An elastic net regression model for predicting the risk of ICU admission and death for hospitalized patients with COVID-19.

This study aimed to develop and validate prediction models to estimate the risk of death and intensive care unit admission in COVID-19 inpatients. All RT-PCR-confirmed adult COVID-19 inpatients admitted to Fujian Provincial Hospital from October 2022 to April 2023 were considered. Elastic Net Regression was used to derive the risk prediction models. Potential risk factors were considered, which included demographic characteristics, clinical symptoms, comorbidities, laboratory results, treatment process, prognosis. A total of 1906 inpatients were included finally by inclusion/exclusion criteria and were divided into derivation and test cohorts in a ratio of 8:2, where 1526 (80%) samples were used to develop prediction models under a repeated cross-validation framework and the remaining 380 (20%) samples were used for performance evaluation. Overall performance, discrimination and calibration were evaluated in the validation set and test cohort and quantified by accuracy, scaled Brier score (SbrS), the area under the ROC curve (AUROC), and Spiegelhalter-Z statistics. The models performed well, with high levels of discrimination (AUROCICU [95%CI]: 0.858 [0.803,0.899]; AUROCdeath [95%CI]: 0.906 [0.850,0.948]); and good calibrations (Spiegelhalter-ZICU: - 0.821 (p-value: 0.412); Spiegelhalter-Zdeath: 0.173) in the test set. We developed and validated prediction models to help clinicians identify high risk patients for death and ICU admission after COVID-19 infection.

Type B3 thymoma complicated with Chlamydia psittaci pneumonia with rare features: A case report.

The case of a patient with type B3 thymomacomorbid with Chlamydia psittaci (C. psittaci) pneumonia exhibiting rare features is presented in the current report. The patient was admitted at the Second Affiliated Hospital of Jiaxing University (Jiaxing, China) with a history of direct contact with poultry. Clinical manifestations included fever, shivers, cough, fatigue and poor appetite. Chest computed tomography (CT) indicated right lung pneumonia, while metagenomics next-generation sequencing using bronchoalveolar lavage fluid confirmed infection with C. psittaci. Additionally, positron emission tomography-CT suggested the presence of thymoma. After surgery and treatment with doxycycline and imipenem cilastatin, the patient was discharged showing signs of improvement.

IL-25 induces airway remodeling in asthma by orchestrating the phenotypic changes of epithelial cell and fibrocyte.

BACKGROUND: Previous studies have shown that IL-25 levels are increased in patients with asthma with fixed airflow limitation (FAL). However, the mechanism by which IL-25 contributes to airway remodeling and FAL remains unclear. Here, we hypothesized that IL-25 facilitates pro-fibrotic phenotypic changes in bronchial epithelial cells (BECs) and circulating fibrocytes (CFs), orchestrates pathological crosstalk from BECs to CFs, and thereby contributes to airway remodeling and FAL. METHODS: Fibrocytes from asthmatic patients with FAL and chronic asthma murine models were detected using flow cytometry, multiplex staining and multispectral imaging analysis. The effect of IL-25 on BECs and CFs and on the crosstalk between BECs and CFs was determined using cell culture and co-culture systems. RESULTS: We found that asthmatic patients with FAL had higher numbers of IL-25 receptor (i.e., IL-17RB)+-CFs, which were negatively correlated with forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC). The number of airway IL-17RB+-fibrocytes was significantly increased in ovalbumin (OVA)- and IL-25-induced asthmatic mice versus the control subjects. BECs stimulated with IL-25 exhibited an epithelial-mesenchymal transition (EMT)-like phenotypic changes. CFs stimulated with IL-25 produced high levels of extracellular matrix (ECM) proteins and connective tissue growth factors (CTGF). These profibrotic effects of IL-25 were partially blocked by the PI3K-AKT inhibitor LY294002. In the cell co-culture system, OVA-challenged BECs facilitated the migration and expression of ECM proteins and CTGF in CFs, which were markedly blocked using an anti-IL-17RB antibody. CONCLUSION: These results suggest that IL-25 may serve as a potential therapeutic target for asthmatic patients with FAL.

Presence and sequence of bronchiectasis onset impact on the clinical characteristics in asthmatic patients.

