Clinical characteristics of obese, fixed airway obstruction, exacerbation-prone phenotype and comorbidities among severe asthma patients: a single-center study.

BACKGROUND: Severe asthma places a large burden on patients and society. The characteristics of patients with severe asthma in the Chinese population remain unclear. METHODS: A retrospective review was conducted in patients with severe asthma. Demographic and clinical data were collected. Patients were grouped according to phenotypes in terms of exacerbations, body mass index (BMI) and fixed airway obstruction (FAO) status, and the characteristics of different groups were compared. Comorbidities, factors that influence asthma phenotypes, were also analyzed in the study. RESULTS: A total of 228 patients with severe asthma were included in our study. They were more likely to be overweight or obese. A total of 41.7% of the patients received GINA step 5 therapy, and 43.4% had a history of receiving regular or intermittent oral corticosteroids (OCS). Severe asthmatic patients with comorbidities were prone to have more asthma symptoms and decreased quality of life than patients without comorbidities. Patients with exacerbations were characterized by longer duration of asthma, poorer lung function, and worse asthma control. Overweight or obese patients tended to have more asthma symptoms, poorer lung function and more asthma-related comorbidities. Compared to patients without FAO, those in the FAO group were older, with longer duration of asthma and more exacerbations. CONCLUSION: The existence of comorbidities in patients with severe asthma could result in more asthma symptoms and decreased quality of life. Patients with exacerbations or with overweight or obese phenotypes were characterized by poorer lung function and worse asthma control. Patients with FAO phenotype tended to have more exacerbations.

Quantitative analysis of a novel DNA hypermethylation panel using bronchial specimen for lung cancer diagnosis.

Non-diagnostic findings are common in transbronchial lung biopsy (TBLB) and endobronchial ultrasound-guided transbronchial lung biopsy (EBUS-TBLB). One of the challenges is to improve the detection of lung cancer using these techniques. To address this issue, we utilized an 850 K methylation chip to identify methylation sites that distinguish malignant from benign lung nodules. Our study found that a combination of HOXA7, SHOX2 and SCT methylation analysis has the best diagnostic yield in bronchial washing (sensitivity: 74.1%; AUC: 0.851) and brushing samples (sensitivity: 86.1%; AUC: 0.915). We developed a kit comprising these three genes and validated it in 329 unique bronchial washing samples, 397 unique brushing samples and 179 unique patients with both washing and brushing samples. The panel's accuracy in lung cancer diagnosis was 86.9%, 91.2% and 95% in bronchial washing, brushing and washing + brushing samples, respectively. When combined with cytology, rapid on-site evaluation (ROSE), and histology, the panel's sensitivity in lung cancer diagnosis was 90.8% and 95.8% in bronchial washing and brushing samples, respectively, and 100% in washing + brushing samples. Our findings suggest that quantitative analysis of the three-gene panel can improve the diagnosis of lung cancer using bronchoscopy.

Perturbation of arachidonic acid and glycerolipid metabolism promoted particulate matter-induced inflammatory responses in human bronchial epithelial cells.

Particulate matter (PM) has become the main risk factor for public health, being linked with an increased risk of respiratory diseases. However, the potential mechanisms underlying PM-induced lung injury have not been well elucidated. In this study, we systematically integrated the metabolomics, lipidomics, and transcriptomics data obtained from the human bronchial epithelial cells (HBECs) exposed to PM to reveal metabolic disorders in PM-induced lung injury. We identified 170 differentially expressed metabolites (82 upregulated and 88 downregulated metabolites), 218 differentially expressed lipid metabolites (125 upregulated and 93 downregulated lipid metabolites), and 1417 differentially expressed genes (643 upregulated and 774 downregulated genes). Seven key metabolites (prostaglandin E2, inosinic acid, L-arginine, L-citrulline, L-leucine, adenosine, and adenosine monophosphate), and two main lipid subclasses (triglyceride and phosphatidylcholine) were identified in PM-exposed HBECs. The amino acid metabolism, lipid metabolism, and carbohydrate metabolism were the significantly enriched pathways of identified differentially expressed genes. Then, conjoint analysis of these three omics data and further qRT-PCR validation showed that arachidonic acid metabolism, glycerolipid metabolism, and glutathione metabolism were the key metabolic pathways in PM-exposed HBECs. The knockout of AKR1C3 in arachidonic acid metabolism or GPAT3 in glycerolipid metabolism could significantly inhibit PM-induced inflammatory responses in HBECs. These results revealed the potential metabolic pathways in PM-exposed HBECs and provided a new target to protect from PM-induced airway damage.

