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Chronic obstructive pulmonary disease (COPD) is a complex and progressive respiratory disease. Autoimmune processes have been hypothesized to contribute to disease progression; however, the presence of autoantibodies in the serum has been variable. Given that COPD is a lung disease, we sought to investigate whether autoantibodies in sputum supernatant would better define pulmonary autoimmune processes. Matched sputum and serum samples were obtained from the Airways Disease Endotyping for Personalized Therapeutics (ADEPT) study and at the Guangzhou Institute of Respiratory Health (GIRH). Samples were collected from patients with varying severity of COPD, asymptomatic smokers, and healthy control subjects. IgG and IgM autoantibodies were detected in sputum and serum of all subjects in both cohorts using a broad-spectrum autoantigen array. No differences were observed in sputum autoantibodies between COPD and asymptomatic smokers in either cohort. In contrast, 16% of detectable sputum IgG autoantibodies were decreased in subjects with COPD compared to healthy controls in the ADEPT cohort. Compared to asymptomatic smokers, approximately 13% of detectable serum IgG and 40% of detectable serum IgM autoantibodies were differentially expressed in GIRH COPD subjects. Of the differentially expressed specificities, anti-nuclear autoantibodies were predominately decreased. A weak correlation between increased serum IgM anti-tissue autoantibodies and a measure of airspace enlargement was observed. The differential expression of specificities varied between the cohorts. In closing, using a comprehensive autoantibody array, we demonstrate that autoantibodies are present in subjects with COPD, asymptomatic smokers, and healthy controls. Cohorts displayed high levels of heterogeneity, precluding the utilization of autoantibodies for diagnostic purposes.

BackgroundSystematic inflammation, nutritional status, and cardiovascular function have been associated with the outcomes of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) patients with heart failure (HF). However, the value of their relevant biomarkers in predicting mortality has not been well defined yet. We aimed to investigate the prognostic value of circulating biomarkers including C-reaction protein (CRP) /albumin (ALB), neutrophil–lymphocyte ratio (NLR), platelet–lymphocyte ratio (PLR), and N-terminal pro-brain natriuretic peptide (NT-proBNP) for AECOPD patients with HF.Methods A total of 146 cases of AECOPD complicated with HF were enrolled and classified into survivor group (n=94) and non-survivor group (n=52). The baseline characteristics and blood-based biomarkers were collected. The predictors for prognosis were analyzed by multivariate logistic regression, and the ability to predict 28-day mortality was evaluated by receiver operating characteristics curve (ROC) and the area under the curve (AUC).ResultsThe patients in non-survivors had significantly higher levels of CRP, CRP/ALB, NLR, PCT and NT-proBNP, but lower ALB levels compared to the survivors [145.8±110.1 VS. 66.6±70.2mg/L, 5.9±4.9 VS. 2.3±2.6, 22.2 (11.1, 40.1) VS. 12.0 (6.2, 24.8), 2.6 (0.2, 10.3) VS. 0.08 (0.1, 0.5)ng/ml, 17912.5 (9344.0, 34344.5) VS. 9809.0 (4415.9, 16387.2)ng/ml, 26.8±6.4 VS. 31.0±4.6g/L; P < 0.001, P=0.413). The logistic analysis revealed that CRP/ALB (OR=1.303, 95%CI: 1.145-1.483, PP=0.009) and NLR (OR=1.010, 95%CI: 0.999-1.022, PPConclusionsHigh levels of NLR, CRP/ALB and NT-proBNP may be clinical usefully predictors for death in AECOPD patients with HF. Combination of NLR with CRP/ALB and NT-proBNP can provide a higher accuracy for predicting 28-day mortality in these patients.

Noninvasive ventilation (NIV) is beneficial in acute respiratory failure (ARF) caused by chest trauma; however, NIV-related complications affect the efficacy. We evaluated whether NIV with helmet decreases the incidence of complications and improves its effects in a single center. Patients with ARF after chest trauma were randomized to receive NIV with helmet or face mask. The primary outcome was the rate of NIV-related complications. Secondary outcomes were PaO2/FiO2, patient’s tolerance, intubation rate, length of intensive care unit (ICU) stay, and ICU mortality. The trial was terminated early after an interim analysis with 59 patients. The incidence of complications was lower in the helmet group [10% (3/29) vs 43% (13/30), P = 0.004], and PaO2/FiO2s were higher at 1 h and at the end of NIV (253.14 ± 64.74 mmHg vs 216.06 ± 43.86 mmHg, 277.07 ± 84.89 mmHg vs 225.81 ± 63.64 mmHg, P = 0.013 and 0.012) compared with them in face mask group. More patients reported excellent tolerance of the helmet vs face mask after 4 h of NIV [83% (24/29) vs 47% (14/30), P = 0.004] and at the end of NIV [69% (20/29) vs 30% (9/30), P = 0.03]. Differences in intubation rate, ICU stay, and mortality were non-significant (P = 0.612, 0.100, 1.000, respectively). NIV with helmet decreased NIV-related complications, increased PaO2/FiO2, and improved tolerance compared with NIV with face mask in patients with chest trauma.Trial registration: Registered in the Chinese Clinical Trial Registry (ChiCTR1900025915), a WHO International Clinical Trials Registry Platform (http://www.chictr.org.cn/searchprojen.aspx).

Fangcang shelter (Cabin) hospitals were set up in order to cope with the rapid growth of confirmed cases of coronavirus disease 2019 (COVID‐19) in Wuhan, China at a time when there were insufficient beds in designated hospitals. This paper describes the layout and functioning of a typical Fangcang shelter hospital, Wuhan Dongxihu Fangcang shelter Hospital, where the author has worked, the working mechanism, experience and effectiveness. A set of patient management protocols was employed for daily practice, which included preset criteria and procedure for admission, examination, medication treatment, referral and discharge. WeChat platform with different groups was used for communication, ward round, test appointments and patient data communication. All these procedures and mechanisms of working enabled the effective management of a larger number of patients with relatively few doctors. As a result, 442 mild or moderate COVID‐19 patients in Hall C were successfully managed by a team of 40 doctors, with 246 (56%) patients were cured and discharged from the Fangcang shelter hospital while the remaining 196 (44%) patients were referred on to designated hospitals for further treatment. The reasons for referral included poor resolution in computerized tomography (CT) scan (59%), persistently positive severe acute respiratory syndrome coronavirus 2 by PCR after 9 days of admission (16%), deterioration in CT image (4%), development of dyspnoea (1%) and other (4%) or unclear reasons (16%) due to no record of reasons for referral on the document. There were no deaths and no complaints from the patients in Hall C. In summary, the Fangcang shelter hospital could be run successfully with a set of patient management protocols under conditions of limited facilities and medical staff. It was effective and safe in isolating patients, providing basic medical care and early identification of potential severe cases. This experience may provide a successful example of a working mechanism for the prevention and control of the COVID‐19 pandemic worldwide.

Background Coronavirus disease 2019 (COVID-19) is a disease caused by severe acute respiratory syndrome-coronavirus-2. Consensus suggestions can standardise care, thereby improving outcomes and facilitating future research. Methods An International Task Force was composed and agreement regarding courses of action was measured using the Convergence of Opinion on Recommendations and Evidence (CORE) process. 70% agreement was necessary to make a consensus suggestion. Results The Task Force made consensus suggestions to treat patients with acute COVID-19 pneumonia with remdesivir and dexamethasone but suggested against hydroxychloroquine except in the context of a clinical trial; these are revisions of prior suggestions resulting from the interim publication of several randomised trials. It also suggested that COVID-19 patients with a venous thromboembolic event be treated with therapeutic anticoagulant therapy for 3 months. The Task Force was unable to reach sufficient agreement to yield consensus suggestions for the post-hospital care of COVID-19 survivors. The Task Force fell one vote shy of suggesting routine screening for depression, anxiety and post-traumatic stress disorder. Conclusions The Task Force addressed questions related to pharmacotherapy in patients with COVID-19 and the post-hospital care of survivors, yielding several consensus suggestions. Management options for which there is insufficient agreement to formulate a suggestion represent research priorities., For patients with acute COVID-19 pneumonia who require oxygen support, the International Task Force made suggestions for remdesivir and dexamethasone, but against hydroxychloroquine. Post-discharge management of COVID-19 survivors is a research priority. https://bit.ly/32B96uI

Objective Spirometric lung function is usually used to evaluate respiratory health. However, the impact of lung function on extra-pulmonary diseases and all-cause mortality has not been fully elucidated, especially in people without chronic obstructive pulmonary disease (COPD). Patients and Methods Participants aged ≥20 and underwent spirometry test from the US National Health and Nutrition Examination Surveys (NHANES) 2007-2012 were analyzed in this study. Multivariate logistic and Cox regressions were used to evaluate the impact of forced expiratory volume in 1 second percent of predicted (FEV1% predicted) and forced vital capacity percent of predicted (FVC% predicted) on 14 extra-pulmonary diseases and all-cause morbidity after adjusting for multiple confounders. Results During 2007-2012, 1800 COPD patients and 11,437 non-COPD subjects were included. The prevalence of hypertension, diabetes mellitus (DM), dyslipidemia, metabolic syndrome (MS), congestive heart failure (CHF), coronary disease, stroke, chronic kidney disease (CKD), arthritis, cancer, underweight and osteoporosis in COPD patients was higher than that in the non-COPD population. After adjusting for confounders, the decrease of FEV1% predicted and FVC% predicted was related with higher odds of having hypertension, DM, obesity, MS, CHF, coronary disease and depression (OR > 1, P

