.81% (8/54) and 12.96% (7/54), respectively.With older age, diabetics diagnosed as having COVID-19 were prone to develop into severe cases and exhibited a high rate of ICU admission and mortality.背景: 2019年12月新型冠状病毒肺炎出现并迅速在全球爆发。糖尿病患者更易于感染包括病毒在内的各种病原体。本研究旨在描述合并糖尿病的新冠肺炎患者的临床特征及预后。 方法: 在武汉市金银潭医院、上海瑞金医院、上海同仁医院及安徽省铜陵医院共4家单位开展多中心回顾性临床研究。采用RT-PCR 或NGS检测呼吸道标本中SARS-Covid-2病毒。 结果: 521位新冠肺炎患者中54位患有糖尿病, 中位年龄63岁(四分位间距52-70), 其中51位患者既往已诊断糖尿病, 3位因糖化血红蛋白超过6.5%新诊断为糖尿病。47位患者有新冠病毒暴露史。发热(47/54,87.04%)、干咳(36/54, 66.67%)、咳痰(21/53, 39.62%) 为主要常见症状。双肺(46/52, 88.46%)、多肺叶浸润(47/52, 90.38%)、磨玻璃影(36/37, 97.30%)为常见影像学改变。合并糖尿病的新冠患者更多发展为重症或危重症型, 也往往合并急性肺损伤、急性呼吸窘迫综合征及急性肾损伤等并发症。这类人群中14.81%(8/54)需入住重症监护病房(ICU)治疗, 12.96%(7/54)最终死亡。 结论: 年龄较大的合并糖尿病的新冠肺炎患者易于发展为重症类型, 有较高的ICU入住及死亡率。.

Purpose To predict the risk of developing severe pneumonia among mild novel coronavirus pneumonia (mNCP) patients on admission. Methods A retrospective cohort study was conducted at three hospitals in Shanghai and Wuhan from January 2020 to February 2020. Real-time polymerasechain-reaction assays were used to detect COVID-19. A total of 529 patients diagnosed with NCP were recruited from three hospitals and classified by four severity types during hospitalization following the standards of the Chinese Diagnosis and Treatment of Pneumonia Caused by New Coronavirus Infection (eighth version). Patients were excluded if admitted by ICU on admission (n=92, on a general ward while meeting the condition of severe or critical type on admission (n=25), or there was insufficient clinical information (n=64). In sum, 348 patients with mNCP were finally included, and 68 developed severe pneumonia. Results mNCP severity prognostic index values were calculated based on multivariate logistic regression: history of diabetes (OR 2.064, 95% CI 1.010-4.683; p=0.043), time from symptom onset to admission ≥7 days (OR 1.945, 95% CI 1.054-3.587; p=0.033), lymphocyte count ≤0.8 (OR 1.816, 95% CI 1.008-3.274; p=0.047), myoglobin ≥90 mg/L (OR 2.496, 95% CI 1.235-5.047; p=0.011), and D-dimer ≥0.5 mg/L (OR 2.740, 95% CI 1.395-5.380; p=0.003). This model showed a c-statistics of 0.747, with sensitivity and specificity 0.764 and 0.644, respectively, under cutoff of 165. Conclusion We designed a clinical predictive tool for risk of severe pneumonia among mNCP patients to provided guidance for medicines. Further studies are required for external validation.

Background Circular RNAs (circRNAs) are a novel class of noncoding RNAs that regulate gene expression at the transcriptional or posttranscriptional level. According to recent studies, circRNAs are involved in the pathogenesis of cancer, but the roles of circRNAs in lung adenocarcinoma are largely unknown. Methods In this study, we identified a novel upregulated circRNA, hsa_circ_0000326, in human lung adenocarcinoma tissues using microarray analysis and qRT-PCR. We then explored the biological role of hsa_circ_0000326 using gain- and loss-of-function assays in adenocarcinoma cells. Bioinformatics databases were used to screen for potential target miRNAs and the luciferase reporter assays and RNA-FISH further validated the interaction. Downstream protein was detected by western blot. Finally, we established xenografts in nude mice to assess the function of hsa_circ_0000326 in vivo. Results We found that high expression of hsa_circ_0000326 was correlated with tumor size, regional lymph node status and differentiation in human lung adenocarcinoma. Additionally, we conducted gain- and loss-of-function assays and found that hsa_circ_0000326 acted as a positive regulator of cell proliferation and migration and a negative regulator of apoptosis. Mechanistic studies showed that hsa_circ_0000326 acted as a miR-338-3p sponge and altered the function of miR-338-3p, which in turn upregulated the expression of the downstream target RAB14 and affected the proliferation, migration and apoptosis of lung adenocarcinoma cells. Conclusions Collectively, our study results reveal crucial roles for hsa_circ_0000326 in the proliferation, migration and apoptosis of lung adenocarcinoma cells and suggest that hsa_circ_0000326 may represent a potential therapeutic target in patients with lung adenocarcinoma.