Comprehensive analysis of transcriptome-wide m6A methylome in the lung tissues of mice with acute particulate matter exposure.

Particulate matter (PM) exposure is identified as a critical risk factor for chronic airway diseases, but the biological mechanism of PM-induced lung damage was not fully elucidated. The m6A methylation, as the main member of epigenetic modifications, has been found to play an important role in different pulmonary diseases, but its regulatory effect on PM-induced lung damage remains unknown. This study firstly used the methylated RNA immunoprecipitation sequencing (MeRIP-seq) to reveal the m6A methylome profiles in the lung tissues of mice with acute PM exposure. Compared with the normal control, a total of 2210 differentially hypermethylated m6A peaks within 1879 genes and 1278 differentially hypomethylated m6A peaks within 1153 genes were identified in the PM-exposed group. Conjoint analysis of MeRIP-seq and high-throughput sequencing for RNA (RNA-seq) data predicated several potential pathways including MAPK signaling pathway, cell senescence, and cell cycle. Four m6A-modified differentially expressed genes (IL-1a, IL-1b, ADAM-8, and HMOX-1) were selected for validation using MeRIP-qPCR. Furthermore, the m6A-modified IL-1a promoted PM-induced inflammation via regulating MAPK signaling pathway. These results provide a new insight into the biological mechanism of PM-induced lung damage, and help us to develop new methods to prevent and treat PM-induced adverse health effects.

SERPINB10 contributes to asthma by inhibiting the apoptosis of allergenic Th2 cells.

BACKGROUND: Serine peptidase inhibitor, clade B, member 10 (SERPINB10) contributes to allergic inflammation in asthma. However, its role in the T-helper type 2 (Th2) response of allergic asthma is not known. The goal of this study was to unveil the function of SERPINB10 in the Th2 response of allergic asthma and the mechanism by which SERPINB10 affects the viability of Th2 cells. METHODS: Th2 cytokines and serum levels of house dust mite (HDM)-specific IgE in bronchoalveolar lavage fluid were examined by ELISA in an HDM-induced asthma model. The number and apoptosis of Th1 and Th2 cells in mouse lungs were measured by flow cytometry. Naïve CD4 T cells from patients with asthma were cultured under appropriate polarizing conditions to generate Th1 and Th2 cells. SERPINB10 expression in polarized Th1 and Th2 cells was quantified by real-time reverse transcription-quantitative polymerase chain reaction. SERPINB10 expression was knocked down in human CD4 T cells with lentivirus. RESULTS: Knockdown of SERPINB10 expression significantly diminished HDM-induced Th2 cytokine secretion and level of HDM-specific IgE. After HDM exposure, SERPINB10-knockdown mice had diminished numbers of Th2 cells, but similar numbers of Th1 cells, compared with those in negative-control mice. Th2 cells of SERPINB10-knockdown mice were more susceptible to apoptosis than that of control mice. Stimulating T-cell receptors (TCRs) with anti-CD3 antibody caused upregulation of SERPINB10 expression in polarized Th2 cells, but not polarized Th1 cells. Knockdown of SERPINB10 expression resulted in fewer numbers and greater apoptosis of polarized Th2 cells. CONCLUSION: Our results suggest that SERPINB10 may contribute to allergic inflammation and the Th2 response of asthma by inhibiting the apoptosis of Th2 cells.

Circular RNAs: a rising star in respiratory diseases.