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent for coronavirus 2019 (COVID-19) pneumonia. Little is known about the kinetics, tissue distribution, cross-reactivity, and neutralization antibody response in patients with COVID-19. Two groups of patients with RT-PCR–confirmed COVID-19 were enrolled in this study: 12 severely ill patients in intensive care units who needed mechanical ventilation and 11 mildly ill patients in isolation wards. Serial clinical samples were collected for laboratory detection. Results showed that most of the severely ill patients had viral shedding in a variety of tissues for 20–40 days after onset of disease (8/12, 66.7%), while the majority of mildly ill patients had viral shedding restricted to the respiratory tract and had no detectable virus RNA 10 days after onset (9/11, 81.8%). Mildly ill patients showed significantly lower IgM response compared with that of the severe group. IgG responses were detected in most patients in both the severe and mild groups at 9 days after onset, and remained at a high level throughout the study. Antibodies cross-reactive to SARS-CoV and SARS-CoV-2 were detected in patients with COVID-19 but not in patients with MERS. High levels of neutralizing antibodies were induced after about 10 days after onset in both severely and mildly ill patients which were higher in the severe group. SARS-CoV-2 pseudotype neutralization test and focus reduction neutralization test with authentic virus showed consistent results. Sera from patients with COVID-19 inhibited SARS-CoV-2 entry. Sera from convalescent patients with SARS or Middle East respiratory syndrome (MERS) did not. Anti–SARS-CoV-2 S and N IgG levels exhibited a moderate correlation with neutralization titers in patients’ plasma. This study improves our understanding of immune response in humans after SARS-CoV-2 infection.

Summary The novel coronavirus disease 2019 (COVID-19) occurred in China (mainly in Wuhan, Hubei Province) at the end of December 2019. Henan province is located in the center of China, borders on Hubei province by land in the south with the nearest distance of 200 kilometers to Wuhan. As the inland provinces in mainland China, frequent communication in transportation and population flow make it difficult to confine the pandemic, which is similar to that in the landlocked countries in Europe. The expected cases in Henan were mainly imported. A bundle of intervention strategies were adopted from 26 January 2020 to cut off the spread between the infected patients and the native residents. The pandemic was controlled 2 month later after the bundle of strategies was adopted although the number of cases continued to increase explosively during the first 10 days. A total of 1273 cases were confirmed, 1251 patients were cured, 22 patients died, and 1 patient was still in hospital until 29 March 2020. The peak of daily increased cases was 109 cases. Our data show that COVID-19 is highly infectious and easy to cause an outbreak, but it can be controlled by early effective interventions. A bundle of strategies according to the specific situation of each country is suggested to be implemented as early as possible.

Purpose This study investigated the feasibility and efficacy of continuous noninvasive ventilation (NIV) support with 100% oxygen using a specially designed face mask, for reducing desaturation during fiberoptic bronchoscopy (FOB)-guided intubation in critically ill patients with respiratory failure. Materials and methods This was a single-center prospective randomized study. All patients undergoing FOB-guided nasal tracheal intubation were randomized to bag-valve-mask ventilation or NIV for preoxygenation followed by intubation. The NIV group were intubated through a sealed hole in a specially designed face mask during continuous NIV support with 100% oxygen. Control patients were intubated with removal of the mask and no ventilatory support. Results We enrolled 106 patients, including 53 in each group. Pulse oxygen saturation (SpO2) after preoxygenation (99% (96%–100%) vs. 96% (90%–99%), p = .001) and minimum SpO2 during intubation (95% (87%–100%) vs. 83% (74%–91%), p, Highlights • Our study is the first to evaluate NIV during FOB-guided nasotracheal intubation. • NIV support during FOB-guided nasotracheal intubation was effectively prevented severe desaturation during intubation. • We used a specially-designed intubation face mask to ensure that there was no interruption of NIV support during intubation.

PURPOSE We investigated the effectiveness, safety and compliance of Zheng's Supine Rehabilitation Exercise (ZSRE) as a rehabilitation programme among elderly patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). PATIENTS AND METHODS About 82 elderly patients with AECOPD were divided into a rehabilitation group and control group on their admission day, and both groups received routine medical treatment. Patients in the rehabilitation group started ZSRE on the second day of admission and continued until 8 weeks after discharge. RESULTS At the 9th week after discharge, the COPD Assessment Test (CAT), 6-minute walking distance (6MWD) and Modified Medical Research Council Dyspnea Scale (mMRC) in the rehabilitation group were all significantly better than those in the control group (P

Introduction: Patients with dyspnea and hypoxemia are common in emergency departments. However, it is unknown whether high-flow nasal cannula (HFNC) reduces the risk of requiring more advanced ventilation support and whether HFNC relieves dyspnea better than conventional oxygen therapy (COT). Areas covered: We searched the PubMed, Cochrane Library, Ovid, and Embase databases from inception to 1 September 2019 to identify relevant-randomized controlled trials comparing the effect of HFNC with COT in emergency departments regarding the severity of dyspnea, hospitalization rate, intubation rate, and hospital mortality. We identified four studies. HFNC was associated with a lower rate of requiring more advanced ventilation. HFNC reduced the rate of dyspnea, lowered the dyspnea scale score, and decreased patients’ respiratory rate significantly. However, there was insufficient evidence to show a significant effect on HFNC regarding patients’ oxygenation and hospital mortality. Expert opinion: For patients with dyspnea and hypoxemia before hospitalization, the short-term effect of HFNC was undeniable. HFNC reduced the risk of requiring more advanced ventilation and relived dyspnea better than COT. HFNC might be considered as a first-line therapy even before making a clear diagnosis for dyspnea. More studies are needed to explore the effect of HFNC on oxygenation and patients’ prognosis.

Rongchang Chen,1 Nanshan Zhong,2 Hao-Yan Wang,3 Li Zhao,4 Xiaodong Mei,5 Zhiqiang Qin,6 Juan Huang,7 Pryseley N Assam,8 Andrea Maes,9 Shahid Siddiqui,10 Ubaldo J Martin,10 Colin Reisner9 1Shenzhen Institute of Respiratory Diseases, Shenzhen People’s Hospital, Shenzhen, Guangdong, People’s Republic of China; 2Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Diseases, National Clinical Research Centre for Respiratory Diseases, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 3Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China; 4Sheng Jing Hospital of China Medical University, Shenyang, Liaoning, People’s Republic of China; 5Anhui Provincial Hospital, Hefei, Anhui, People’s Republic of China; 6The People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning City, Guangxi Zhuang Autonomous Region, People’s Republic of China; 7Formerly of AstraZeneca, Shanghai, People’s Republic of China; 8AstraZeneca, Shanghai, People’s Republic of China; 9AstraZeneca, Morristown, NJ, USA; 10AstraZeneca, Gaithersburg, MD, USACorrespondence: Nanshan ZhongGuangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Diseases, National Clinical Research Centre for Respiratory Diseases, First Affiliated Hospital of Guangzhou Medical University, 151 Yanjiang Road, Guangzhou 510120, Guangdong, People’s Republic of ChinaTel +86 20 83062719Email nanshan@vip.163.comBackground: Glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI) is a long-acting muscarinic antagonist/long-acting β2-agonist fixed-dose combination therapy delivered by MDI, formulated using innovative co-suspension delivery technology. The PINNACLE-4 study evaluated the efficacy and safety of GFF MDI in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD) from Asia, Europe, and the USA. This article presents the results from the China subpopulation of PINNACLE-4.Methods: In this randomized, double-blind, placebo-controlled, parallel-group Phase III study (NCT02343458), patients received GFF MDI 18/9.6 μg, glycopyrrolate (GP) MDI 18 μg, formoterol fumarate (FF) MDI 9.6 μg, or placebo MDI (all twice daily) for 24 weeks. The primary endpoint was change from baseline in morning pre-dose trough forced expiratory volume in 1 second at Week 24. Secondary lung function endpoints and patient-reported outcome measures were also assessed. Safety was monitored throughout the study.Results: Overall, 466 patients from China were included in the intent-to-treat population (mean age 63.6 years, 95.7% male). Treatment with GFF MDI improved the primary endpoint compared to GP MDI, FF MDI, and placebo MDI (least squares mean differences: 98, 104, and 173 mL, respectively; all P≤0.0001). GFF MDI also improved daily total symptom scores and time to first clinically important deterioration versus monocomponents and placebo MDI, and Transition Dyspnea Index focal score versus placebo MDI. Rates of treatment-emergent adverse events were similar across the active treatment groups and slightly higher in the placebo MDI group.Conclusion: GFF MDI improved lung function and daily symptoms versus monocomponents and placebo MDI and improved dyspnea versus placebo MDI. All treatments were well tolerated with no unexpected safety findings. Efficacy and safety results were generally consistent with the global PINNACLE-4 population, supporting the use of GFF MDI in patients with COPD from China.Keywords: bronchodilator, COPD, co-suspension delivery technology, LAMA/LABA, exacerbations

Background Effective strategies are dramatically needed to prevent and improve the recovery from myocardial ischemia and reperfusion (I/R) injury. Direct interactions between the mitochondria and endoplasmic reticulum (ER) during heart diseases have been recently investigated. This study was designed to explore the cardioprotective effects of gypenoside XVII (GP-17) against I/R injury. The roles of ER stress, mitochondrial injury, and their crosstalk within I/R injury and in GP-17–induced cardioprotection are also explored. Methods Cardiac contractility function was recorded in Langendorff-perfused rat hearts. The effects of GP-17 on mitochondrial function including mitochondrial permeability transition pore opening, reactive oxygen species production, and respiratory function were determined using fluorescence detection kits on mitochondria isolated from the rat hearts. H9c2 cardiomyocytes were used to explore the effects of GP-17 on hypoxia/reoxygenation. Results We found that GP-17 inhibits myocardial apoptosis, reduces cardiac dysfunction, and improves contractile recovery in rat hearts. Our results also demonstrate that apoptosis induced by I/R is predominantly mediated by ER stress and associated with mitochondrial injury. Moreover, the cardioprotective effects of GP-17 are controlled by the PI3K/AKT and P38 signaling pathways. Conclusion GP-17 inhibits I/R-induced mitochondrial injury by delaying the onset of ER stress through the PI3K/AKT and P38 signaling pathways.