Tartrate-resistant acid phosphatase 5 (TRAP/ACP5) has been shown to involve the development and prognosis of multiple tumors in previous studies; however, the mechanism in lung cancer is still unclear, and thus this study investigated the role of ACP5 in the progression of lung adenocarcinoma. After a series of in vitro and in vivo experiments, we observed that ACP5 expression was increased in lung adenocarcinomas (40/69, 57.97%); importantly, an increased ACP5 level was associated with patient age (p = 0.044) and lymph node metastasis (p = 0.0385). ACP5 overexpression significantly enhanced A549 and NCI-H1975 cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) and reduced cell apoptosis. Knocking down the expression of ACP5 could rescue the above cell phenotypes. Furthermore, enhancing ACP5 expression promoted lung adenocarcinoma cell hyperplasia and intrapulmonary metastasis in a mouse model. Additionally, mechanistic studies revealed that ACP5 might regulate p53 phosphorylation at Ser392, thereby enhancing the ubiquitination of p53, which then underwent degradation. Reducing the levels of p53 intensified the transcription of SMAD3, which promotes EMT in lung adenocarcinoma cells. In summary, the present study provides a theoretical basis and important scientific evidence on the key role of ACP5 in lung adenocarcinoma progression by inducing EMT via the regulation of p53/SMAD3 signaling. Keywords: ACP5, lung adenocarcinoma, epithelial-mesenchymal transition, p53, SMAD3, metastasis

Objective To develop a practicable nomogram aimed at predicting the risk of severe exacerbations in COPD patients at three and five years. Methods COPD patients with prospective follow-up data were extracted from Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) obtained from National Heart, Lung and Blood Institute (NHLBI) Biologic Specimen and Data Repository Information Coordinating Center. We comprehensively considered the demographic characteristics, clinical data and inflammation marker of disease severity. Cox proportional hazard regression was performed to identify the best combination of predictors on the basis of the smallest Akaike Information Criterion. A nomogram was developed and evaluated on discrimination, calibration, and clinical efficacy by the concordance index (C-index), calibration plot and decision curve analysis, respectively. Internal validation of the nomogram was assessed by the calibration plot with 1000 bootstrapped resamples. Results Among 1711 COPD patients, 523 (30.6%) suffered from at least one severe exacerbation during follow-up. After stepwise regression analysis, six variables were determined including BMI, severe exacerbations in the prior year, comorbidity index, post-bronchodilator FEV1% predicted, and white blood cells. Nomogram to estimate patients' likelihood of severe exacerbations at three and five years was established. The C-index of the nomogram was 0.74 (95%CI: 0.71-0.76), outperforming ADO, BODE and DOSE risk score. Besides, the calibration plot of three and five years showed great agreement between nomogram predicted possibility and actual risk. Decision curve analysis indicated that implementation of the nomogram in clinical practice would be beneficial and better than aforementioned risk scores. Conclusion Our new nomogram was a useful tool to assess the probability of severe exacerbations at three and five years for COPD patients and could facilitate clinicians in stratifying patients and providing optimal therapies.

Particulate matter (PM) is a huge environmental threat and is of major public concern. Oxidative stress and systemic inflammation are known factors that contribute to PM- related damage; however, a systematic understanding of the deleterious pulmonary effects of PM using multi-omics analysis is lacking. In this study, we performed transcriptomic, proteomic, and metabolomic analyses in a mouse model exposed to PM for three months to identify molecular changes in lung tissues. We identified 1690 genes, 326 proteins, and 67 metabolites exhibiting significant differences between PM-challenged and control mice (p0.05). Differentially expressed genes and proteins regulated in PM-challenged mice were involved in lipid metabolism and in the immune and inflammatory response processes. Moreover, a comprehensive analysis of transcript, protein, and metabolite datasets revealed that the genes, proteins, and metabolites in the PM-treated group were involved in lysosomal function and lipid metabolism. Specifically, Cathepsin D (Ctsd), Ferritin light chain (Ftl), Lactotransferrin (Ltf), Lipocalin 2 (Lcn2), and Prosaposin (Psap) were major proteins/genes associated with PM-induced pulmonary damage, while two lipid molecules PC (18:1(11Z)/16:0) and PA (16:0/18:1(11Z)) were major metabolites related to PM-induced pulmonary injury. In summary, lipid metabolism might be used as successful precautions and therapeutic targets in PM-induced pulmonary injury to maintain the stability of cellular lysosomal function.