Circular RNAs (CircRNAs), as a new class of non-coding RNA molecules that, unlike linear RNAs, have covalently closed loop structures from the ligation of exons, introns, or both. CircRNAs are widely expressed in various organisms in a specie-, tissue-, disease- and developmental stage-specific manner, and have been demonstrated to play a vital role in the pathogenesis and progression of human diseases. An increasing number of recent studies has revealed that circRNAs are intensively associated with different respiratory diseases, including lung cancer, acute respiratory distress syndrome, pulmonary hypertension, pulmonary tuberculosis, and silicosis. However, to the best of our knowledge, there has been no systematic review of studies on the role of circRNAs in respiratory diseases. In this review, we elaborate on the biogenesis, functions, and identification of circRNAs and focus particularly on the potential implications of circRNAs in respiratory diseases.

Osteopontin potentiates PM-induced IL-1α and IL-1ß production via the ERK/JNK signaling pathway.

Ambient particulate matter (PM) poses a great threat to global health and contributes to pulmonary inflammation. However, the potential mechanism of PM-induced inflammation of the lung remains unclear. Osteopontin (OPN) is a multifunctional protein that reportedly regulates inflammatory responses in different diseases. Here, we explored the expression of OPN with PM exposure in vivo and in vitro and attempted to elucidate the regulatory role of OPN in PM-induced airway inflammation. Our results showed that PM exposure increased the expression of OPN in the bronchial epithelium, serum, and bronchoalveolar lavage fluid (BALF) of mice. Moreover, PM induced OPN expression in human bronchial epithelial cells (HBECs) in a dose and time-dependent manner. In vitro, inflammatory cytokines such as IL-1α and IL-1ß were increased in HBECs with PM exposure via the ERK and JNK signaling pathways. Recombinant human OPN could potentiate PM-induced expression of IL-1α and IL-1ß, while OPN siRNA could alleviate PM-induced inflammatory responses in HBECs. Furthermore, we showed that OPN regulated PM-induced inflammatory cytokines via the ERK and JNK pathways in HBECs. This study shows for the first time the positive effect of OPN on PM-induced airway inflammation and contributes to a better understanding of its potential mechanism of action.

Plasma Proteomics Study Between the Frequent Exacerbation and Infrequent Exacerbation Phenotypes of Chronic Obstructive Pulmonary Disease.

Background: Frequent exacerbation (FE) and infrequent exacerbation (IE) are two phenotypes of chronic obstructive pulmonary disease (COPD), of which FE is associated with a higher incidence of exacerbation and a serious threat to human health. Because the pathogenesis mechanisms of FE are unclear, this study aims to identify FE-related proteins in the plasma via proteomics for use as predictive, diagnostic, and therapeutic biomarkers of COPD. Methods: A cross-sectional study was conducted in which plasma protein profiles were analyzed in COPD patients at stable stage, and differentially expressed proteins (DEPs) were screened out between the FE and IE patients. FE-related DEPs were identified using data-independent acquisition-based proteomics and bioinformatics analyses. In addition, FE-related candidates were verified by enzyme-linked immunosorbent assay. Results: In this study, 47 DEPs were screened out between the FE and IE groups, including 20 upregulated and 27 downregulated proteins. Key biological functions (eg, neutrophil degranulation, extracellular exosome, protein homodimerization activity) and signaling pathways (eg, arginine and proline metabolism) were enriched in association with the FE phenotype. Receiver operating characteristic (ROC) analysis of the 11 combined DEPs revealed an area under the curve of 0.985 (p <0.05) for discriminating FE from IE. Moreover, correlation and ROC curve analyses indicated that creatine kinase, M-type (CKM) and fat storage-inducing transmembrane protein 1 (FITM1) might be clinically significant in patients with the FE phenotype. In addition, plasma expression levels of CKM and FITM1 were validated to be significantly decreased in the FE group compared with the IE group (CKM: p <0.01; FITM1: p <0.05). Conclusion: In this study, novel insights into COPD pathogenesis were provided by investigating and comparing plasma protein profiles between the FE and IE patients. CKM, FITM1, and a combinative biomarker panel may serve as useful tools for assisting in the precision diagnosis and effective treatment of the FE phenotype of COPD.