Background Pulmonary lymphoepithelioma-like carcinoma (PLELC) is a rare subtype of lung cancer that is less reported and not well-understood. Materials and Methods We investigated the clinical features of 85 patients with PLELC to determine the prognostic factors. Results PLELC preferentially affected the young (71.8%) and nonsmokers (72.9%), without a significant difference in gender. Most (50.6%) patients were at the early stage with opportunity for operation, and patients at advanced stages mainly received multimodality treatment. The median follow-up duration was 17 months (range, 1-39 months) for the whole group, and the 3-year overall survival rate for patients in the early stage was 100%, whereas the 1-year and 2-year overall survival rate for patients in the advanced stage were 93% and 77%, respectively. The tumor stages (P = .031), distant lymph node metastasis (P = .035) and performance status (P = .008) were associated with progression-free survival in the univariate analysis, whereas performance status was an independent prognostic factor in the multivariate analysis (P = .016). The median progression-free survival in the paclitaxel plus platinum (12 months) group and gemcitabine plus platinum (10 months) group were significantly longer than that in the pemetrexed plus platinum (5 months) group (P = .001). Conclusion PLELC had a better prognosis compared with other types of non–small-cell lung cancer and was sensitive to radiotherapy and chemotherapy. Gemcitabine plus platinum and paclitaxel plus platinum should be used as first-line treatment of PLELC, whereas the second-line treatment, if necessary, was always decided by the managing oncologist. The tumor stages and performance status were predictive in the prognosis of patients with PLELC.

Multiple studies have addressed the vital role of Nod-like receptor protein 3(NLRP3)/caspase-1/IL-1β signaling in asthma. Yet, the role of NLRP3/caspase-1 in toluene diisocyanate (TDI)-induced asthma is still obscure. The aim of this study is to investigate the role of the NLRP3/caspase-1 axis in TDI-induced asthma. Using an established murine model of TDI-induced asthma as described previously, we gave the asthmatic mice a highly selective NLRP3 inhibitor, MCC950, as well as the specific caspase-1 inhibitors VX-765 and Ac-YVAD-CHO for therapeutic purposes. Airway resistance was measured and bronchoalveolar lavage fluid was analyzed. Lungs were examined by histology, immunohistochemistry, Western blotting, and flow cytometry. TDI exposure elevated the expression of NLRP3 and caspase-1 that was coupled with increased airway hyperresponsiveness (AHR), neutrophil-dominated cell infiltration, pronounced goblet cell metaplasia, extensive collagen deposition, and increased TH2/TH17 responses. Both VX-765 and Ac-YVAD-CHO effectively inhibited the activation of caspase-1 in TDI-asthmatic mice that was accompanied by dramatic attenuation of AHR, airway inflammation, and airway remodeling, in addition to a decreased TH2 response and lower levels of IL-18 and IL-1β. MCC950 blocked the activation of NLRP3 and downregulated protein expression of caspase-1, IL-1β, and IL-18 in TDI-exposed mice. Furthermore, MCC950 remarkably alleviated AHR, airway inflammation, airway remodeling, and significantly suppressed TH2/TH17 responses. These findings suggested that blockade of the NLRP3/caspase-1 axis effectively prevents the progression of TDI-induced asthma and could be used as therapeutic targets for asthmatics.

We aimed to evaluate the alteration of diagnosis of individual expert and multidisciplinary discussion (MDD) team in the longitudinal diagnostic assessment of idiopathic interstitial pneumonia (IIP). The retrospective analysis included 56 patients diagnosed as IIP by The First Affiliated Hospital of Guangzhou Medical University with follow-up visits during Jan 1st to Aug 31st 2014. Each expert was provided information in a sequential manner and was asked to assign an individual diagnosis and an MDD diagnosis after group discussion. The level of agreement among individual experts and between different visits was calculated by kappa and the agreement between individual specialist and MDD team with different consensus levels was measured by weighted-kappa coefficients. Follow-up data changed the original clinical diagnosis and MDD diagnosis in 24.1% and 10.7% of all cases, respectively, and clinician and MDD consensus level in 55.4% and 25.0%, respectively. The diagnostic performance of individual clinicians or radiologist was closer to that of the MDD compared with the pathologist, and follow-up further increased the agreement. The longitudinal evaluation of patients with IIP improved the inter-observer agreement in a multidisciplinary team. The performance of individual clinicians or radiologist was approaching the accuracy of multidisciplinary team when provided with follow-up data.

Disruption of epithelial cell-cell junctions is essential for the initiation and perpetuation of airway inflammation in asthma. We’ve previously reported compromised epithelial barrier integrity in a toluene diisocyanate (TDI)-induced occupational asthma model. This study is aimed to explore the role of transient receptor potential vanilloid 4 (TRPV4) and transient receptor potential ankyrin 1 (TRPA1) in the dysfunction of adherens junctions in TDI-induced asthma. Mice were sensitized and challenged with TDI for a chemical-induced asthma model. Selective blockers of TRPV4 glycogen synthase kinase (GSK)2193874, 5 and 10 mg/kg) and TRPA1 (HC030031, 10 and 20 mg/kg) were intraperitoneally given to the mice. Immunohistochemistry revealed different expression pattern of TRPV4 and TRPA1 in lung. TDI exposure increased TRPV4 expression in the airway, which can be suppressed by GSK2193874, while treatment with neither TDI alone nor TDI together with HC030031 led to changes of TRPA1 expression in the lung. Blocking either TRPV4 or TRPA1 blunted TDI-induced airway hyperreactivity, airway neutrophilia and eosinophilia, as well as Th2 responses in a dose-dependent manner. At the same time, membrane levels of E-cadherin and β-catenin were significantly decreased after TDI inhalation, which were inhibited by GSK2193874 or HC030031. Moreover, GSK2193874 and HC030031 also suppressed serine phosphorylation of glycogen synthase kinase 3β, tyrosine phosphorylation of β-catenin, as well as activation and nuclear transport of β-catenin in mice sensitized and challenged with TDI. Our study suggested that both TRPV4 and TRPA1 contribute critically to E-cadherin and β-catenin dysfunction in TDI-induced asthma, proposing novel therapeutic targets for asthma.

Introduction: Noninvasive ventilation (NIV) has been used to alleviate hypoxemia and dyspnea, but there is no consensus on the application of NIV in patients with coronavirus disease 2019 (COVID-19). Some staff use NIV as the rescue therapy which might lead to the adverse outcomes. This study was to identify early factors associated with intubation to help the medical staff select appropriate patients for receiving NIV treatment.Methods: Patients with laboratory-confirmed COVID-19 who were treated with NIV in emergency department or ICU of the Third People's Hospital (the only designated hospital for treating COVID-19 in Shenzhen) between January 1 and August 31, 2020, were retrospectively analyzed.Results: Thirty-nine patients with COVID-19 treated with NIV were included; of them, 16 (41%) received endotracheal intubation and 3 (8%) died. Significant differences were observed between intubated and non-intubated patients in PaO2/FiO2 before NIV initiation, hospitalization duration, NIV as the rescue therapy, and PaO2/FiO2 of ≤200 mmHg after 1–2 h of NIV initiation. Notably, 1–2 h after NIV initiation, a PaO2/FiO2 of ≤200 mmHg (odds ratio [OR], 9.35; 95% confidence interval [CI], 1.84–47.62; P = 0.007) and NIV as the rescue therapy (OR, 5.43; 95% CI, 1.09–27.12; P = 0.039) were the risk factors for intubation.Conclusions: In patients with COVID-19-related acute hypoxemic respiratory failure receiving NIV, close attention should be paid to PaO2/FiO2 after 1–2 h of NIV initiation. Also, using NIV as rescue therapy should draw our awareness that it might delay escalation of respiratory support and lead to adverse outcomes.

Background Differences between adult patients with severe early-onset and late-onset asthma have not been well studied. Objectives To determine the phenotypic distinction regarding age at onset in patients with severe asthma. Methods The present study enrolled thirty-two patients with severe early-onset (onset age 12 years) asthma. Severe asthma was defined according to Global Initiative for Asthma criteria. The clinical, spirometric, and laboratory parameters were collected for group comparisons. Results Among the 64 patients included (mean age, 46.22 ± 13.90 years; 53.1% male), the mean percent of predicted forced expiratory volume in 1 s (FEV1) was 68.43 ± 20.55%. Patients with severe early-onset asthma had a younger age, longer duration of asthma, higher rate of family history, and better small-airway function (MEF25% and MMEF75/25%) compared with severe late-onset asthma. Furthermore, levels of serum IL-17 and sputum neutrophil percentage were significantly higher for patients with severe early-onset asthma (P = 0.016, 0.033, respectively). Multiple logistic regression analysis revealed that increased serum IL-17 (odds ratio = 1.065, P = 0.016) was independently associated with severe early-onset asthma. The combination of serum IL-17 and sputum neutrophil percentage yielded a sensitivity of 80.0% and a specificity of 86.7% for identifying patients with severe early-onset asthma. Conclusions Patients with severe early-onset asthma exhibit elevated levels of serum IL-17 and sputum neutrophil percentage, suggesting a potential role in the pathogenesis of severe early-onset phenotype.