Background: Asthmatic patients with comorbid bronchiectasis (ACB) show significantly severe condition with various inflammatory phenotypes; bronchiectasis is a heterogeneous disease caused by asthma and other multiple etiological factors. We aimed to investigate the inflammatory characteristics and their clinical significance in asthmatic patients according to the presence and onset time of bronchiectasis. Methods: This prospective cohort study recruited outpatients with stable asthma. All the enrolled patients were divided into the non-bronchiectasis group and the ACB group, and the ACB group was separated into the bronchiectasis-prior group and the asthma-prior group. Demographic and clinical data were collected, and peripheral blood and induced sputum eosinophil counts, sputum pathogens, the fraction of exhaled nitric oxide (FeNO), lung function, and chest high-resolution computed tomography were examined. Results: A total of 602 patients (mean age: 55.36±14.58 years) were included, of which 255 (42.4%) were males. Bronchiectasis was present in 268 (44.5%) patients, with 171 (28.41%) in the asthma-prior group and 97 (16.11%) in the bronchiectasis-prior group. For the asthma-prior group, the presence of bronchiectasis was positively correlated with age, presence of nasal polyps, severe asthma, ≥1 pneumonia in the last 12 months, ≥1 severe exacerbation of asthma in the last 12 months (SEA), peripheral blood eosinophil counts, and sputum eosinophil ratio; the extent and severity of bronchiectasis were positively correlated with ≥1 SEA and FeNO levels; and the bronchiectasis severity index (BSI) scores were positively correlated with ≥1 SEA and immunoglobulin E levels. For the bronchiectasis-prior group, bronchiectasis was positively correlated with previous pulmonary tuberculosis or pneumonia in childhood and ≥1 pneumonia in the last 12 months and negatively correlated with forced expiratory volume in one second (FEV1) % and the FeNO level. The extent and severity of bronchiectasis were positively correlated with ≥1 pneumonia in the last 12 months and negatively correlated with FEV1%. The BSI scores were positively correlated with the duration of bronchiectasis. Conclusions: The sequence of bronchiectasis onset may indicate distinct inflammatory characteristics and may be helpful in targeted therapy for patients with asthma.

Circular RNAs Hsa_circ_101555 and Hsa_circ_008068 as Diagnostic Biomarkers for Early-Stage Lung Adenocarcinoma.

Background: Lung adenocarcinoma (LUAD) is a life-threatening disease worldwide with a high mortality rate. The early diagnosis of LUAD is crucial for improving subsequent treatment and prognosis. However, biomarkers for early detection remain a clinical challenge in LUAD. Here, we aimed to develop circular RNAs (circRNAs) in circulating plasma from LUAD patients as valuable diagnostic biomarkers in LUAD. Methods: CircRNA expression was determined by circRNA microarray in three pairs of LUAD tumour tissues and patient-matched normal lung tissues. Hsa_circ_101555 and hsa_circ_008068 were selected as potential biomarkers in LUAD tissues and plasma by RT-PCR, respectively. The diagnostic value was analysed by the area under the curve (AUC) and the receiver operating characteristic (ROC) test. Results: Our results showed that 6261 circRNAs were upregulated and 7238 circRNAs were downregulated in LUAD tumour tissues compared with patient-matched normal lung tissues. Hsa_circ_101555 and hsa_circ_008068 were filtered as biomarkers for early-stage LUAD. Q-PCR results showed that hsa_circ_101555 and hsa_circ_008068 were significantly upregulated in both LUAD cancer tissues and circulating plasma. Hsa_circ_101555 and hsa_circ_008068 were positively associated with tumour differentiation, tumour size and CEA (P<0.05). The ROC analysis showed that hsa_circ_101555 and hsa_circ_008068 had a better diagnostic potential compared to the traditional biomarkers (CEA, SCC, CYFRA21-1) in the detection of early-stage LUAD. Conclusion: The circular RNAs hsa_circ_101555 and hsa_circ_008068 could serve as novel diagnostic biomarkers for early-stage LUAD.

Ipratropium bromide and noninvasive ventilation treatment for COPD.

OBJECTIVE: To explore the effects of ipratropium bromide combined with non-invasive ventilation for patients with both chronic obstructive pulmonary disease (COPD) and respiratory failure. METHODS: A total of 110 patients with both COPD and respiratory failure who were admitted to our hospital from April 2018 to August 2019 were enrolled in this study; of which 52 patients were treated with a noninvasive ventilator as Group A, and the rest were treated with ipratropium bromide combined with noninvasive ventilation as Group B. The two groups were compared for blood gas indexes, pulmonary function, and treatment efficacy, and adverse reactions. RESULTS: After treatment, Group B showed better blood gas indexes and pulmonary function than Group A (both P < 0.05), and Group B also showed significantly lower levels of inflammatory factors than Group A (P < 0.05). In addition, the efficacy and life quality of Group B were better than those of Group A, and adverse reactions of Group B were less than those of Group A (all P < 0.05). CONCLUSION: Ipratropium bromide combined with noninvasive ventilation is effective in the treatment of patients with both COPD and respiratory failure.