Edaravone Attenuated Particulate Matter-Induced Lung Inflammation by Inhibiting ROS-NF-κB Signaling Pathway.

Background: Particulate matter (PM) exposure is related to mitochondria dysfunction and airway inflammation. Antioxidant drug edaravone (EDA) is reported to improve the occurrence and development of oxidative stress-related diseases. At present, there is no data on whether EDA can alleviate lung inflammation caused by PM. Methods: The anti-inflammatory effects of EDA were investigated in urban PM-induced human bronchial epithelial cells (HBECs) and C57/BL6J mouse models. In vitro, its effects on the production of intracellular reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and inflammatory cytokines were assessed by DCFH-DA staining, JC-1 assay, and real-time PCR, respectively. In vivo, the oxidant stress in lung tissues was assessed by dihydroethidium (DHE) staining and malondialdehyde (MDA) activity, and inflammatory cytokines in bronchoalveolar lavage fluid (BALF) were assessed by ELISA, respectively. Furthermore, the potential signaling pathways were studied by siRNA transfection and western blot. Results: PM increased the expression of inflammatory cytokines and protein, including IL-6, IL-1α, IL-1ß, and COX-2, while these alternations were significantly alleviated following EDA treatment in a dose-dependent manner. EDA treatment also alleviated the inflammatory responses in lung tissues of PM-exposed mice. We further showed mitochondrial dysfunction in PM-exposed HBECs and mice, which were reversed by EDA treatment. Moreover, the phosphorylation of NF-κB p65 in PM-exposed HBECs and mice was weakened by EDA. Transfection with NF-κB p65 siRNA further inhibited PM-induced inflammation in HBECs. Conclusion: We demonstrated that EDA treatment had a protective role in PM-induced lung inflammation through maintaining mitochondrial balance and regulating the ROS-NF-κB p65 signaling pathway. This provided a new therapeutic method for PM-induced lung inflammation in the future.

The circular RNA circTXNRD1 promoted ambient particulate matter-induced inflammation in human bronchial epithelial cells by regulating miR-892a/COX-2 axis.

Particulate matter (PM)-induced airway inflammation contributes to the development and exacerbation of chronic airway diseases. Circular RNA (circRNA) is a new class of non-coding RNA that participates in gene regulation in various respiratory diseases, but the regulatory role of circRNA in PM-induced airway inflammation has not been fully elucidated. In this study, we performed the human circRNA microarray to reveal differentially expressed circRNAs in PM-induced human bronchial epithelial cells (HBECs). A total of 176 upregulated and 15 downregulated circRNAs were identified. Of these, a new circRNA termed circTXNRD1 was upregulated by PM exposure in a dose- and time-dependent manner. Knockdown of circTXNRD1 significantly attenuated PM-induced expression of proinflammatory cytokine interleukin 6 (IL-6). CircRNA pull-down, dual-luciferase reporter assay and fluorescence in situ hybridization showed that circTXNRD1 acted as an endogenous sponge to decrease miR-892a levels in HBECs. Downregulation of miR-892a could increase cyclooxygenase-2 (COX-2) expression and eventually promote IL-6 secretion in PM-induced HBECs. Taken together, our findings reveal circTXNRD1 as a novel inflammatory mediator in PM-induced inflammation in HBECs via regulating miR-892a/COX-2 axis. These results provide new insight into the biological mechanism underlying PM-induced inflammation in chronic airway diseases.

ROS-Responsive miR-150-5p Downregulation Contributes to Cigarette Smoke-Induced COPD via Targeting IRE1α.