Jie Li, Chen Qiu, Peng Xu, Yongzhen Lu, Rongchang Chen Key Laboratory of Shenzhen Respiratory Disease, Shenzhen Institute of Respiratory Disease, Shenzhen People’s Hospital (The First Affiliated Hospital of Southern University of Science and Technology, The Second Clinical Medical College of Jinan University), Shenzhen, Guangdong, People’s Republic of ChinaCorrespondence: Jie Li; Rongchang ChenKey Laboratory of Shenzhen Respiratory Disease, Shenzhen Institute of Respiratory Disease, Shenzhen People’s Hospital (The First Affiliated Hospital of Southern University of Science and Technology, The Second Clinical Medical College of Jinan University), Shenzhen, Guangdong, People’s Republic of ChinaEmail ljszry2018@126.com; chenrc@vip.163.comObjective: The present study was conducted to elucidate the protective effect of Casticin against chronic obstructive pulmonary disease (COPD) in rats.Methods: The COPD in rats was induced by the controlled cigarette smoke, and CST (10, 20, and 30 mg/kg) was injected into the cigarette-smoke exposed rats. Blood was taken from the abdominal vein and centrifuged (1500×g, 4°C, 15min); plasma was collected and used for the determination of various biochemical parameters.Results: The results of the study suggested that CST significantly improved the lung functions of the rats in a dose-dependent manner. It also causes a reduction of white blood cells, neutrophils, and macrophages in BALF of rats. The plasma level of leptin and C-reactive protein together with pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) were also significantly restored to near to normal in CST-treated group. In Western blot analysis, CST causes significant inhibition of the NF-ĸB and iNOS pathway.Conclusion: Our study demonstrated that the CST protects lungs against COPD via improving lung functions and inhibition of oxidative stress and inflammation.Keywords: COPD, Casticin, smoke, inflammation, oxidative stress, NF-ĸB

Coronavirus disease (COVID-19) is an emerging viral infection that is rapidly spreading across the globe. SARS-CoV-2 belongs to the same coronavirus class that caused respiratory illnesses such as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). During the SARS and MERS outbreaks, many frontline healthcare workers were infected when performing high-risk aerosol-generating medical procedures as well as when providing basic patient care. Similarly, COVID-19 disease has been reported to infect healthcare workers at a rate of ~ 3% of cases treated in the USA. In this review, we conducted an extensive literature search to develop practical strategies that can be implemented when providing respiratory treatments to COVID-19 patients, with the aim to help prevent nosocomial transmission to the frontline workers.

Background Diabetic cardiomyopathy (DCM) is a serious complication of diabetes that can lead to significant mortality. Cyclocarya paliurus is a tree, the leaves of which are often utilized to prevent and treat diabetes mellitus. Whether C. paliurus leaves can prevent or treat DCM, however, it remains to be formally assessed. The present study was therefore designed to assess the ability of C. paliurus to protect against DCM in db/db mice. Methods Male wild-type (WT) and db/db mice were administered C. paliurus ethanol leaf extracts (ECL) or appropriate vehicle controls daily via gavage, and levels of blood glucose in treated animals were assessed on a weekly basis. After a 10-week treatment, the levels of cardiac troponin I (cTn-I), lactate dehydrogenase (LDH), creatine kinase MB (CK-MB), aspartate transaminase (AST), total triglycerides (TG), and total cholesterol (TC) in serum were measured. Activities of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) and the levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 in heart tissues were detected. Hematoxylin-eosin (HE) and Masson staining were conducted. The protein expression that related with oxidative stress and inflammatory reaction was evaluated by Western blotting. Results Compared with WT mice, the TG, TC, and blood glucose levels in db/db mice increased significantly, which were reduced by ECL treatment. Compared with WT mice, the levels of LDH, CK-MB, AST, and cTn-I in serum and MDA in heart tissues of db/db mice increased significantly. Activities of SOD, GSH-Px, and CAT in heart tissues of db/db mice decreased significantly. The levels of inflammatory cytokines (TNF-α, IL-1β, and IL-6) in heart tissues of db/db mice increased remarkably. However, ECL treatment improved the above pathological changes significantly. ECL alleviated pathological injury and fibrosis in heart tissues of mice. Western blotting showed that ECL increased Bcl-2 level and decreased Bax, cle-caspase-3, and cle-caspase-9 expression. Furthermore, ECL inhibited NF-κB nuclear translocation and increased PI3K and p-Akt expressions. Conclusion Our results indicate that ECL treatment can markedly reduce pathological cardiac damage in db/db mice through antiapoptotic, antifibrotic, and anti-inflammatory mechanisms. Specifically, this extract was able to suppress NF-κB activation via the PI3K/Akt signaling pathway. Given its diverse activities and lack of significant side effects, ECL may thus have therapeutic value for the treatment of DCM.

Summary COVID-19, caused by SARS-CoV-2, is a virulent pneumonia, with >4,000,000 confirmed cases worldwide and >290,000 deaths as of May 15, 2020. It is critical that vaccines and therapeutics be developed very rapidly. Mice, the ideal animal for assessing such interventions, are resistant to SARS-CoV-2. Here, we overcome this difficulty by exogenous delivery of human ACE2 with a replication-deficient adenovirus (Ad5-hACE2). Ad5-hACE2-sensitized mice developed pneumonia characterized by weight loss, severe pulmonary pathology, and high-titer virus replication in lungs. Type I interferon, T cells and, most importantly, signal transducer and activator of transcription 1 (STAT1) are critical for virus clearance and disease resolution in these mice. Ad5-hACE2-transduced mice enabled rapid assessments of a vaccine candidate, of human convalescent plasma, and of two antiviral therapies (poly I:C and remdesivir). In summary, we describe a murine model of broad and immediate utility to investigate COVID-19 pathogenesis, and to evaluate new therapies and vaccines., An adenoviral transduction-based mouse model that can be infected with SARS-CoV-2 provides a tool to understand host factors involved in viral infection and clearance as well as potential therapeutic modalities.

Background Autoimmunity plays a role in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, the autoantibody responses and their clinical correlation patterns in COPD patients with and without airway eosinophilic inflammation are unknown. The aim of this study was to compare the autoantibody profiles and their clinical associations in stable COPD patients, stratified by airway inflammatory phenotypes. Methods Matched sputum and serum, obtained from 62 stable COPD patients and 14 age-matched controls, were assayed for the presence of IgG and IgM antibodies against 13 autoantigens using protein array. A sputum eosinophil count ≥3% was used as cut-off value to stratify COPD patients into eosinophilic and non-eosinophilic groups. Correlation network analysis was used to evaluate the correlation patterns among autoantibody and clinical variables in each group. Results There were no significant differences of clinical parameters and autoantibody levels between the two COPD groups. In non-eosinophilic COPD, sputum anti-CytochromeC_IgG and anti-Aggrecan_IgM were significantly higher than those in healthy controls, and prior exacerbation was positively associated with lung function and sputum anti-Collagen-IV_IgG. While in eosinophilic COPD, sputum/serum anti-heat shock protein (HSP)47_IgG, serum anti-HSP70_IgG and serum anti-Amyloid-beta_IgG were significantly lower than those in healthy controls, and no significant correlation between prior exacerbations and lung function was found. Differences were also observed in network hubs, with the network for non-eosinophilic COPD possessing 9 hubs comprising two lung function parameters and seven autoantibodies, compared with eosinophilic COPD possessing 12 hubs all comprising autoantibodies. Conclusions Autoantibody responses were heterogeneous and differentially correlated with the exacerbation risk and other clinical parameters in COPD patients of different inflammatory phenotypes. These findings provide useful insight into the need for personalized management for preventing COPD exacerbations.

Identification of risk factors for antibiotic treatment failure is urgently needed in acute exacerbations of chronic obstructive pulmonary disease (AECOPD). Here we investigated the relationship between sputum microbiome and clinical outcome of choice of initial antibiotics during hospitalization of AECOPD patients. Sputum samples of 41 AECOPD patients and 26 healthy controls were collected from Guangzhou Medical University, China. Samples were processed for 16S rRNA gene-based microbiome profiling. Thirty patients recovered with initial antibiotic treatment (antibiotic success or AS), while 11 patients showed poor outcome (antibiotic failure or AF). Substantial differences in microbiome were observed in AF versus AS patients and healthy controls. There was significantly decreased alpha diversity and increased relative abundances of Pseudomonas, Achromobacter, Stenotrophomonas and Ralstonia in AF patients. Conversely, Prevotella, Peptostreptococcus, Leptotrichia and Selenomonas were depleted. The prevalence of Selenomonas was markedly reduced in AF versus AS patients (9.1 % versus 60.0 %, P = 0.004). The AF patients with similar microbiome profiles in general responded well to the same new antibiotics in the adjusted therapy, indicating sputum microbiome may help guide the adjustment of antibiotics. Random forest analysis identified five microbiome operational taxonomic units together with C-reactive protein, procalcitonin and blood neutrophil count showing best predictability for antibiotic treatment outcome (area under curve 0.885). Functional inference revealed an enrichment of microbial genes in xenobiotic metabolism and antimicrobial resistance in AF patients, whereas genes in DNA repair and amino acid metabolism were depleted. Sputum microbiome may determine the clinical outcome of initial antibiotic treatment and be considered in the risk management of antibiotics in AECOPD.