Anti-inflammatory effects of brucea javanica oil via inhibition of NF-κB activation.

OBJECTIVE: As a traditional herbal medicine extracted from the seeds of Brucea javanica, Brucea javanica oil (BJO) has been clinically used to treat wart, chronic gastroenteritis and a variety of malignant tumors, including gastrointestinal cancer and lung cancer. We have recently reported the anti-tumor role and possible molecular mechanisms of BJO in treatment of lung cancer. However, it remains elusive whether BJO also has an anti-inflammatory effect. METHODS: The pneumonia-related inflammatory factors of macrophages under LPS treatment were investigated by real-time PCR and ELISA assays. LPS-induced acute pneumonia rat model was established. Hematoxylin and eosin (HE) examination was performed to detect histopathological changes in the lung tissues. Real-time PCR and ELISA assays were also used to detect the pneumonia-related inflammatory factors in lung tissues. RESULTS: LPS-induced expression and secretion of pneumonia-related inflammatory factors (TNF-α, IL-1ß, IL-6 and IL-8) were significantly suppressed by BJO in a concentration-dependent manner in RAW264.7 cells. However, BJO did not affect cell proliferation and survival rate. Further mechanistic studies revealed that BJO down-regulated the phosphorylation of IκB and p65, thereby inhibiting NF-κB pathway of macrophages and exerting its anti-inflammatory function. Western blot analysis showed that the phosphorylation levels of IκB and p65 were significantly up-regulated while the protein level of IκB was inhibited upon LPS stimulation in RAW264.7 cells and in lung tissue. Notably, LPS stimulation levels of IκB and p65 were effectively reversed under BJO co-treatment. The expression level of p65 was not influenced by LPS and BJO treatment. HE staining results showed that BJO can reduce the infiltration of inflammatory cells in lung. CONCLUSION: BJO can reduce the level of inflammatory factors in lung tissue, which provides a theoretical basis for BJO emulsion as an adjuvant therapy for pneumonia.

Prevalence and clinical implications of bronchiectasis in patients with overlapping asthma and chronic rhinosinusitis: a single-center prospective study.

BACKGROUND: As a typical "united airway" disease, asthma-chronic rhinosinusitis (CRS) overlap has recently drawn more attention. Bronchiectasis is a heterogeneous disease related to a variety of diseases. Whether bronchiectasis exists and correlates with asthma-CRS patients has not been fully elucidated. The purpose of the study was to explore the presence and characteristics of bronchiectasis in patients with overlapping asthma and CRS. METHODS: This report describes a prospective study with consecutive asthma-CRS patients. The diagnosis and severity of bronchiectasis were obtained by thorax high-resolution computed tomography (HRCT), the Smith radiology scale and the Bhalla scoring system. CRS severity was evaluated by paranasal sinus CT and the Lund-Mackay (LM) scoring system. The correlations between bronchiectasis and clinical data, fraction of exhaled nitric oxide, peripheral blood eosinophil counts and lung function were analyzed. RESULTS: Seventy-two (40.91%) of 176 asthma-CRS patients were diagnosed with bronchiectasis. Asthma-CRS patients with overlapping bronchiectasis had a higher incidence rate of nasal polyps (NPs) (P = 0.004), higher LM scores (P = 0.044), higher proportion of ≥ 1 severe exacerbation of asthma in the last 12 months (P = 0.003), lower postbronchodilator forced expiratory volume in one second (FEV1) % predicted (P = 0.006), and elevated peripheral blood eosinophil counts (P = 0.022). Smith and Bhalla scores were shown to correlate positively with NPs and negatively with FEV1% predicted and body mass index. Cutoff values of FEV1% predicted ≤ 71.40%, peripheral blood eosinophil counts > 0.60 × 109/L, presence of NPs, and ≥ 1 severe exacerbation of asthma in the last 12 months were shown to differentiate bronchiectasis in asthma-CRS patients. CONCLUSIONS: Bronchiectasis commonly overlaps in asthma-CRS patients. The coexistence of bronchiectasis predicts a more severe disease subset in terms of asthma and CRS. We suggest that asthma-CRS patients with NPs, severe airflow obstruction, eosinophilic inflammation, and poor asthma control should receive HRCT for the early diagnosis of bronchiectasis.