MicroRNAs (miRNAs) have been reported in human diseases, in which chronic obstructive pulmonary disease (COPD) is included. Herein, we assessed the role along with the possible mechanisms of miR-150-5p in cigarette smoke- (CS-) induced COPD. The plasma miR-150-5p expression was lower in patients with COPD and acute exacerbation of COPD (AECOPD) and was related to disease diagnosis, disease severity, and lung function. Consistently, exposure to CS for 3 months or 3 days reduced miR-150-5p in the plasma and lung tissues of mice, and CS extract (CSE) inhibited miR-150-5p in human bronchial epithelial cells (HBECs) in a concentration along with time-dependent approach. In vitro, miR-150-5p overexpression decreased the contents of inflammatory factors interleukin- (IL-) 6, IL-8 along with cyclooxygenase-2 (COX-2), and endoplasmic reticulum (ER) stress markers glucose-regulated protein (GRP) 78 and C/-EBP homologous protein (CHOP) and promoted cell migrate. Mechanistically, miR-150-5p could bind with the 3'-untranslated region (UTR) of inositol requiring enzyme 1α (IRE1α), while IRE1α overexpression obliterated the impacts of miR-150-5p. Besides, N-acetyl-cysteine (NAC) reversed CSE-induced miR-150-5p downregulation and its downstream effects. In vivo, miR-150-5p overexpression counteracted CS-triggered IRE1α upregulation, inflammation, and ER stress in the lung tissues of mice. In conclusion, our findings illustrated that ROS-mediated downregulation of miR-150-5p led to CS-induced COPD by inhibiting IRE1α expression, suggesting to serve as a useful biomarker for diagnosing and treating COPD.

Clinical Characteristics and Prognosis of Allergic Bronchopulmonary Aspergillosis: A Retrospective Cohort Study.

BACKGROUND: The clinical features, treatment, and prognosis of allergic bronchopulmonary aspergillosis (ABPA) are not well-defined. OBJECTIVE: We aimed to investigate the clinical characteristics, therapy, and prognosis of ABPA to aid its clinical recognition. METHODS: A total of 232 patients with ABPA were analyzed retrospectively. The characteristics of ABPA in terms of its misdiagnosis, computed tomography classification, therapy, and its relationship with asthma were analyzed, and risk factors for acute exacerbation of ABPA were analyzed based on follow-up data. RESULTS: Of the 232 ABPA patients, 132 had a history of misdiagnosis. Compared with the misdiagnosed patients, ABPA patients with central bronchiectasis, a high total eosinophil count, and mucus plugs were less likely to be misdiagnosed. Compared with serological ABPA, ABPA with central bronchiectasis was more likely to occur in older people and in patients with mucus plugs, and decreased forced vital capacity and diffusing capacity for carbon monoxide. ABPA patients with asthma were more likely to have bronchiectasis, decreased lung function in 1 s FEV1 and FEV1/FVC, and shorter time to first acute exacerbation compared with ABPA patients without asthma. Patients receiving glucocorticoids plus antifungal therapy had a longer time to first exacerbation than those receiving glucocorticoid therapy alone. Univariate and multivariate analyses revealed that duration of asthma history, duration of misdiagnosis, mucus plugs, and poor pulmonary function were risk factors for acute exacerbation of ABPA. CONCLUSION: To our knowledge, this is the largest sample size study of ABPA in China. ABPA patients with a history of asthma and/or central bronchiectasis on high-resolution computed tomography are prone to frequent acute exacerbations. The use of glucocorticoids combined with antifungal drugs can prolong the time to the first acute exacerbation in ABPA patients. Longer durations of asthma history and misdiagnosis, mucus plugs, and poor pulmonary function are risk factors for acute exacerbation of ABPA.

Transcriptomic analysis of key genes and pathways in human bronchial epithelial cells BEAS-2B exposed to urban particulate matter.