Background Patients with cervical spinal cord injuries (CSCIs) may be required to undergo tracheostomy. However, in patients undergoing anterior cervical fusion (ACF), percutaneous dilational tracheostomy (PDT) may be delayed given the risk of cross-contamination. We aimed to evaluate the risk of surgical site infection (SSI) in early PDT in patients with traumatic CSCI after ACF. Methods All trauma patients admitted to the intensive care unit from 2008 to 2018 were retrospectively analyzed. Patients with CSCIs who underwent both ACF and PDT were identified, with or without posterior cervical fusion. Cases were classified as having undergone early PDT (≤4 days after ACF) versus late PDT (>4 days after ACF). Propensity scores were matched, and outcomes were compared between matched groups to reduce confounding by indication. Results From a total of 133 enrolled patients, a well-balanced propensity-matched cohort of 68 patients was defined. On the basis of the comparison of outcomes after matching, no significant difference in SSI was observed between both groups. There was no patient with SSI in the early PDT group (0%), whereas there were 2 SSI patients (5.9%) in the late PDT group (P = 0.493): The tracheostomy site was involved in 1, and the posterior approach site was involved in the other. Early PDT was associated with a shorter duration of mechanical ventilation (P = 0.042). There were no significant differences in the length of intensive care unit stay and hospital mortality between groups. Conclusions Early PDT within 4 days after ACF did not increase the risk of SSI compared with late PDT in patients with traumatic CSCIs.

Background Epstein-Barr virus (EBV) is implicated in the progression of chronic obstructive pulmonary disease. We aimed to determine whether EBV correlates with bronchiectasis severity, exacerbations, and progression. Methods We collected induced sputum in healthy controls and spontaneous sputum at 3–6-month intervals and onset of exacerbations in bronchiectasis patients between March 2017 and October 2018. EBV DNA was detected with quantitative polymerase chain reaction. Results We collected 442 sputum samples from 108 bronchiectasis patients and 50 induced sputum samples from 50 healthy controls. When stable, bronchiectasis patients yielded higher detection rates of EBV DNA (48.1% vs 20.0%; P = .001), but not viral loads (mean log10 load, 4.45 vs 4.76; P = .266), compared with controls; 64.9% of patients yielded consistent detection status between 2 consecutive stable visits. Neither detection rate (40.8% vs 48.1%; P = .393) nor load (mean log10 load, 4.34 vs 4.45; P = .580) differed between the onset of exacerbations and stable visits, nor between exacerbations and convalescence. Neither detection status nor viral loads correlated with bronchiectasis severity. EBV loads correlated negatively with sputum interleukin-1β (P = .002), CXC motif chemokine-8 (P = .008), and tumor necrosis factor–α levels (P = .005). Patients initially detected with, or repeatedly detected with, EBV DNA had significantly faster lung function decline and shorter time to next exacerbations (both P < .05) than those without. Detection of EBV DNA was unrelated to influenza virus and opportunistic bacteria (all P > .05). The EBV strains detected in bronchiectasis patients were phylogenetically homologous. Conclusions Patients with detection of EBV DNA have a shorter time to bronchiectasis exacerbations. EBV may contribute to bronchiectasis progression., The role of chronic viral infections in bronchiectasis is unclear. In this prospective study, we summarize the association between viral loads or detection rate and the clinical status as well as inflammatory response of bronchiectasis.

Brian J Lipworth,1 David J Collier,2 Yasuhiro Gon,3 Nanshan Zhong,4 Koichi Nishi,5 Rongchang Chen,4 Samir Arora,6 Andrea Maes,7 Shahid Siddiqui,8 Colin Reisner,7,8 Ubaldo J Martin8 1Scottish Centre for Respiratory Research, Ninewells Hospital, University of Dundee, Dundee, Scotland, UK; 2William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK; 3Itabashi Hospital, Nihon University School of Medicine, Itabashi, Tokyo, Japan; 4Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Diseases, National Clinical Research Center of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 5Ishikawa Prefectural Central Hospital, Kanazawa, Ishikawa, Japan; 6Aventiv Research Inc., Columbus, OH, USA; 7Pearl – a member of the AstraZeneca group, Morristown, NJ, USA; 8AstraZeneca, Gaithersburg, MD, USA Background: COPD is a major global cause of mortality and morbidity. PINNACLE-4 evaluated the efficacy and safety of GFF MDI (glycopyrrolate/formoterol fumarate metered dose inhaler) in patients from Asia, Europe, and the USA with moderate-to-very severe COPD. Methods: In this double-blind, placebo-controlled, Phase III study, patients were randomized to treatment with GFF MDI 18/9.6µg, glycopyrrolate (GP) MDI 18µg, formoterol fumarate (FF) MDI 9.6µg, or placebo MDI (all twice daily) for 24weeks. Lung function, patient-reported outcomes (symptoms and health-related quality of life), and safety were assessed. Results: Of the 1,756 patients randomized, 1,740 patients were included in the intent-to-treat population (mean age 64.2years, 74.1% male, and 40.2% Asian). GFF MDI significantly improved morning predose trough FEV1 at Week 24 (primary endpoint) vs placebo MDI, GP MDI, and FF MDI (least squares mean differences: 165, 59, and 72mL, respectively; all P

Bronchiectasis is a debilitating chronic inflammatory airway disease which arises from multiple etiologies. The interplay among the etiology, altered microenvironment and defective host-defense may have predisposed to recurrent chest infections of pathogens (1,2) that correlate with bronchiectasis exacerbations and increased mortality.

Background: Interstitial lung disease (ILD) is a slowly progressing fatal fibrotic lung disease with a widely variable clinical course and a poor prognosis. Clinicians and patients would benefit from a highly efficient and accurate predictor for ILD. The purpose of this study was to evaluate whether blood biomarkers can predict ILD progression. Methods: In this study, 85 patients diagnosed as having ILD at the Guangzhou Institute of Respiratory Health participated, including 20 patients with idiopathic pulmonary fibrosis (IPF). During the mean follow-up time of 12 months, every patient was examined during four or five visits in our center. Serum samples were collected at baseline, and after 1, 2, 6, and 12 months and tested for the Klebs von den Lungen-6 (KL-6) concentration. Dynamic fluctuations in this biomarker concentration were examined using a logistic regression model to see if they reflected the progression of ILD. Results: The baseline levels of serum KL-6 in the ILD patients were significantly increased compared to healthy controls. Serum KL-6 levels were significantly elevated in patients with progression of disease (1,985.2±1,497.8 vs . 1,387.6±1,313.1 µg/mL; P Conclusions: Serum levels of KL-6 were elevated in ILD patients with severe respiratory function compared to those without. The rate of poor prognosis and mortality was associated with increased biomarker concentrations. Sequential measurements of biomarkers could be valuable in disease monitoring and evaluations in clinical management.

This study correlated serial blood transcriptomic profiles of patients with avian influenza A (H7N9) virus infection with clinical data of patients. Biologically significant transcriptomic profiles associated with blood oxygenation and viral load in the lower respiratory tract were defined., Background Avian influenza A (H7N9) viruses emerged in China in 2013 and caused zoonotic disease associated with a case-fatality ratio of over 30%. Transcriptional profiles in peripheral blood reflect host responses and can help to elucidate disease pathogenesis. Methods We correlated serial blood transcriptomic profiles of patients with avian influenza A (H7N9) virus infection and determined the biological significances from the analysis. Results We found that specific gene expression profiles in the blood were strongly correlated with the Pao 2/Fio 2 ratio and viral load in the lower respiratory tract. Cell cycle and leukocyte-related immunity were activated at the acute stage of the infection while T-cell functions and various metabolic processes were associated with the recovery phase of the illness. A transition from systemic innate to adaptive immunity was found. Conclusions We developed a novel approach for transcriptomic analysis to identify key host responses that were strongly correlated with specific clinical and virologic parameters in patients with H7N9 infection.