Single-Channel Blind Source Separation of Spatial Aliasing Signal Based on Stacked-LSTM.

Aiming at the problem of insufficient separation accuracy of aliased signals in space Internet satellite-ground communication scenarios, a stacked long short-term memory network (Stacked-LSTM) separation method based on deep learning is proposed. First, the coding feature representation of the mixed signal is extracted. Then, the long sequence input is divided into smaller blocks through the Stacked-LSTM network with the attention mechanism of the SE module, and the deep feature mask of the source signal is trained to obtain the Hadamard product of the mask of each source and the coding feature of the mixed signal, which is the encoding feature representation of the source signal. Finally, characteristics of the source signal is decoded by 1-D convolution to to obtain the original waveform. The negative scale-invariant source-to-noise ratio (SISNR) is used as the loss function of network training, that is, the evaluation index of single-channel blind source separation performance. The results show that in the single-channel separation of spatially aliased signals, the Stacked-LSTM method improves SISNR by 10.09∼38.17 dB compared with the two classic separation algorithms of ICA and NMF and the three deep learning separation methods of TasNet, Conv-TasNet and Wave-U-Net. The Stacked-LSTM method has better separation accuracy and noise robustness.

IL-25R+ circulating fibrocytes are increased in asthma and correlate with fixed airflow limitation.

INTRODUCTION: Interleukin (IL)-25 is a T helper (Th) type-2 cytokine implicated in the pathogenesis of asthma. Fibrocytes are progenitor cells that can migrate into circulation and inflamed bronchial epithelium. OBJECTIVES: We aim to test the hypothesis that circulating fibrocytes may be the novel cellular targets of IL-25 and the recruitment of IL-25R+ circulating fibrocytes may correlate with asthmatic airway obstruction. METHODS: By using flow cytometry analysis, IL-25R+ fibrocytes (i.e., IL-17RB+ fibrocytes) in the freshly isolated peripheral blood mononuclear cells (PBMCs) from 15 control subjects and 35 patients with asthma were enumerated and compared. Enzyme-linked immunosorbent assay (ELISA) was used to detect the plasma levels of IL-25. RESULTS: We found the percentage of total and IL-25R+ (IL-17RB+ ) fibrocytes in PBMCs was significantly increased in patients with asthma when compared with control subjects. Subgroup analysis further showed that the percentage of circulating total and IL-25R+ fibrocytes in PBMCs was markedly increased in asthma patients with severe-to-very severe fixed airflow limitation. Furthermore, IL-25R+ circulating fibrocytes in asthma patients were shown to significantly correlate with forced expiratory volume in 1 s/forced vital capacity (FEV1 /FVC), FEV1 % predicted, blood eosinophils, serum IgE and plasma IL-25 levels. CONCLUSION: We concluded that circulating fibrocytes are the novel potential cellular targets of IL-25. IL-25R+ fibrocytes are increased in asthma patients. Increased proportions of IL-25R+ fibrocytes predict a distinct asthma phenotype with fixed airflow limitation. Biological therapy-targeting IL-25-fibrocytes axis may offer great promise for the control of asthma patients with severe airway remodelling and obstruction.

The chest CT features of coronavirus disease 2019 (COVID-19) in China: a meta-analysis of 19 retrospective studies.

OBJECTIVE: Aimed to summarize the characteristics of chest CT imaging in Chinese hospitalized patients with Coronavirus Disease 2019 (COVID-19) to provide reliable evidence for further guiding clinical routine. METHODS: PubMed, Embase and Web of Science databases were searched to identify relevant articles involving the features of chest CT imaging in Chinese patients with COVID-19. All data were analyzed utilizing R i386 4.0.0 software. Random-effects models were employed to calculate pooled mean differences. RESULTS: 19 retrospective studies (1332 cases) were included. The results demonstrated that the combined proportion of ground-glass opacities (GGO) was 0.79 (95% CI 0.68, 0.89), consolidation was 0.34 (95% CI 0.23, 0.47); mixed GGO and consolidation was 0.46 (95% CI 0.37; 0.56); air bronchogram sign was 0.41 (95% CI 0.26; 0.55); crazy paving pattern was 0.32 (95% CI 0.17, 0.47); interlobular septal thickening was 0.55 (95% CI 0.42, 0.67); reticulation was 0.30 (95% CI 0.12, 0.48); bronchial wall thickening was 0.24 (95% CI 0.11, 0.40); vascular enlargement was 0.74 (95% CI 0.64, 0.86); subpleural linear opacity was 0.28 (95% CI 0.12, 0.48); intrathoracic lymph node enlargement was 0.03 (95% CI 0.00, 0.07); pleural effusions was 0.03 (95% CI 0.02, 0.06). The distribution in lung: the combined proportion of central was 0.05 (95% CI 0.01, 0.11); peripheral was 0.74 (95% CI 0.62, 0.84); peripheral involving central was 0.38 (95% CI 0.19, 0.75); diffuse was 0.19 (95% CI 0.06, 0.32); unifocal involvement was 0.09 (95% CI 0.05, 0.14); multifocal involvement was 0.57 (95% CI 0.48, 0.68); unilateral was 0.16 (95% CI 0.10, 0.23); bilateral was 0.83 (95% CI 0.78, 0.89); The combined proportion of lobes involved (> 2) was 0.70 (95% CI 0.61, 0.78); lobes involved (≦ 2) was 0.35 (95% CI 0.26, 0.44). CONCLUSION: GGO, vascular enlargement, interlobular septal thickening more frequently occurred in patients with COVID-19, which distribution features were peripheral, bilateral, involved lobes > 2. Therefore, based on chest CT features of COVID-19 mentioned, it might be a promising means for identifying COVID-19.