Urban particulate matter (PM), a great danger to public health, is associated with increasing risk of pulmonary diseases. However, the involved key genes and signaling pathways mediating the cellular responses to urban PM are largely unknown. In this study, human bronchial epithelial cells BEAS-2B was exposed to Standard reference material (SRM) 1649b, followed by RNA-sequencing (RNA-seq) and a combination of different bioinformatics analysis. A total of 201 genes (111 upregulated and 90 downregulated) were identified as the differentially expressed genes (DEGs). Moreover, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) unveiled several significant genes and pathways involved in PM-induced lung toxicity. Protein-protein interaction (PPI) network was performed with the Search Tool for the Retrieval of Interacting Genes (STRING), and the hub gene modules were recognized by Molecular Complex Detection (MCODE), a plug-in of Cytoscape. Moreover, Connectivity Map (CMap) analysis found six candidate small molecular compounds to reverse PM-altered gene expression, including aminohippuric acid, captopril, cinoxacin, fasudil, pargyline, and altizide. Finally, the expressions of part vital genes related to inflammation (IL-1ß, CXCL2, CXCL5, CXCL8), ferroptosis (HMOX1, GCLM), and autophagy (BECN1, MAPK1LC3B) were in accordance with the RNA-seq data, with a concentration-dependent manner. This study may be helpful in revealing the complex molecular mechanisms underlying PM-induced lung toxicity and provide some new therapeutic targets for PM-related pulmonary diseases.

Small Proline-Rich Protein 3 Regulates IL-33/ILC2 Axis to Promote Allergic Airway Inflammation.

Small proline-rich proteins (SPRRs), components of cornified cell envelope precursors, have recently been found to participate in airway diseases. However, their role in allergic airway inflammatory conditions remains unknown. Here, we explored the expression of SPRR3 in house dust mite (HDM)-sensitized/challenged mice and attempted to elucidate the regulatory role of SPRR3 in allergic airway inflammation. SPRR3 was identified via bioinformatics analysis of Gene Expression Omnibus (GEO) databases and further confirmed to be upregulated in the lungs of asthmatic mice. Knockdown of SPRR3 via the intratracheal route significantly inhibited eosinophils in bronchoalveolar lavage fluid (BALF) and suppressed the expressions of type 2 cytokines (IL-4, IL-5, and IL-13) in BALF and lung tissues. Further, SPRR3 knockdown reduced the expression of IL-33 and further attenuated the activation of the PI3K/AKT/NF-κB signaling pathway in the recruitment of group 2 innate lymphoid cells (ILC2s) to inhibit allergic airway inflammation. In vitro, SPRR3 siRNA could alleviate HDM-induced inflammatory responses in BEAS-2B cells. This study reveals the regulatory role of SPRR3 in allergic airway inflammation, identifying this protein as a potential novel therapeutic target for asthma.

Clinical predictors of COVID-19 disease progression and death: Analysis of 214 hospitalised patients from Wuhan, China.

INTRODUCTION: COVID-19 has spread rapidly worldwide and has been declared a pandemic. OBJECTIVES: To delineate clinical features of COVID-19 patients with different severities and prognoses and clarify the risk factors for disease progression and death at an early stage. METHODS: Medical history, laboratory findings, treatment and outcome data from 214 hospitalised patients with COVID-19 pneumonia admitted to Eastern Campus of Renmin Hospital, Wuhan University in China were collected from 30 January 2020 to 20 February 2020, and risk factors associated with clinical deterioration and death were analysed. The final date of follow-up was 21 March 2020. RESULTS: Age, comorbidities, higher neutrophil cell counts, lower lymphocyte counts and subsets, impairment of liver, renal, heart, coagulation systems, systematic inflammation and clinical scores at admission were significantly associated with disease severity. Ten (16.1%) moderate and 45 (47.9%) severe patients experienced deterioration after admission, and median time from illness onset to clinical deterioration was 14.7 (IQR 11.3-18.5) and 14.5 days (IQR 11.8-20.0), respectively. Multivariate analysis showed increased Hazards Ratio of disease progression associated with older age, lymphocyte count <1.1 × 109/L, blood urea nitrogen (BUN)> 9.5 mmol/L, lactate dehydrogenase >250 U/L and procalcitonin >0.1 ng/mL at admission. These factors were also associated with the risk of death except for BUN. Prediction models in terms of nomogram for clinical deterioration and death were established to illustrate the probability. CONCLUSIONS: These findings provide insights for early detection and management of patients at risk of disease progression or even death, especially older patients and those with comorbidities.

Construction of Potential miRNA-mRNA Regulatory Network in COPD Plasma by Bioinformatics Analysis.