Lili Guan,1,* Jiawen Xu,1,* Weiliang Wu,1,* Jianhua Chen,1,* Xiaoying Li,2,* Bingpeng Guo,1 Yuqiong Yang,1 Yating Huo,1 Luqian Zhou,1 Rongchang Chen1 1State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China; 2The First Affiliated Hospital, School of Clinical Medicine of Guangdong Pharmaceutical University, Guangzhou, China *These authors contributed equally to this work Purpose: Patients with advanced-stage COPD often experience severe hypoxemia. Treatment with long-term oxygen therapy (LTOT) may relieve patients’ symptoms and increase survival. As COPD is incurable, improving patients’ health-related quality of life is important. The Chinese version of the Severe Respiratory Insufficiency Questionnaire (SRI) is valid for patients with hypercapnic COPD undergoing noninvasive positive airway pressure ventilation at home. However, the reliability and validity of the Chinese SRI for patients with COPD undergoing LTOT have not been investigated. Patients and methods: We analyzed reliability using Cronbach’s α coefficient. Construct validity was assessed with principal, exploratory, and confirmatory factor analysis. Concurrent validity was evaluated through the correlation between SRI domains and Chronic Respiratory Disease Questionnaire (CRQ) domains. Content validity was assessed by calculating the correlation between each SRI item score and the total score for the relevant domain. Results: In total, 161 patients participated in this study. The Cronbach’s α coefficient for all SRI domains was >0.7, except for the attendant symptoms and sleep domain. Exploratory and confirmatory factor analysis showed a good model fit for each domain, but the factors extracted from each domain were correlated. SRI and CRQ domains correlated well with respect to similar aspects of health-related quality of life, indicating good concurrent validity. Content validity was indirectly shown by a good correlation between each item score and the total score of the relevant domain. Conclusion: The Chinese version of the SRI has a good reliability and validity for patients with COPD undergoing LTOT in China. Keywords: severe respiratory insufficiency questionnaire, long-term oxygen therapy, health-related quality of life, chronic obstructive pulmonary disease

Yating Huo, Lili Guan, Jiawen Xu, Luqian Zhou, Rongchang Chen State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China Background: Airway remodeling is an important feature of chronic obstructive pulmonary disease (COPD) that is associated with disease severity and irreversible airflow limitation. An extensive alteration of the extracellular matrix (ECM) surrounding the airway smooth muscle (ASM) bundle is one of the pathological manifestations of airway remodeling, which contributes to the decline in lung function. Tiotropium, a long-acting inhaled muscarinic receptor antagonist, has been confirmed to play a role in preventing airway remodeling including ECM deposition beyond bronchodilation in vivo, but the relationship between ASM cell (ASMC) relaxation and ECM production remains unclear. Purpose: In this study, we attempted to investigate the influence of tiotropium on ECM production by ASMCs and the underlying mechanism. Methods: Tiotropium was added 30 minutes before the addition of methacholine to primary cultured human ASMCs. Protein expression was analylized by Western Blot and mRNA abundance was determined by real-time PCR. Results: We found that tiotropium reduced collagen I protein expression, and the mRNA abundance of collagen I, fibronectin, and versican. β-catenin signaling was inactivated by inhibiting glycogen synthase kinase 3β (GSK3β) phosphorylation in this process. Tiotropum inhibited the amount of active β-catenin and its transcription activity. Furthermore, overexpression of active β-catenin by adenoviruses carrying the S33Y mutant resisted the suppressive effect of tiotropium on collagen I protein expression. However, silencing β-catenin by specific small interfering RNA enhanced the negative effect of tiotropium. Conclusion: These findings suggest that relaxation of ASMCs by tiotropium can prevent ECM production through β-catenin signaling. Keywords: tiotropium, collagen I, β-catenin, airway smooth muscle cell

Background: Defective airway host-defense (e.g., altered mucus properties, ciliary defects) contributes to the pathogenesis of bronchiectasis. This study aims to determine whether genetic mutations associated with defective airway host-defense are implicated in the pathogenesis of bronchiectasis. Methods: Based on the systematic screening of 32 frequently reported bronchiectasis-associated genes, we performed next-generation sequencing (NGS) on peripheral blood samples from 192 bronchiectasis patients and 100 healthy subjects. The variant distribution frequency and pathogenicity of mutations were analyzed. Results: We identified 162 rare variants in 192 bronchiectasis patients, and 85 rare variants among 100 healthy subjects. Among bronchiectasis patients, 25 (15.4%), 117 (72.2%) and 18 (11.1%) rare variants were associated with cystic fibrosis transmembrane receptor ( CFTR ), epithelial sodium channel, and primary ciliary dyskinesia genes, respectively. Biallelic CFTR variants were detected in four bronchiectasis patients but none of the healthy subjects. Carriers of homozygous p.M470 plus at least one CFTR rare variant were detected in 6.3% of bronchiectasis patients (n=12) and in 1.0% of healthy subjects (n=1, P=0.039). Twenty-six patients (16 with idiopathic and 6 with post-infectious bronchiectasis) harbored biallelic variants. Bronchiectasis patients with biallelic DNAH5 variants, or biallelic CFTR variants plus an epithelial sodium channel variant, tended to have greater disease severity. Conclusions: Genetic mutations leading to impaired host-defense might have implicated in the pathogenesis of bronchiectasis. Genetic screening may be a useful tool for unraveling the underlying causes of bronchiectasis, and offers molecular information which is complementary to conventional etiologic assessment for bronchiectasis.

Background and aims Pseudomonas aeruginosa (PA) is the most common pathogen in bronchiectasis and frequently develops resistance to multiple classes of antibiotics, but little is known about the clinical impacts of PA-resistant (PA-R) isolates on bronchiectasis. We, therefore, investigated the prevalence, risk factors and prognostic implications of PA-R isolates in hospitalized bronchiectasis patients. Patients and methods Between June 2011 and July 2016, data from adult bronchiectasis patients isolated with PA at the First Affiliated Hospital of Zhengzhou University were retrospectively analyzed. PA was classified as PA-R in case antibiogram demonstrated resistance on at least one occasion. Results Seven hundred forty-seven bronchiectasis patients were assessed. Of these, 147 (19.7%) had PA isolate in the sputum or bronchoscopic culture. PA-R and PA-sensitive accounted for 88 (59.9%) and 59 (31.1%) patients, respectively. In multivariate model, factors associated with PA-R isolate in bronchiectasis included prior exposure to antibiotics (odds ratio [OR] =6.18), three or more exacerbations in the previous year (OR =2.81), higher modified Medical Research Council dyspnea scores (OR =1.93) and greater radiologic severity (OR =1.15). During follow-up (median: 26 months; interquartile range: 6-59 months), 36 patients died, of whom 24 (66.7%) had PA-R isolate at baseline. However, PA-R isolate was not associated with greater all-cause mortality in bronchiectasis. Conclusion PA-R infection is common among bronchiectasis patients, mainly determined by prior exposure to antibiotics, frequent exacerbations, more pronounced dyspnea and more severe radiologic involvement. However, PA-R isolate is not an independent risk factor for all-cause mortality in bronchiectasis.

Monochromatic-beam-based dynamic X-ray computed microtomography (CT) was developed to observe evolution of microstructure inside samples. However, the low flux density results in low efficiency in data collection. To increase efficiency, reducing the number of projections should be a practical solution. However, it has disadvantages of low image reconstruction quality using the traditional filtered back projection (FBP) algorithm. In this study, an iterative reconstruction method using an ordered subset expectation maximization-total variation (OSEM-TV) algorithm was employed to address and solve this problem. The simulated results demonstrated that normalized mean square error of the image slices reconstructed by the OSEM-TV algorithm was about 1/4 of that by FBP. Experimental results also demonstrated that the density resolution of OSEM-TV was high enough to resolve different materials with the number of projections less than 100. As a result, with the introduction of OSEM-TV, the monochromatic-beam-based dynamic X-ray microtomography is potentially practicable for the quantitative and non-destructive analysis to the evolution of microstructure with acceptable efficiency in data collection and reconstructed image quality.

Weiliang Wu,1,* Lili Guan,1,* Xiaoying Li,2,* Lin Lin,1 Bingpeng Guo,1 Yuqiong Yang,1 Zhenyu Liang,1 Fengyan Wang,1 Luqian Zhou,1 Rongchang Chen1 1Guangzhou Institute of Respiratory Disease, State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, 2Department of Respiratory Medicine, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China *These authors contributed equally to this work Purpose: To evaluate the compatibility and correlation between noninvasive surface respiratory electromyography and invasive transesophageal diaphragmatic electromyography measurements as facilitating indicators of neural respiratory drive (NRD) evaluation during treadmill exercise.Patients and methods: Transesophageal diaphragmatic electromyogram activity (EMGdi,es) and surface inspiratory electromyogram (EMG) activity, including surface diaphragmatic EMG activity (EMGdi,sur), surface parasternal intercostal muscle EMG activity (EMGpara), and surface sternocleidomastoid EMG activity (EMGsc), were detected simultaneously during increasing exercise capacity in 20 stable patients with COPD. EMGdi,es, EMGdi,sur, EMGpara, and EMGsc were quantified using the root mean square (RMS) and were represented as RMSdi,es, RMSdi,sur, RMSpara, and RMSsc, respectively.Results: There was a significant association between EMGdi,es and EMGdi,sur (r=0.966, p

We conducted a randomised controlled trial to assess the effects of daily breathing pattern changes to stable patients with COPD excluding the confounding factors of inspiratory muscle mobilization, by ensuring the load intensities of two inspiratory training devices were equal.Sixty patients with COPD were randomised to three groups: resistive-IMT group (T-IMT, 21 patients), threshold-IMT (R-IMT, 19 patients), and a control group (20 patients). Inspiratory load intensity for both methods was set at 60% of maximal inspiratory pressure (MIP), a measure of inspiratory muscle strength, which, along with health-related quality of life (HRQoL), degree of dyspnoea, and exercise capacity, were conducted before and after 8 weeks of daily IMT.At 8 weeks, there was no significantly difference of MIP between the R- and T-IMT groups (P 0.05). Chronic Respiratory Disease Questionnaire and Transition Dyspnea Index scores improved significantly after each training program compared with controls (P 0.05), and R-IMT was significant better (P 0.05). R-IMT was better than T-IMT in performance of exercise (P 0.05).In summary, in clinically stable patients with COPD, 8 weeks of R-IMT was superior to 8 weeks of equal-intensity T-IMT in improving HRQoL, degree of dyspnoea, and exercise capacity.