Protective Effects of MitoTEMPO on Nonalcoholic Fatty Liver Disease via Regulating Myeloid-Derived Suppressor Cells and Inflammation in Mice.

MitoTEMPO, a mitochondrial antioxidant, has protective effects on liver-related diseases. However, the role of MitoTEMPO on nonalcoholic fatty liver disease (NAFLD) and its possible mechanisms are largely unknown. Here, we investigated the effects of MitoTEMPO on NAFLD using high fat diet- (HFD-) induced obese mice as animal models. MitoTEMPO was intraperitoneally injected into HFD mice. Liver morphological changes were observed by H&E and Oil Red O staining, and the frequency of MDSCs in peripheral blood was analyzed by flow cytometry. Moreover, real-time quantitative PCR, western blot, and immunohistochemistry were conducted to detect the mRNA and protein expressions in the liver tissues. The results showed that the hepatic steatosis in liver tissues of HFD mice injected with MitoTEMPO was significantly ameliorated. Additionally, MitoTEMPO reduced the frequency of CD11b+Gr-1+ MDSCs in peripheral circulation and decreased Gr-1+ cell accumulation in the livers. Further studies demonstrated that MitoTEMPO administration suppressed the mRNA and protein expressions of MDSC-associated proinflammatory mediators, such as monocyte chemoattractant protein-1 (MCP-1), S100 calcium-binding protein A8 (S100A8), and S100 calcium-binding protein A9 (S100A9). Our results suggest that MitoTEMPO appears to be a potential chemical compound affecting certain immune cells and further ameliorates inflammation in obese-associated NAFLD.

Value of Exhaled Nitric Oxide and FEF25-75 in Identifying Factors Associated With Chronic Cough in Allergic Rhinitis.

PURPOSE: Chronic cough in allergic rhinitis (AR) patients is common with multiple etiologies including cough variant asthma (CVA), non-asthmatic eosinophilic bronchitis (NAEB), gastroesophageal reflux-related cough (GERC), and upper airway cough syndrome (UACS). Practical indicators that distinguish these categories are lacking. We aimed to explore the diagnostic value of the fraction of exhaled nitric oxide (FeNO) and forced expiratory flow at 25% and 75% of pulmonary volume (FEF25-75) in specifically identifying CVA and NAEB in these patients. METHODS: Consecutive AR patients with chronic cough were screened and underwent induced sputum, FeNO, nasal nitric oxide, spirometry, and methacholine bronchial provocation testing. All patients also completed gastroesophageal reflux disease questionnaires. RESULTS: Among 1,680 AR patients, 324 (19.3%) were identified with chronic cough, of whom 316 (97.5%) underwent etiology analyses. Overall, 87 (27.5%) patients had chronic cough caused by NAEB, 78 (24.7%) by CVA, 16 (5.1%) by GERC, and 81 (25.6%) by UACS. Patients with either NAEB or CVA (n = 165, in total) were further assigned to a common group designated as CVA/NAEB, because they both responded to corticosteroid therapy. Receiver operating characteristic curves of FeNO revealed obvious differences among CVA, NAEB, and CVA/NAEB (area under the curve = 0.855, 0.699, and 0.923, respectively). The cutoff values of FeNO at 43.5 and 32.5 ppb were shown to best differentiate CVA and CVA/NAEB, respectively. FEF25-75 was significantly lower in patients with CVA than in those with other causes. A FEF25-75 value of 74.6% showed good sensitivity and specificity for identifying patients with CVA. CONCLUSIONS: NAEB, CVA, and UACS are common causes of chronic cough in patients with AR. FeNO can first be used to discriminate patients with CVA/NAEB, then FEF25-75 (or combined with FeNO) can further discriminate patients with CVA from those with CVA/NAEB.