Background: Chronic obstructive pulmonary disease (COPD) has become a major cause of morbidity and mortality worldwide. Increasing evidence indicates that aberrantly expressed microRNAs (miRNAs) are involved in the pathogenesis of COPD. However, an integrative exploration of miRNA-mRNA regulatory network in COPD plasma remains lacking. Methods: The microarray datasets GSE24709, GSE61741, and GSE31568 were downloaded from the GEO database and analyzed using GEO2R tool to identify differentially expressed miRNAs (DEMs) between COPD and normal plasma. The consistently changing miRNAs in the three datasets were screened out as candidate DEMs. Potential upstream transcription factors and downstream target genes of candidate DEMs were predicted by FunRich and miRNet, respectively. Next, GO annotation and KEGG pathway enrichment analysis for target genes were performed using DAVID. Then, PPI and DEM-hub gene network were constructed using the STRING database and Cytoscape software. Finally, GSE56768 was used to evaluate the hub gene expressions. Results: A total of nine (six upregulated and three downregulated) DEMs were screened out in the above three datasets. SP1 was predicted to potentially regulate most of the downregulated DEMs, while YY1 and E2F1 could regulate both upregulated and downregulated DEMs. 1139 target genes were then predicted, including 596 upregulated DEM target genes and 543 downregulated DEM target genes. Target genes of DEMs were mainly enriched in PI3K/Akt signaling pathway, mTOR signaling pathway, and autophagy. Through the DEM-hub gene network construction, most of the hub genes were found to be potentially modulated by miR-497-5p, miR-130b-5p, and miR-126-5p. Among the top 12 hub genes, MYC and FOXO1 expressions were consistent with that in the GSE56768 dataset. Conclusion: In the study, potential miRNA-mRNA regulatory network was firstly constructed in COPD plasma, which may provide a new insight into the pathogenesis and treatment of COPD.

MiR-29b-3p promotes particulate matter-induced inflammatory responses by regulating the C1QTNF6/AMPK pathway.

Inflammatory responses are considered to be the critical mechanism underlying particulate matter (PM)-induced development and exacerbation of chronic respiratory diseases. MiR-29b-3p has been found to participate in various biological processes, but its role in PM-induced inflammatory responses was previously unknown. Here, we constructed a miRNA PCR array to find that miR-29b-3p was the most highly expressed in human bronchial epithelial cells (HBECs) exposed to PM. MiR-29b-3p promoted PM-induced pro-inflammatory cytokines (IL-1ß, IL-6, and IL-8) expression via inhibiting the AMPK signaling pathway in HBECs. RNA sequencing and luciferase reporter assay identified that miR-29b-3p targeted complement C1q tumor necrosis factor-related protein 6 (C1QTNF6), a protein that protected from PM-induced inflammatory responses via activating the AMPK signaling pathway. In vivo, miR-29b-3p antagomirs delivered via the tail vein prior to PM exposure significantly counteracted PM-induced miR-29b-3p upregulation and C1QTNF6 downregulation in lung tissues. Furthermore, miR-29b-3p inhibition alleviated inflammatory cells infiltration and pro-inflammatory cytokines secretion in the lung of PM-exposed mice. These findings firstly revealed that miR-29b-3p acted as a novel modulator of PM-induced inflammatory responses by targeting the C1QTNF6/AMPK signaling pathway, which contributes to a better understanding of the biological mechanisms underlying adverse PM-induced respiratory health effects.

Possible Novel Therapeutic Targets in Lymphangioleiomyomatosis Treatment.

Lymphangioleiomyomatosis (LAM) is a rare systemic neoplastic disease that exclusively happens in women. Studies focusing on LAM and tuberous sclerosis complex (TSC) have made great progress in understanding the pathogenesis and searching for treatment. The inactive mutation of TSC1 or TSC2 is found in patients with LAM to activate the crucial mammalian target of rapamycin (mTOR) signaling pathway and result in enhanced cell proliferation and migration. However, it does not explain every step of tumorigenesis in LAM. Because cessation of rapamycin would break the stabilization of lung function or improved quality of life and lead to disease recurrent, continued studies on the pathogenesis of LAM are necessary to identify novel targets and new treatment. Researchers have found several aberrant regulations that affect the mTOR pathway such as its upstream or downstream molecules and compensatory pathways in LAM. Some therapeutic targets have been under study in clinical trials. New methods like genome-wide association studies have located a novel gene related to LAM. Herein, we review the current knowledge regarding pathogenesis and treatment of LAM and summarize novel targets of therapeutic potential recently.