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease characterized by the infiltration of macrophages in the fibrotic region. Currently, no therapeutic strategies effectively control disease progression, and the 5-year mortality of patients after diagnosis is unacceptably high. Thus, developing an effective and safe treatment for IPF is urgently needed. The present study illustrated that methyl-CpG-binding protein 2 (MECP2), a protein responsible for the interpretation of DNA methylome-encoded information, was abnormally expressed in lung and bronchoalveolar lavage fluid samples of IPF patients and mice with onset of pulmonary fibrosis. And further studies verified that the overexpression of MECP2 occurred mainly in macrophages. Inhibition of Mecp2 expression in macrophages robustly abrogated alternatively activated macrophage (M2) polarization by regulating interferon regulatory factor 4 expression. Accordingly, cationic liposomes loading

Objective The aim of the study was to determine the expression profile of long noncoding RNAs (lncRNAs) in CD4+ T cells from COPD patients and explore the clinical value of the lncRNAs. Methods First, microarray analysis was performed. Differentially expressed lncRNAs were validated by quantitative real-time reverse transcription-PCR (qRT-PCR) in samples from 56 patients with acute exacerbations of COPD (AECOPD), 56 patients with stable COPD, and 35 healthy controls. Meanwhile, the clinical value was tested by receiver operating characteristic curve analysis. The functions of lncRNAs were analyzed by the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes database. The potential target genes that might be regulated by NR-026690 and ENST00000447867 were identified by the lncRNA-mRNA network and competing endogenous RNA network. The transcriptional expression level of rap guanine nucleotide exchange factor 3 (RAPGEF3) was tested by qRT-PCR. The correlation of the expression between NR-026690, ENST00000447867, and RAPGEF3 was analyzed by Spearman's correlation test. Results We found that the relative expression levels of ENST00000447867 and NR-026690 in the CD4+ T cells of AECOPD patients were significantly higher than in the stable COPD patients and control subjects by microarray and qRT-PCR validation. The transcriptional expression level of RAPGEF3 in the CD4+ T cells was significantly higher in the AECOPD group compared to the control group (P

Background Idiopathic pulmonary fibrosis (IPF) is a genetic heterogeneous disease with high mortality and poor prognosis. Hyaluronidase 1 (HYAL1) was found to be upregulated in fibroblasts from IPF patients, and overexpression of HYAL1 could prevent human fetal lung fibroblast proliferation. However, the genetic correlation between the HYAL1 and IPF or connective tissue diseases related interstitial lung disease (CTD‐ILD) has not been determined. Methods A two‐stage study was conducted in Southern Han Chinese population. We sequenced the coding regions and flanking regulatory regions of HYAL1 in stage one (253 IPF cases and 125 controls). A statistically significant variant was further genotyped in stage two (162 IPF cases, 182 CTD‐ILD cases, and 225 controls). Results We identified a nonsynonymous polymorphism (rs117179004, T392M) significantly associated with increased IPF risk (dominant model: OR = 2.239, 95% CI = 1.212–4.137, p = 0.010 in stage one; OR = 2.383, 95% CI = 1.376–4.128, p = 0.002 in stage two). However, we did not observe this association in CTD‐ILD (OR = 1.401, 95% CI = 0.790–2.485, p = 0.248). Conclusion Our findings suggest that the nonsynonymous polymorphism (rs117179004, T392M) may confer susceptibility to IPF in Southern Han Chinese, but is not associated with susceptibility to CTD‐ILD., A nonsynonymous polymorphism (rs117179004, T392M) of hyaluronidase 1 (HYAL1) is associated with increased risk of idiopathic pulmonary fibrosis (IPF) (p = 0.002 in allele‐model) but not connective tissue diseases related interstitial lung disease (CTD‐ILD) (p = 0.181 in allele‐model) in Southern Han Chinese.