Large exchange bias and enhanced coercivity in strongly-coupled Ni/NiO binary nanoparticles.

In this study, Ni/NiO binary nanoparticles are synthesized utilizing a reflux method combined with a calcination process. The average size of the nanoparticles is 5-20 nm and the Ni content is 3.55%. Both the microstructures of the Ni/NiO interface and the states of different phases have significant impacts on the magnetic properties. By tuning the temperature and the cooling field during the loop measurement, the change rule of several critical parameters such as coercivity H C and exchange bias H E was complicated in nature. Both large H E (482 Oe) and enhanced H C (1335 Oe) were observed at 5 K, mainly due to the strong coupling interaction between Ni and NiO components. For current studies of the Ni/NiO binary nanoparticles, the complex magnetic behaviors are related to (i) the ferromagnetic contribution of Ni nanoparticles, (ii) the intrinsic antiferromagnetism of the volume phase of NiO, and (iii) the spin-glass-like characteristic corresponding to the frozen disordered state at the surface of partial NiO particles. The comprehensive effect of these three magnetic structures promotes the generation of a strongly-coupled Ni/NiO binary system, and improves the magnetic performance.

Potential Role of Interleukin-25/Interleukin-33/Thymic Stromal Lymphopoietin-Fibrocyte Axis in the Pathogenesis of Allergic Airway Diseases.

OBJECTIVE: Allergic airway diseases (AADs) are a group of heterogeneous disease mediated by T-helper type 2 (Th2) immune response and characterized with airway inflammation and remodeling, including allergic asthma, allergic rhinitis, and chronic rhinosinusitis with allergic background. This review aimed to discuss the abnormal epithelial-mesenchymal crosstalk in the pathogenesis of AADs. DATA SOURCES: Articles referred in this review were collected from the database of PubMed published in English up to January 2018. STUDY SELECTION: We had done a literature search using the following terms "allergic airway disease OR asthma OR allergic rhinitis OR chronic sinusitis AND IL-25 OR IL-33 OR thymic stromal lymphopoietin OR fibrocyte". Related original or review articles were included and carefully analyzed. RESULTS: It is now believed that abnormal epithelial-mesenchymal crosstalk underlies the pathogenesis of AADs. However, the key regulatory factors and molecular events involved in this process still remain unclear. Epithelium-derived triple cytokines, including interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin (TSLP), are shown to act on various target cells and promote the Th2 immune response. Circulating fibrocyte is an important mesenchymal cell that can mediate tissue remodeling. We previously found that IL-25-circulating fibrocyte axis was significantly upregulated in patients with asthma, which may greatly contribute to asthmatic airway inflammation and remodeling. CONCLUSIONS: In view of the redundancy of cytokines and "united airway" theory, we propose a new concept that IL-25/IL-33/TSLP-fibrocyte axis may play a vital role in the abnormal epithelial-mesenchymal crosstalk in some endotypes of AADs. This novel idea will guide potential new intervention schema for the common treatment of AADs sharing common pathogenesis in the future.

Comprehensive attenuation of IL-25-induced airway hyperresponsiveness, inflammation and remodelling by the PI3K inhibitor LY294002.

BACKGROUND AND OBJECTIVE: Existing in vitro and in vivo studies suggest that both IL-25 and phosphoinositide 3-kinases (PI3Ks) exhibit broad effects on the functions of immune cells implicated in the pathogenesis of asthma. Whether the blockade of PI3K signalling directly inhibits the asthma relevant pathogenetic changes induced by IL-25 in an in vivo condition is still unclear. Using an established IL-25-induced murine model of asthma, we undertook a comprehensive evaluation of the effects of co-administered LY294002, a pharmacological pan-inhibitor of PI3K on IL-25-induced changes on this model, with particular regard to airway remodelling. METHODS: BALB/c mice were serially intranasally challenged with IL-25 according to an established protocol to induce airway inflammation, hyperresponsiveness (AHR) and remodelling. In an additional subgroup LY294002 was administered intranasally. Lung function and airway cytokine and chemokine concentrations and cellular infiltration and remodelling changes assessed by histology and immunohistochemistry were measured at specific time points. RESULTS: Intranasal administration of LY294002 significantly inhibited IL-25-induced AHR and recruitment of inflammatory cells into bronchoalveolar lavage fluid. LY294002 also attenuated IL-25-induced increased concentrations of cytokines and chemokines in lung tissue. Histological and immunohistochemical analysis showed that LY294002 also significantly inhibited IL-25-induced lung tissue eosinophilia, mucus production, collagen deposition, smooth muscle hypertrophy and angiogenesis. CONCLUSION: The PI3K pan-inhibitor LY294002 attenuated not only IL-25-induced asthma-like AHR and airway inflammation but also remodelling in this model, suggesting that PI3K is a major downstream messenger for IL-25 and that targeting this pathway might reduce asthma symptoms in the short term and airway remodelling in the longer term.