Anxiety and depression might frequently affect bronchiectasis patients, but data in Chinese patients, including their association with disease severity assessed with Bronchiectasis Severity Index (BSI) and FACED score, are limited.To investigate the rate, risk factors, association with disease severity and impact of anxiety and depression on health-related quality of life (HRQoL) in adult outpatients with steady-state bronchiectasis.This cross-sectional study included 163 outpatients (102 females; mean age, 45.8 years) and 80 healthy subjects (47 females; mean age, 47.1 years). Demographic, clinical indices, radiology, spirometry, aetiology, sputum bacteriology, Hospital Anxiety and Depression Scales (HADS), Pittsburgh Sleep Quality Index (PSQI) and St. George's Respiratory Questionnaire (SGRQ) were assessed.Patients with steady-state bronchiectasis had a higher rate of depression (HADS-depression7) (30.1% vs 10.0%, P = .001) and anxiety (HADS-anxiety7; 39.9% vs 6.3%, P .001) compared with healthy subjects. Notably, no significant differences in the rate of anxiety and depression were found across different disease severity, assessed with BSI and FACED score (all P .05). In multivariate model, factors associated with anxiety included younger age (OR = 1.05), education below college graduate (OR = 4.55) and sleep disturbance (PSQI ≥ 6; OR = 2.95); whereas sleep disturbance was the sole factor associated with depression (OR = 5.98). Patients with either depression or anxiety had more markedly impaired HRQoL affecting most domains than those without.Anxiety and depression are common in bronchiectasis and can negatively affect HRQoL, but not related to disease severity. Prompt assessment and treatment of these mental disorders, regardless of bronchiectasis severity, are advocated and might improve HRQoL.

Background Cycle ergometer training (CET) has been shown to improve exercise performance of the quadriceps muscles in patients with COPD, and inspiratory muscle training (IMT) may improve the pressure-generating capacity of the inspiratory muscles. However, the effects of combined CET and IMT remain unclear and there is a lack of comprehensive assessment. Materials and methods Eighty-one patients with COPD were randomly allocated to three groups: 28 received 8 weeks of CET + IMT (combined training group), 27 received 8 weeks of CET alone (CET group), and 26 only received 8 weeks of free walking (control group). Comprehensive assessment including respiratory muscle strength, exercise capacity, pulmonary function, dyspnea, quality of life, emotional status, nutritional status, and body mass index, airflow obstruction, and exercise capacity index were measured before and after the pulmonary rehabilitation program. Results Respiratory muscle strength, exercise capacity, inspiratory capacity, dyspnea, quality of life, depression and anxiety, and nutritional status were all improved in the combined training and CET groups when compared with that in the control group (P0.05). Patients with weakened respiratory muscles in the combined training group derived no greater benefit than those without respiratory muscle weakness (P>0.05). There were no significant differences in these indices between the patients with malnutrition and normal nutrition after pulmonary rehabilitation program (P>0.05). Conclusion Combined training is more effective than CET alone for increasing inspiratory muscle strength. IMT may not be useful when combined with CET in patients with weakened inspiratory muscles. Nutritional status had slight impact on the effects of pulmonary rehabilitation. A comprehensive assessment approach can be more objective to evaluate the effects of combined CET and IMT., Video abstract

Background: Mucin 1 (MUC1) is a membrane tethered protein on airway epithelial cells. This protein is upregulated and plays an important anti-inflammatory role during acute lung inflammation. However, the relationship between sputum MUC1 level and acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is unknown. Methods: The levels of MUC1, IL-8, and TNF-α in induced sputum from 78 COPD patients were assessed by ELISA. The association between COPD exacerbation and MUC1 fragment levels was analyzed. An acute airway inflammation mouse model was established by intranasal LPS inhalation. The expression of Muc1 in lung and the levels of Muc1, TNF-α and KC in BAL fluid from mice were determined with western blotting and ELISA, respectively. Results: Higher levels of MUC1 membrane-tethered (CT) and extracellular (EC) fragments, cytokines TNF-α and IL-8, more leucocyte and neutrophil counts were found in sputum from COPD patients in acute than in remission phase. Linear regression analysis confirmed that the level of sputum MUC1 CT fragment is positively correlated with sputum neutrophil number and patients’ age; whereas the sputum EC fragment level is correlated inversely with FEV1/FVC value and positively with patients’ age. Inhalation of lipopolysaccharide (LPS) induced acute lung inflammation in mice which exhibited increased levels of Muc1 CT fragment in lung and only Muc1 EC fragment increase in BAL fluid. Conclusions: Unlike pure bacterial induced lung inflammation, both sputum MUC1 CT and EC fragments are increased during acute exacerbation of COPD. The clinical benefits from measuring the changes of various sputum MUC1 fragments in AECOPD need to be elucidated in future studies.

Luqian Zhou,1,* Xiaoying Li,1,* Lili Guan,1,* Jianhua Chen,1 Bingpeng Guo,1 Weiliang Wu,1 Yating Huo,1 Ziqing Zhou,1 Zhenyu Liang,1 Yuqi Zhou,2 Jie Tan,3 Xin Chen,4 Yuanlin Song,5 Rongchang Chen1 1Department of Respiratory Medicine, State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, 2Department of Respiratory Medicine, The Third Affiliated Hospital of Sun-Yat Sen University, 3Department of Respiratory Medicine, The First Affiliated Hospital, School of Clinical Medicine of Guangzhou Pharmaceutical University, 4Department of Respiratory Medicine, Zhujiang Hospital of Southern Medical University, Guangzhou, 5Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China *These authors contributed equally to this work Background: The benefits of noninvasive positive pressure ventilation (NPPV) in patients with hypercapnic COPD are controversial. It is presumed that methodology and appropriate use of NIV ventilator might be crucial for the outcomes. With the new built-in software, the performance of NIV can be monitored at home, which can guarantee the compliance and appropriate use. This study investigated effects of home use of NIV in hypercapnia in COPD patients using the NIV ventilator with built-in software for monitoring. Methods: The current multicenter prospective, randomized, controlled trial enrolled patients with stable GOLD stages III and IV hypercapnic COPD. Patients were randomly assigned via a computer-generated randomization sequence, with a block size of four patients, to continue optimized treatment (control group) or to receive additional NPPV (intervention group) for 3months. The primary outcome was arterial carbon dioxide pressure (PaCO2). Data were derived from built-in software and analyzed every 4weeks. Analysis was carried out with the intention to treat. This study is registered with ClinicalTrials.gov, number NCT02499718. Results: Patients were recruited from 20 respiratory units in China from October 1, 2015, and recruitment was terminated with a record of the vital statistics on May 31, 2016. A total of 115 patients were randomly assigned to the NPPV group (n=57) or the control group (n=58). Patients complied well with NPPV therapy (mean [± standard deviation] day use 5.6±1.4h). The mean estimation of leaks was 37.99±13.71L/min. The changes in PaCO2 (-10.41±0.97 vs -4.32±0.68mmHg, P=0.03) and 6-min walk distance (6MWD) (38.2% vs 18.2%,P=0.02) were statistically significant in the NPPV group versus the control group. COPD assessment test (CAT) showed a positive trend (P=0.06) in favor of the NPPV group. Pulmonary function and dyspnea were not different between groups. Conclusion: Ventilators equipped with built-in software provided methodology for monitoring NIV use at home, which could facilitate the improvement of compliance and quality control of NIV use. It was shown that three months use of NIV at home could reduce the PaCO2 and improve exercise tolerance (6MWD) in chronic hypercapnic COPD patients. Keywords: COPD, noninvasive positive pressure ventilation, long-term oxygen therapy, chronic respiratory failure, built-in software

Resumen Este resumen ejecutivo del Informe de 2017 de la Global Strategy for the Diagnosis, Management, and Prevention of COPD (GOLD) se basa principalmente en las modificaciones y novedades del documento anterior. Los cambios mas destacados incluyen: a) se ha diferenciado entre la exploracion espirometrica y la de los sintomas para evaluar la enfermedad pulmonar obstructiva cronica (EPOC). En la propuesta actual, los grupos ABCD se refieren exclusivamente a sintomas y antecedentes de exacerbaciones de los pacientes; b) para cada uno de los grupos, se proponen estrategias de intensificacion de los tratamientos farmacologicos; c) se introduce el concepto de reduccion escalonada de la terapia en el esquema de evaluacion del tratamiento; d) se detalla mas extensamente el tratamiento no farmacologico; y, f) se revisa la importancia de las diferentes co-morbilidades en lo que respecta al tratamiento de la EPOC.

Background Scutellarin (Scu) shows both anti-inflammatory and antioxidant activities. The study investigates cardioprotective effects of Scu in mice with type 1 diabetes and the underlying molecular mechanism. Methods Streptozotocin (STZ) was used to induce diabetic cardiomyopathy (DCM) in C57BL/6 mice by intraperitoneal injection (i.p.). Normal and diabetic mice were divided into 6 groups: control, diabetic model group (DM), DM + Scu (5 mg/kg), DM + Scu (10 mg/kg), DM + Scu (20 mg/kg), DM + pioglitazone (Pio) (10 mg/kg). Scu was administered to the mice intraperitoneally and Pio was administrated by oral. Mice in control and DM groups were simply treated normal saline. Four weeks later, myocardial function, myocardial fibrosis, the levels inflammatory factors and oxidative stress were detected. Results Scu improved cardiac function and reduced heart injury in diabetic mice, which was indicated by increasing Left ventricular (LV) end-diastolic volume (LVVd), fractional shortening (FS), and ejection fraction (EF) levels and decreased pathological changes of heart. Scu inhibited the level of myocardial fibrosis by reducing the release of inflammatory cytokines and increasing activities of antioxidant enzymes. Further study showed that Scu inhibited the activation of nucleotide-binding oligomerization domain-like receptor with a pyrin domain 3 (NLRP3) and nuclear factor-kappa B (NF-κB) and activated phospho-protein kinase B (p-AKT), nuclear factor E2-related factor 2 (Nrf2), and heme oxygenase (HO-1). Conclusions Scu protects against DCM in STZ-induced diabetic mice by inhibiting oxidative stress and inflammatory responses and might be a potential therapeutic agent to treat DCM.