BACKGROUND: Although studies have identified hundreds of genetic variants associated with asthma risk, a large fraction of heritability remains unexplained, especially in Chinese individuals. METHODS: To identify genetic risk factors for asthma in a Han Chinese population, 211 asthma‐related genes were first selected based on database searches. The genes were then sequenced for subjects in a Discovery Cohort (284 asthma patients and 205 older healthy controls) using targeted next‐generation sequencing. Bioinformatics analysis and statistical association analyses were performed to reveal the associations between rare/common variants and asthma, respectively. The identified common risk variants underwent a validation analysis using a Replication Cohort (664 patients and 650 controls). RESULTS: First, we identified 18 potentially functional rare loss‐of‐function (LOF) variants in 21/284 (7.4%) of the asthma cases. Second, using burden tests, we found that the asthma group had nominally significant (p

Liposomes carrying MBD2 siRNA protect mice against BLM-induced lung injury and fibrosis by targeting macrophage M2 program., Despite past extensive studies, the mechanisms underlying pulmonary fibrosis (PF) still remain poorly understood. Here, we demonstrated that lungs originating from different types of patients with PF, including coronavirus disease 2019, systemic sclerosis–associated interstitial lung disease, and idiopathic PF, and from mice following bleomycin (BLM)–induced PF are characterized by the altered methyl-CpG–binding domain 2 (MBD2) expression in macrophages. Depletion of Mbd2 in macrophages protected mice against BLM-induced PF. Mbd2 deficiency significantly attenuated transforming growth factor–β1 (TGF-β1) production and reduced M2 macrophage accumulation in the lung following BLM induction. Mechanistically, Mbd2 selectively bound to the Ship promoter in macrophages, by which it repressed Ship expression and enhanced PI3K/Akt signaling to promote the macrophage M2 program. Therefore, intratracheal administration of liposomes loaded with Mbd2 siRNA protected mice from BLM-induced lung injuries and fibrosis. Together, our data support the possibility that MBD2 could be a viable target against PF in clinical settings.

Idiopathic pulmonary fibrosis (IPF) is the most common fatal interstitial lung disease, with limited therapeutic options. The abnormal and uncontrolled differentiation and proliferation of fibroblasts have been confirmed to play a crucial role in driving the pathogenesis of IPF. Therefore, effective and well-tolerated antifibrotic agents that interfere with fibroblasts would be an ideal treatment, but no such treatments are available. Remarkably, we found that dopamine (DA) receptor D1 (D1R) and DA receptor D2 (D2R) were both upregulated in myofibroblasts in lungs of IPF patients and a bleomycin (BLM)-induced mouse model. Then, we explored the safety and efficacy of DA, fenoldopam (FNP, a selective D1R agonist) and sumanirole (SMR, a selective D2R agonist) in reversing BLM-induced pulmonary fibrosis. Further data showed that DA receptor agonists exerted potent antifibrotic effects in BLM-induced pulmonary fibrosis by attenuating the differentiation and proliferation of fibroblasts. Detailed pathway analysis revealed that DA receptor agonists decreased the phosphorylation of Smad2 induced by TGF-β1 in primary human lung fibroblasts (PHLFs) and IMR-90 cells. Overall, DA receptor agonists protected mice from BLM-induced pulmonary fibrosis and may be therapeutically beneficial for IPF patients in a clinical setting.

Background The impact of corticosteroid therapy on outcomes of patients with coronavirus disease 2019 (COVID-19) is highly controversial. We aimed to compare the risk of death between COVID-19-related ARDS patients with corticosteroid treatment and those without. Methods In this single-center retrospective observational study, patients with ARDS caused by COVID-19 between January 20, 2020, and February 24, 2020, were enrolled. The primary outcome was 60-day in-hospital death. The exposure was prescribed systemic corticosteroids or not. Time-dependent Cox regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for 60-day in-hospital mortality. Results A total of 382 patients [60.7 ± 14.1 years old (mean ± SD), 61.3% males] were analyzed. The median of sequential organ failure assessment (SOFA) score was 2.0 (IQR 2.0–3.0). Of these cases, 94 (24.6%) patients had invasive mechanical ventilation. The number of patients received systemic corticosteroids was 226 (59.2%), and 156 (40.8%) received standard treatment. The maximum dose of corticosteroids was 80.0 (IQR 40.0–80.0) mg equivalent methylprednisolone per day, and duration of corticosteroid treatment was 7.0 (4.0–12.0) days in total. In Cox regression analysis using corticosteroid treatment as a time-varying variable, corticosteroid treatment was associated with a significant reduction in risk of in-hospital death within 60 days after adjusting for age, sex, SOFA score at hospital admission, propensity score of corticosteroid treatment, comorbidities, antiviral treatment, and respiratory supports (HR 0.42; 95% CI 0.21, 0.85; p = 0.0160). Corticosteroids were not associated with delayed viral RNA clearance in our cohort. Conclusion In this clinical practice setting, low-dose corticosteroid treatment was associated with reduced risk of in-hospital death within 60 days in COVID-19 patients who developed ARDS.