Effects of the tumor suppressor PTEN on the pathogenesis of idiopathic pulmonary fibrosis in Chinese patients.

Idiopathic pulmonary fibrosis (IPF) is characterized by progressive interstitial fibrosis, and is associated with a fatal outcome. The critical pathological mechanisms underlying IPF are largely unknown; however, accumulating evidence has indicated similarities between IPF and cancer. Therefore, the present study examined the expression levels of the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in Chinese patients with IPF, using an enzyme­linked immunosorbent assay. To determine the effects of PTEN on the development of pulmonary fibrosis, PTEN was overexpressed in transforming growth factor (TGF)­ß1­treated human embryonic lung fibroblasts (HFL­I cells). The serum levels of PTEN were significantly lower in 42 patients with IPF, as compared with in the healthy controls. In addition, PTEN overexpression enhanced apoptosis, and suppressed basal levels of proliferation and migration in fibroblasts. Notably, PTEN was able to specifically inhibit TGF­ß1­induced proliferation and migration of the cells. Overexpression of PTEN also suppressed phosphorylation of Akt and Smad3, and decreased the expression levels of numerous proteins with critical roles in TGF­ß1­induced fibrosis, including α­smooth muscle actin, matrix metalloproteinase (MMP)­2 and MMP­9. These results indicated that PTEN may inhibit TGF­ß1­mediated myofibroblast differentiation of fibroblasts by attenuating signaling via the phosphatidylinositol 3­kinase/Akt and TGF­ß/Smad3 pathways.

Interleukin (IL)-25: Pleiotropic roles in asthma.

IL-25, also named IL-17E, is a distinct member of the IL-17 cytokine family, which can promote and augment T helper type 2 (Th2) responses locally or systemically. Growing evidence from experimental and clinical studies indicates that the expression of IL-25 and its cognate receptor, IL-17RB/RA, is markedly upregulated in asthmatic conditions. It has also been found that IL-25 induces not only typical eosinophilic inflammation and airway hyperresponsiveness (AHR), but also airway remodelling, manifested by goblet cell hyperplasia, subepithelial collagen deposition and angiogenesis. This review will focus on the discovery, cellular origins and targets of IL-25, and try to update current animal and human studies elucidating the roles of IL-25 in asthma. We conclude that although IL-25 is a pleiotropic cytokine, it may only play its dominant role in a certain specific asthmatic endotype, named 'IL-25 high' phenotype. Thus, targeting IL-25 or its receptor might selectively benefit some subgroups with asthma. Furthermore, the major IL-25 producing as well as responsive cells in the changeable milieu of asthma should be assessed in the future.

[Evaluation of a mouse model of chronic obstructive pulmonary disease induced by intraperitoneal injections of cigarette smoke extract].