Rongchang Chen,1 Yue Gao,2 He Wang,3 Hongyan Shang,3 Jianwei Xuan4 1State Key Laboratory of Respiratory Disease, National Clinical Research Center, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 2Health Economics, Shanghai Centennial Scientific Co. Ltd., Shanghai, People’s Republic of China; 3Medical Affairs, AstraZeneca China, Shanghai, People’s Republic of China; 4Health Economics Research Institute, Sun Yat-Sen University, Guangzhou, People’s Republic of ChinaCorrespondence: Rongchang ChenState Key Laboratory of Respiratory Disease, National Clinical Research Center, Guangzhou Institute of Respiratory Disease, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of ChinaTel +86 20 83062870Email chenrc@vip.163.comBackground: This study aimed to evaluate the association between adherence to maintenance medication (ie, inhaled bronchodilators, inhaled corticosteroid/long-acting beta-2 agonist [ICS/LABA] combinations, and oral therapy) and acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and related costs among patients withchronic obstructive pulmonary disease (COPD) in China.Patients andMethods: Claims data from the hospitals of a metropolitan city in south China between January 2014 and December 2016 were obtained. Patients with COPD with ≥ 2 maintenance medication claims during 1 year were included. Adherence was measured by the proportion of days covered (PDC). The interaction of medication class×adherence was considered when building models.Results: A totalof 11,708 patients met the inclusion criteria, of whom 10.8% were highly adherent (PDC≥ 0.8). There were significant interaction effects of drug category on hospitalized AECOPD risk (P≤ 0.001), hospitalized AECOPD rate (P< 0.001), and 1-year hospitalized AECOPD treatment costs (P=0.012). There was a relationship between high adherence and outcomes for ICS/LABA combinations (n=3,419), ie, relative risk of hospitalized AECOPD was reduced by 34.8% (adjusted odds ratio=0.65; 95% confidence interval (CI): 0.54– 0.79; P< 0.001) while the frequency of hospitalized AECOPD per patient-year was reduced by 24.4% (adjusted rate ratio=0.76; 95% CI: 0.65 to 0.87; P< 0.001). Mean 1-year per-patient hospitalized AECOPD costs were reduced by 37.8% (mean difference=− 848 USD; 95% CI: − 1435– 262 USD; P< 0.001). Patients taking oral mucolytics and having high adherence had worse AECOPD outcomes than patients with poor adherence.Conclusion: High adherence to ICS/LABA maintenance therapy was associated with reduced hospitalized AECOPD rates and costs in Chinese patients with COPD.Keywords: chronic obstructive pulmonary disease, adherence, acute exacerbation of chronic obstructive pulmonary disease, cost, ICS/LABA

BACKGROUND: To investigate patient-ventilator interaction during different levels of noninvasive proportional assist ventilation (PAV) compared with noninvasive pressure support ventilation (PSV). METHODS: Fifteen subjects with severe COPD and hypercapnia were consecutively recruited. After the baseline assessment of unassisted spontaneous breathing, 3 levels of ventilatory support were applied. The proportional assist (PA) and pressure support (PS) levels were set by subject comfort. PA−, PS− or PA+, PS+ were set at 25% more or less of PA or PS (PA− = 75% PA, PA+ = 125% PA, PS− = 75% PS, PS+ = 125% PS). Each level lasted at least 20 min. To demonstrate the patient-ventilator interaction, the neural respiratory drive, respiratory muscle effort, flow signal, and airway pressure were simultaneously monitored. RESULTS: The expiratory cycle delay (time between the termination of the diaphragm electromyogram [EMGdi] signal and the end of the inspiratory flow) progressively increased with increasing assist level in both modes. However, compared with PSV, the expiratory cycle delay was significantly longer in each assist level during noninvasive PAV. The runaway phenomenon was observed in PA+. The time between the peak EMGdi signal and the maximum value of the flow signal and the time difference between the peak EMGdi signal and the maximum value of inspiratory pressure were significantly increased with the increasing assist level of PAV. CONCLUSIONS: The expiratory cycle delay of noninvasive PAV was significantly longer than that of noninvasive PSV in the subjects with COPD with respiratory failure. During the levels of PAV, the lag time between neural respiratory drive and airway pressurization was significantly increased and the “runaway” phenomenon may be observed. (ClinicalTrials.gov registration NCT01782768.)

Background and purpose The purpose of this study was to investigate that on the basis of ICS-LABA treatment, whether or not adding on short course of oral corticosteroid could increase the rate of asthma control. Methodology This was a double blind, randomized controlled study. Patients with moderate to severe persistent asthma who are maintenance treatment naive were recruited from the out-patients clinic. All patients included in the study received ICS-LABA as initial treatment. Two weeks oral corticosteroid or placebo were added on at the beginning of treatment. All the subjects were followed-up by daily measurement of PEF and asthma diary for 12 week and spirometry at 4 weeks and 12 weeks. Results 13 cases were randomized to Corticosteroid group (M/F: 9/4, age: 45.0 ± 5.0 yrs), 11 to Placebo group (M/F: 4/7, age: 35.7 ± 9.6yrs). After treatment, significant improvement in ACT、ACQ、AQLQ、FEV1、FEV1% were observed in both groups as compared with baseline data (all P 0.05). After 4 weeks of treatment, total control was achieved in 3 (30.8%) in corticosteroid group and 2 (18.2%) in placebo group; Partial control was achieved in 7 (61.5%)in corticosteroid group and in 7 (63.6%) in placebo group. There was no significant difference in control rates between two groups (X2 = 0.919, P = 0.632). Similar findings were observed after 12 weeks of treatment. Conclusion In maintenance treatment naive moderate to severe persistent asthma, ICS-LABA therapy was adequate initial treatment for achieving asthma control in majority of the patients. Add on short course of oral corticosteroid provided no significant clinical benefit.

Background Activation of NLRP3 inflammasome plays a key role in cardiac dysfunction for acute myocardial ischemia-reperfusion injury. Scutellarin (Scu) is a flavonoid purified from Erigeron breviscapus. Whether Scu has any influence on the activation of NLRP3 inflammasome in cardiomyocytes remains unknown. Purpose We aimed to examine the therapeutic effect of Scu on cardiomyocyte ischemia-reperfusion (I/R) injury and its effect on NLRP3 inflammasome in rats with acute myocardial I/R injury and anoxia/reoxygenation (A/R)-induced H9c2 injuries. Methods Heart injuries were induced through 30 min of ischemia followed by 24 h of reperfusion. Scu was intraperitoneally administered 15 min before vascular ligation. Effects of Scu on cardiac injury were detected by echocardiograms, TTC staining, and histological and immunohistochemical analyses. The effects of Scu on biochemical parameters were analyzed. H9c2 cells were pretreated with different concentrations of Scu for 6 h before A/R exposure. Afterward, cell viability, LDH release, and Hoechst 33342 and peromide iodine double staining were determined. Western blot analyses of proteins, including those involved in autophagy, NLRP3, mTOR complex 1 (mTORC1), and Akt signaling, were conducted. Results In vivo study revealed that Scu improved diastolic dysfunction, ameliorated myocardium structure abnormality, inhibited myocyte apoptosis and inflammatory response, and promoted autophagy. Scu reduced NLRP3 inflammasome activation, inhibited mTORC1 activity, and increased Akt phosphorylation. In vitro investigation showed the same results. The Scu-mediated NLRP3 inflammasome and mTORC1 inhibition and cardioprotection were abolished through the genetic silencing of Akt by siRNA. Conclusions The cardioprotective effect of Scu was achieved through its anti-inflammatory effect. It suppressed the activation of NLRP3 inflammasome. In addition, inflammasome restriction by Scu was dependent on Akt activation and mTORC1 inhibition.

The aim of our study was to elucidate the landscapes of genetic alterations of TSC1 and TSC2 as well as other possible non-TSC1/2 in Lymphangioleiomyomatosis (LAM) patients. Sixty-one Chinese LAM patients’ clinical information was collected. Tumor biopsies and matched leukocytes from these patients were retrospectively analyzed by next generation sequencing (NGS), chromosomal microarray analysis (CMA), and multiplex ligation-dependent probe amplification (MLPA). Eighty-six TSC1/2 variants were identified in 46 of the 61 LAM patients (75.4%) in which TSC2 and TSC1 variants were 88.37% and 11.63% respectively. The 86 variants are composed of (i) 52 single nucleotide variants (SNVs) (including 30 novel variants), (ii) 23 indels (including 21deletions, and 2 insertions), (iii) a germline duplication of exon 31–42 of TSC2, (iv) a 2.68 Mb somatic duplication containing TSC2, and (v) 9 regions with copy-neutral loss of heterogeneity (CN-LOHs) present only in the LAM patients with single TSC1/2 mutations. Sixty-one non-TSC1/2 variants in 31 genes were identified in 37 LAM patients. Combined applications of different techniques are necessary to achieve maximal detection rate of TSC1/2 variants in LAM patients. Thirty novel TSC1/2 variants expands the spectrum of TSC1/2 in LAM patients. Identification of 61 non-TSC1/2 variants suggests that alternative genes might have contributed to the initiation and progression of LAM.