Background and objective Idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing interstitial lung disease with a poor prognosis. Indirubin, a compound obtained from indigo-bearing plants or mollusks of the family Muricidae, has various bioactivities, including anti-tumor activity and anti-inflammation effect. However, whether indirubin could mediate its therapeutic effects on bleomycin (BLM)-induced pulmonary fibrosis has not been addressed. Methods The impacts of indirubin on bleomycin (BLM)-induced pulmonary fibrosis were evaluated by pathological staining, western blot, RT-PCR and immunofluorescent staining. The effects of indirubin on fibroblast differentiation and related signaling were next investigated to demonstrate the underlying mechanisms. Results The results indicated that indirubin-treated mice exhibited a definitively improved survival rate than that of the BLM-induced mice in a dose-depend manner. Additionally, administration of indirubin significantly alleviated inflammatory cells infiltration in BLM mice. Importantly, indirubin provided protection for mice against BLM-induced pulmonary fibrosis as manifested by the attenuating expression of fibrotic hallmarks, including fibronectin, collagen I and α-smooth muscle actin (α-SMA). Subsequently, we providedin vitro evidence revealing that indirubin suppressed fibroblast to myofibroblast differentiation by repressed TGF-β/Smad signaling in a dose-dependent manner. Notably, our data showed that indirubin seemed to be safe in mice and fibroblasts. Conclusion Overall, indirubin could protect the mice against BLM-induced pulmonary fibrosis by alleviated fibroblast differentiation and may be therapeutically beneficial for IPF patients.

Idiopathic pulmonary fibrosis (IPF) is a chronic and diffuse form of interstitial lung disease of unknown etiology with a fatal outcome. Although various strategies for IPF have been developed over the last few decades, no significant positive impact on the prognosis of IPF has been observed. According to the current paradigm, macrophages have been recognized to play a significant role in IPF pathogenesis. Here, we report a potential nanomedicine-based gene therapy for IPF based on regulate macrophage polarization. Method: C57BL/6 mice were obtained and used to establish a bleomycin (BLM)-induced pulmonary fibrosis animal model, and Sart1 siRNA-loaded liposomes were designed for in vivo experiment. The experimental animals were administered BLM intratracheally on day 0 and treated with Sart1 siRNA on days 14 and 17. In the in vitro experiment, we further examined the function of Sart1 in macrophages. Results: Our data indicated that the liposomes could passively target the fibrotic area in the lung and efficiently accumulate in macrophages. The suppression of Sart1 by siRNA-loaded liposomes significantly protected mice against BLM-induced lung injury and fibrosis, which was attributed to attenuated M2 macrophage infiltration in the lung. Conclusion: Our study provides a valuable reference for modulating macrophage polarization and a promising strategy for the treatment of pulmonary fibrosis in clinical settings.

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with limited therapeutic options. Tartrate-resistant acid phosphatase 5 (ACP5) performs a variety of functions. However, its role in IPF remains unclear. Here, we demonstrated that the levels of ACP5 were increased in IPF patient samples and mice with bleomycin (BLM)-induced pulmonary fibrosis. In particular, higher levels of ACP5 were noted in the sera of IPF patients with a diffusing capacity of the lungs for carbon monoxide (DLCO) less than 40% of the predicted value. Additionally, Acp5 deficiency protected mice from BLM-induced lung injury and fibrosis and reduced the differentiation and proliferation of fibroblasts. Mechanistic studies revealed that Acp5 was upregulated by TGF-β1 in a TGFβR1/Smad3-dependent manner, after which Acp5 dephosphorylated p-β-catenin at Ser33 and Thr41, inhibiting the degradation of β-catenin and subsequently enhancing β-catenin signaling in the nucleus, which promoted the differentiation and proliferation of fibroblast. Notably, the treatment of mice with BLM-induced fibrosis with Acp5 siRNA-loaded liposomes robustly reversed lung fibrosis. Collectively, these data indicate that Acp5 plays an essential role in the initiation and progression of pulmonary fibrosis; therefore, strategies aimed at silencing Acp5 could be novel therapeutic approaches against pulmonary fibrosis in a clinical setting.