OBJECTIVE: To evaluate a mouse model of chronic obstructive pulmonary disease (COPD) induced by intraperitoneal injections of cigarette smoke extract (CSE), and to study the potential mechanisms. METHODS: Mice were injected intraperitoneally with CSE at different time points to establish a mouse model of COPD. Mouse lung mechanics parameters were measured, and the total numbers and differentials of cells in bronchoalveolar lavage fluid (BALF) were counted. Pathological changes of lung tissue were observed and mean linear intercept (MLI) and alveolar destructive index (DI) were measured. The expressions of matrix metalloproteinases-12(MMP12), neutrophil elastase (NE),tissue inhibitor of metalloproteinase-1(TIMP1), pro-inflammatory cytokines (TNF-α, IL-1ß, IL-6), Th1 cytokines (IFN-γ), Th2 cytokines (IL-5, IL-13) and the neutrophil chemokine KC were determined in the lungs of all mice. RESULTS: Significant increase of total lung capacity(TLC) [(0.73 ± 0.02), (0.83 ± 0.04), (0.97 ± 0.02)ml] was found in the CSE group as compared with the PBS control group [(0.65 ± 0.01), (0.67 ± 0.02), (0.71 ± 0.04)ml, t= 4.109, 3.666, 5.994, P<0.01] at day 21, 41, 61. Lung compliance was higher in the CSE group [(0.041 ± 0.002) ml/cmH2O (1 cmH2O= 0.098 kPa), (0.039 ± 0.001) ml/cmH2O] than the PBS control group [(0.030 ± 0.001) ml/cmH2O, (0.032 ± 0.003) ml/cmH2O, t= 4.788,2.508, P<0.05] at day 41,61, but airway resistance in the lungs (R) was lower in the CSE group [(0.959 ± 0.016) cmH2O·s·ml⁻¹, (0.976±0.020) cmH2O·s·ml⁻¹] than the PBS control group [(1.043 ± 0.022) cmH2O·s·ml(-1), (1.085±0.043) cmH2O·s·ml⁻¹] (t= 2.928,2.321, P<0.05). The total numbers of BALF cells in the CSE group [(23.83 ± 2.63)×104, (20.67±1.69)×104, (18.67±1.56) × 104] were increased compared with the PBS control group [(7.33 ± 0.61)×104, (7.67 ± 0.76)×104, (6.67 ± 0.88)×104, t= 6.119,7.027,6.685,P<0.01] at day 21,41,61, predominantly with neutrophils and macrophages. Typical COPD pathological changes of lung tissue were evident, including Inflammatory cell infiltration in the lung parenchyma and increased mean linear intercept (MLI) in the CSE group [(48.0 ± 1.4), (56.1 ± 2.4), (59.3 ± 3.3)µm] as compared with the PBS control group [(40.5 ± 1.2), (43.7 ± 1.2), (43.5 ± 1.2)µm, t= 4.015,4.695,4.612, P<0.01] as well as increased alveolar destructive index (DI) in the CSE group [(15.2 ± 1.3)%, (22.4 ± 1.3)%, (23.8 ± 1.0)%] as compared with the PBS control group [(11.1 ± 0.9)%, (10.8 ± 1.0)%, (12.4 ± 0.7)%,t= 2.532, 7.225, 8.471, P < 0.05] at the 3 time points. The expressions of MMP12 and NE increased significantly in the CSE-treated mice. Pro-inflammatory cytokines (TNF-α, IL-1ß, L-6), Th1 cytokine IFN-γ and KC all increased significantly in the CSE-treated mice as compared with the PBS-control mice. CONCLUSIONS: A mouse model of COPD was successfully established by repeated intraperitoneal injections of CSE in a shorter period of time. Local inflammation and proteinase/anti-proteinase imbalance as a result of CSE-induced immunological responses may be the underlying mechanisms.

Characteristics of IL-25 and allergen-induced airway fibrosis in a murine model of asthma.

BACKGROUND AND OBJECTIVE: Interleukin (IL)-25 has been implicated in the pathogenesis of human asthma by inducing a Th2 cytokine response, but its possible role in the development of airway remodelling is less clear. METHODS: We developed a murine surrogate of chronic airway inflammation induced by intranasal application of IL-25 alone. Comparison was with the 'classical' surrogate of ovalbumin (OVA) intranasal instillation into previously sensitized animals. Airway fibrotic biomarkers were analysed by immunohistochemistry and enzyme-linked immunosorbent assay. Additionally, proliferation assay and real-time polymerase chain reaction analysis were performed to assess IL-25's effects on primary human bronchial fibroblasts in vitro. RESULTS: In Balb/c mice, intranasal instillation of IL-25 alone induced florid airway fibrosis, including increased lay down of extracellular matrix proteins such as collagen I, III, V and fibronectin, increased numbers of fibroblasts/myofibroblasts, a profibrotic imbalance in matrix metalloproteinase/tissue inhibitor of metalloproteinase production and increased expression of profibrotic mediators including connective tissue growth factor and transforming growth factor-ß1. These changes broadly reproduced those seen with classical intranasal OVA challenge in OVA-sensitized animals. Furthermore, IL-25 induced proliferation and expression of collagen I and III and smooth muscle α-actin in primary human lung fibroblasts. CONCLUSIONS: We conclude that chronic exposure of the airways to IL-25 alone is sufficient to cause functionally relevant airway remodelling, with the corollary that targeting of IL-25 may attenuate bronchial remodelling and fibrosis in human asthmatics.