Salidroside suppresses group 2 innate lymphoid cell-mediated allergic airway inflammation by targeting IL-33/ST2 axis.

Salidroside, an active component extracted from Rhodiola rosea, has been reported to inhibit allergic asthma. However, its mechanism has not been fully elucidated. Group 2 innate lymphoid cells (ILC2s) accumulate in the lung and cooperate with other cells to drive type 2 inflammation stimulated by inhaled allergens. The study aims to explore the suppressive effect of salidroside on ILC2s and IL-33/IL-33R (ST2) axis in allergic airway inflammation. The ovalbumin (OVA)-sensitized/challenged mice were established. Airway eosinophil recruitment, increased total IgE in the serum and type 2 cytokines IL-4, IL-5, and IL-13 in the bronchoalveolar lavage fluids and lung tissues were identified in the OVA-induced mice model, all of which were inhibited by pretreatment with different doses of salidroside. Moreover, salidroside suppressed lung total ILC2 and ST2-expressing ILC2 accumulation, lung IL-33 and ST2 expressions in mice. In vitro, OVA could induce IL-33 expression in BEAS-2B cells, which was also effectively inhibited by salidroside. This study firstly reveals salidroside as a potential therapeutic drug for allergic asthma by inhibiting ILC2-mediated airway inflammation via targeting IL-33/ST2 axis.

Amphiregulin potentiates airway inflammation and mucus hypersecretion induced by urban particulate matter via the EGFR-PI3Kα-AKT/ERK pathway.

Ambient particulate matter (PM) promotes the development and exacerbation of chronic respiratory diseases, including chronic obstructive pulmonary disease (COPD) and asthma, by increasing inflammation and mucus hypersecretion. However, the biological mechanisms underlying PM-induced airway inflammation and mucus hypersecretion remain unclear. Amphiregulin (AREG) is an important ligand for epidermal growth factor receptor (EGFR) and participates in the regulation of several biological functions. Here, the PM-exposed human bronchial epithelial cell (HBEC) model was used to define the role of AREG in PM-induced inflammation and mucus hypersecretion and its related signaling pathways. The expression of AREG was significantly increased in a dose-dependent manner in HBECs subjected to PM exposure. Moreover, PM could induce inflammation and mucus hypersecretion by upregulating the expression of IL-1α, IL-1ß, and Muc-5ac in HBECs. The EGFR, AKT, and ERK signaling pathways were also activated in a time- and dose-dependent manner. The AREG siRNA markedly attenuated PM-induced inflammation and mucus hypersecretion, and activation of the EGFR-AKT/ERK pathway. Exogenous AREG significantly increased the expression of IL-1α, IL-1ß, and Muc-5ac, and induced activation of the EGFR-AKT/ERK pathway in HBECs. Further, under PM exposure, exogenous AREG significantly potentiated PM-induced inflammation and mucus hypersecretion, and activation of the EGFR-AKT/ERK pathway. Tumor-necrosis factor-alpha converting enzyme (TACE) and EGFR specific inhibitor pretreatment showed that AREG was secreted by TACE-mediated cleavage to regulate PM-induced inflammation and mucus hypersecretion by binding to the EGFR. Moreover, according to the inhibitory effect of specific inhibitors of the class I PI3K isoforms, AKT and ERK, PM-induced inflammation and mucus hypersecretion was regulated by PI3Kα activation and its downstream AKT and ERK pathways. This study strongly suggests the adverse effect of AREG in PM-induced inflammation and mucus hypersecretion via the EGFR-PI3Kα-AKT/ERK pathway. These findings contribute to a better understanding of the biological mechanisms underlying exacerbation of chronic respiratory diseases induced by PM exposure.