Background The impact of corticosteroid therapy on outcomes of patients with Coronavirus disease-2019 (COVID-19) is highly controversial. We aimed to compare the risk of death between COVID-19-related ARDS patients with corticosteroid treatment and those without. Methods In this single-centre retrospective observational study, patients with ARDS caused by COVID-19 between 24 December 2019 and 24 February 2020 were enrolled. The primary outcome was 60-day in-hospital death. The exposure was prescribed systemic corticosteroids or not. Time-dependent Cox regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for 60-day in-hospital mortality. Results A total of 382 patients including 226 (59.2%) patients who received systemic corticosteroids and 156 (40.8%) patients with standard treatment were analyzed. The maximum dose of corticosteroids was 80.0 (IQR 40.0–80.0) mg equivalent methylprednisolone per day, and duration of corticosteroid treatment was 7.0 (4.0–12.0) days in total. In Cox regression analysis using corticosteroid treatment as a time-varying variable, corticosteroid treatment was associated with a significant reduction in risk of in-hospital death within 60 days (HR, 0.48; 95% CI, 0.25, 0.93; p = 0.0285). The association remained significantly after adjusting for age, sex, Sequential Organ Failure Assessment score at hospital admission, propensity score of corticosteroid treatment, and comorbidities (HR: 0.51; CI: 0.27, 0.99; p = 0.0471). Corticosteroids were not associated with delayed viral RNA clearance in our cohort. Conclusion In this clinical practice setting, low-to-moderate dose corticosteroid treatment was associated with reduced risk of death in COVID-19 patients who developed ARDS.

Rationale: The coronavirus disease (COVID-19) pandemic is now a global health concern.Objectives: We compared the clinical characteristics, laboratory examinations, computed tomography images, and treatments of patients with COVID-19 from three different cities in China.Methods: A total of 476 patients were recruited from January 1, 2020, to February 15, 2020, at three hospitals in Wuhan, Shanghai, and Anhui. The patients were divided into four groups according to age and into three groups (moderate, severe, and critical) according to the fifth edition of the Guidelines on the Diagnosis and Treatment of COVID-19 issued by the National Health Commission of China.Measurements and Main Results: The incidence of comorbidities was higher in the severe (46.3%) and critical (67.1%) groups than in the moderate group (37.8%). More patients were taking angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers in the moderate group than in the severe and critical groups. More patients had multiple lung lobe involvement and pleural effusion in the critical group than in the moderate group. More patients received antiviral agents within the first 4 days in the moderate group than in the severe group, and more patients received antibiotics and corticosteroids in the critical and severe groups. Patients >75 years old had a significantly lower survival rate than younger patients.Conclusions: Multiple organ dysfunction and impaired immune function were the typical characteristics of patients with severe or critical illness. There was a significant difference in the use of angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers among patients with different severities of disease. Involvement of multiple lung lobes and pleural effusion were associated with the severity of COVID-19. Advanced age (≥75 yr) was a risk factor for mortality.

Importance Coronavirus disease 2019 (COVID-19) is an emerging infectious disease that was first reported in Wuhan, China, and has subsequently spread worldwide. Risk factors for the clinical outcomes of COVID-19 pneumonia have not yet been well delineated. Objective To describe the clinical characteristics and outcomes in patients with COVID-19 pneumonia who developed acute respiratory distress syndrome (ARDS) or died. Design, Setting, and Participants Retrospective cohort study of 201 patients with confirmed COVID-19 pneumonia admitted to Wuhan Jinyintan Hospital in China between December 25, 2019, and January 26, 2020. The final date of follow-up was February 13, 2020. Exposures Confirmed COVID-19 pneumonia. Main Outcomes and Measures The development of ARDS and death. Epidemiological, demographic, clinical, laboratory, management, treatment, and outcome data were also collected and analyzed. Results Of 201 patients, the median age was 51 years (interquartile range, 43-60 years), and 128 (63.7%) patients were men. Eighty-four patients (41.8%) developed ARDS, and of those 84 patients, 44 (52.4%) died. In those who developed ARDS, compared with those who did not, more patients presented with dyspnea (50 of 84 [59.5%] patients and 30 of 117 [25.6%] patients, respectively [difference, 33.9%; 95% CI, 19.7%-48.1%]) and had comorbidities such as hypertension (23 of 84 [27.4%] patients and 16 of 117 [13.7%] patients, respectively [difference, 13.7%; 95% CI, 1.3%-26.1%]) and diabetes (16 of 84 [19.0%] patients and 6 of 117 [5.1%] patients, respectively [difference, 13.9%; 95% CI, 3.6%-24.2%]). In bivariate Cox regression analysis, risk factors associated with the development of ARDS and progression from ARDS to death included older age (hazard ratio [HR], 3.26; 95% CI 2.08-5.11; and HR, 6.17; 95% CI, 3.26-11.67, respectively), neutrophilia (HR, 1.14; 95% CI, 1.09-1.19; and HR, 1.08; 95% CI, 1.01-1.17, respectively), and organ and coagulation dysfunction (eg, higher lactate dehydrogenase [HR, 1.61; 95% CI, 1.44-1.79; and HR, 1.30; 95% CI, 1.11-1.52, respectively] and D-dimer [HR, 1.03; 95% CI, 1.01-1.04; and HR, 1.02; 95% CI, 1.01-1.04, respectively]). High fever (≥39 °C) was associated with higher likelihood of ARDS development (HR, 1.77; 95% CI, 1.11-2.84) and lower likelihood of death (HR, 0.41; 95% CI, 0.21-0.82). Among patients with ARDS, treatment with methylprednisolone decreased the risk of death (HR, 0.38; 95% CI, 0.20-0.72). Conclusions and Relevance Older age was associated with greater risk of development of ARDS and death likely owing to less rigorous immune response. Although high fever was associated with the development of ARDS, it was also associated with better outcomes among patients with ARDS. Moreover, treatment with methylprednisolone may be beneficial for patients who develop ARDS.

ImportanceHeart injury can be easily induced by viral infection such as adenovirus and enterovirus. However, whether coronavirus disease 2019 (COVID-19) causes heart injury and hereby impacts mortality has not yet been fully evaluated.ObjectiveTo explore whether heart injury occurs in COVID-19 on admission and hereby aggravates mortality later.Design, Setting, and ParticipantsA single-center retrospective cohort study including 188 COVID-19 patients admitted from December 25, 2019 to January 27, 2020 in Wuhan Jinyintan Hospital, China; follow up was completed on February 11, 2020.ExposuresHigh levels of heart injury indicators on admission (hs-TNI; CK; CK-MB; LDH; α-HBDH).Main Outcomes and MeasuresMortality in hospital and days from admission to mortality (survival days).ResultsOf 188 patients with COVID-19, the mean age was 51.9 years (standard deviation: 14.26; range: 21∼83 years) and 119 (63.3%) were male. Increased hs-TnI levels on admission tended to occur in older patients and patients with comorbidity (especially hypertension). High hs-TnI on admission (≥ 6.126 pg/mL), even within the clinical normal range (0∼28 pg/mL), already can be associated with higher mortality. High hs-TnI was associated with increased inflammatory levels (neutrophils, IL-6, CRP, and PCT) and decreased immune levels (lymphocytes, monocytes, and CD4+ and CD8+ T cells). CK was not associated with mortality. Increased CK-MB levels tended to occur in male patients and patients with current smoking. High CK-MB on admission was associated with higher mortality. High CK-MB was associated with increased inflammatory levels and decreased lymphocytes. Increased LDH and α-HBDH levels tended to occur in older patients and patients with hypertension. Both high LDH and α-HBDH on admission were associated with higher mortality. Both high LDH and α-HBDH were associated with increased inflammatory levels and decreased immune levels. hs-TNI level on admission was negatively correlated with survival days (r= -0.42, 95% CI= -0.64∼-0.12, P=0.005). LDH level on admission was negatively correlated with survival days (r= -0.35, 95% CI= -0.59∼-0.05, P=0.022).Conclusions and RelevanceHeart injury signs arise in COVID-19, especially in older patients, patients with hypertension and male patients with current smoking. COVID-19 virus might attack heart via inducing inflammatory storm. High levels of heart injury indicators on admission are associated with higher mortality and shorter survival days. COVID-19 patients with signs of heart injury on admission must be early identified and carefully managed by cardiologists, because COVID-19 is never just confined to respiratory injury.Key pointsQuestionDoes coronavirus disease 2019 (COVID-19) cause heart injury and hereby impact mortality?FindingsIn this retrospective cohort study including 188 patients with COVID-19, patients with high levels of high-sensitivity cardiac troponin I (hs-TNI) on admission had significantly higher mortality (50.0%) than patients with moderate or low levels of hs-TNI (10.0% or 9.1%). hs-TNI level on admission was significantly negatively correlated with survival days (r= -0.42, 95% CI= -0.64∼-0.12, P=0.005).MeaningCOVID-19 patients with signs of heart injury on admission must be early identified and carefully managed by cardiologists, in order to maximally prevent or rescue heart injury-related mortality in COVID-19.

The cover image is based on the Original Article Blockade of JAK2 protects mice against hypoxia‐induced pulmonary arterial hypertension by repressing pulmonary arterial smooth muscle cell proliferation by Lei Zhang et al., https://doi.org/10.1111/cpr.12742. [Image: see text]

Introduction: Circular RNAs (circRNAs) are an endogenous mircoRNA sponge that could act as potential biomarkers for the diagnosis and treatment of diseases. However, the role of circRNAs in asthma is far from clear. Objective: The aim of this study is to assess the diagnostic and therapeutic value of hsa_circ_0002594 for T helper (Th) 2-mediated allergic asthma. Methods: The expression profiles of hsa_circ_0002594 in CD4+ T cells were revealed by circRNA microarray. Hsa_circ_0002594 expression was confirmed via quantitative real-time PCR (qRT-PCR) in asthmatic patients and healthy subjects. Hsa_circ_0002594 levels were compared between subgroups. The clinical diagnostic abilities and therapeutic response of hsa_circ_0002594 were evaluated. The analyses utilized included a student’s t test, nonparametric tests, Spearman’s rank-order correlation, Fisher’s exact test, and the generation of receiver operating characteristic (ROC) curves. Results: Hsa_circ_0002594 was upregulated and positively correlated with fraction of exhaled nitric oxide while negatively correlated with methacholine dose producing a decrease of 20% from baseline in forced expiratory volume in the first second (PD20) in CD4+ T cells of asthma. Furthermore, hsa_circ_0002594 expression was higher in subgroups with a family history, skin pricking test (SPT)-positive, or Th2-high. The hsa_circ_0002594-high subgroup was more frequently associated with Th2-high biomarker profiles and positive SPT. Hsa_circ_0002594 was decreased after inhaled corticosteroids (ICS) treatment. ROC curve analyses of hsa_circ_0002594 showed high area under the curve values in the presence of ICS or not. Conclusions: Our data suggested that hsa_circ_0002594 was upregulated in CD4+ T cells and might have potential value in the diagnosis and treatment of Th2-mediated allergic asthma.

Background Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible disease characterized by excessive fibroblast to myofibroblast differentiation with limited therapeutic options. Curdione, a sesquiterpene compound extracted from the essential oil of Curcuma aromatica Salisb, has anti-inflammatory and anti-tumor effects. However, the role of curdione in IPF is still unclear. Methods The effects of curdione were evaluated in a bleomycin (BLM)-induced pulmonary fibrosis mouse model. C57BL/6 mice were treated with BLM on day 0 by intratracheal injection and intraperitoneal administered curdione or vehicle. In vitro study, expression of fibrotic protein was examined and the transforming growth factor (TGF)-β-related signaling was evaluated in human pulmonary fibroblasts (HPFs) treated with curdione following TGF-β1 stimulation. Results Histological and immunofluorescent examination showed that curdione alleviated BLM-induced lung injury and fibrosis. Specifically, curdione significantly attenuated fibroblast to myofibroblast differentiation in the lung in BLM induced mice. Furthermore, curdione also decreased TGF-β1 induced fibroblast to myofibroblast differentiation in vitro, as evidenced by low expression of α-SMA, collagen 1 and fibronectin in a dose dependent manner. Mechanistically, curdione suppressed the phosphorylation of Smad3 following TGF-β1 treatment, thereby inhibiting fibroblast differentiation. Conclusions Overall, curdione exerted therapeutic effects against pulmonary fibrosis via attenuating fibroblast to myofibroblast differentiation. As curdione had been shown to be safe and well-tolerated in BLM-induced mouse model, curdione might be useful for developing novel therapeutics for IPF.

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.

Additional file 1: eMethods, eTable 1 and 2, and eFigure 1 were included.