A prostacyclin analogue, iloprost, protects from bleomycin-induced pulmonary fibrosis in mice

<p>Abstract</p> <p>Background</p> <p>Metabolites of arachidonic acid such as prostacyclin (PGI₂) have been shown to participate in the pathogenesis of pulmonary fibrosis by inhibiting the expression of pro-inflammatory and pro-fibrotic mediators. In this investigation, we examined whether iloprost, a stable PGI₂analogue, could prevent bleomycin-induced pulmonary inflammation and fibrosis in a mouse model.</p> <p>Methods</p> <p>Mice received a single intratracheal injection of bleomycin with or without intraperitoneal iloprost. Pulmonary inflammation and fibrosis were analysed by histological evaluation, cellular composition of bronchoalveolar lavage (BAL) fluid, and hydroxyproline content. Lung mechanics were measured. We also analysed the expression of inflammatory mediators in BAL fluid and lung tissue.</p> <p>Results</p> <p>Administration of iloprost significantly improved survival rate and reduced weight loss in the mice induced by bleomycin. The severe inflammatory response and fibrotic changes were significantly attenuated in the mice treated with iloprost as shown by reduction in infiltration of inflammatory cells into the airways and pulmonary parenchyma, diminution in interstitial collagen deposition, and lung hydroxyproline content. Iloprost significantly improved lung static compliance and tissue elastance. It increased the expression of IFNγ and CXCL10 in lung tissue measured by RT-PCR and their levels in BAL fluid as measured by ELISA. Levels of TNFα, IL-6 and TGFβ1 were lowered by iloprost.</p> <p>Conclusions</p> <p>Iloprost prevents bleomycin-induced pulmonary fibrosis, possibly by upregulating antifibrotic mediators (IFNγ and CXCL10) and downregulating pro-inflammatory and pro-fibrotic cytokines (TNFα, IL-6, and TGFβ1). Prostacyclin may represent a novel pharmacological agent for treating pulmonary fibrotic diseases.</p

Attenuation of antigen-induced airway hyperresponsiveness and inflammation in CXCR3 knockout mice

<p>Abstract</p> <p>Background</p> <p>CD8+ T cells participate in airway hyperresponsiveness (AHR) and allergic pulmonary inflammation that are characteristics of asthma. CXCL10 by binding to CXCR3 expressed preferentially on activated CD8+ T cells, attracts T cells homing to the lung. We studied the contribution and limitation of CXCR3 to AHR and airway inflammation induced by ovalbumin (OVA) using CXCR3 knockout (KO) mice.</p> <p>Methods</p> <p>Mice were sensitized and challenged with OVA. Lung histopathological changes, AHR, cellular composition and levels of inflammatory mediators in bronchoalveolar lavage (BAL) fluid, and lungs at mRNA and protein levels, were compared between CXCR3 KO mice and wild type (WT) mice.</p> <p>Results</p> <p>Compared with the WT controls, CXCR3 KO mice showed less OVA-induced infiltration of inflammatory cells around airways and vessels, and less mucus production. CXCR3 KO mice failed to develop significant AHR. They also demonstrated significantly fewer CD8+ T and CD4+ T cells in BAL fluid, lower levels of TNFα and IL-4 in lung tissue measured by real-time RT-PCR and in BAL fluid by ELISA, with significant elevation of IFNγ mRNA and protein expression levels.</p> <p>Conclusions</p> <p>We conclude that CXCR3 is crucial for AHR and airway inflammation by promoting recruitment of more CD8+ T cells, as well as CD4+ T cells, and initiating release of proinflammatory mediators following OVA sensitization and challenge. CXCR3 may represent a novel therapeutic target for asthma.</p

Periodontal health: A national cross‐sectional study of knowledge, attitudes and practices for the public oral health strategy in China

Aim To assess the status of periodontal health knowledge, attitudes and practices (KAP) among Chinese adults. Materials and Methods A cross‐sectional study was conducted in a nationally representative sample of adults (N = 50,991) aged 20 years or older from ten provinces, autonomous regions, and municipalities. Percentages of Chinese adults with correct periodontal knowledge, positive periodontal attitudes, and practices were estimated. Multiple logistic regression analyses were used to examine the related factors. Results Less than 20% of Chinese adults were knowledgeable about periodontal disease. Very few (2.6%) of Chinese adults use dental floss ≥once a day and undergo scaling ≥once a year and visit a dentist (6.4%) in the case of gingival bleeding. Periodontal health KAP was associated with gender, age, body mass index, marital status, place of residence, education level, income, smoking status, and history of periodontal disease. Conclusions Periodontal health KAP are generally poor among the Chinese adult population. Community‐based health strategies to improve periodontal health KAP need to be implemented. Increasing knowledge of periodontal disease, the cultivation of correct practices in response to gingival bleeding, and the development of good habits concerning the use of dental floss and regular scaling should be public oral health priorities

Alterations to the Lung Microbiome in Idiopathic Pulmonary Fibrosis Patients

Lung microbiome ecosystem homeostasis in idiopathic pulmonary fibrosis (IPF) remains uncharacterized. The aims of this study were to identify unique microbial signatures of the lung microbiome and analyze microbial gene function in IPF patients. DNA isolated from BALF samples was obtained for high-throughput gene sequencing. Microbial metagenomic data were used for principal component analysis (PCA) and analyzed at different taxonomic levels. Shotgun metagenomic data were annotated using the KEGG database and were analyzed for functional and metabolic pathways. In this study, 17 IPF patients and 38 healthy subjects (smokers and non-smokers) were recruited. For the PCA, the first and the second principal component explained 16.3 and 13.4% of the overall variability, respectively. The β diversity of microbiome was reduced in the IPF group. Signature of IPF's microbes was enriched of Streptococcus, Pseudobutyrivibrio, and Anaerorhabdus. The translocation of lung microbiome was shown that 32.84% of them were from oral. After analysis of gene function, ABC transporter systems, biofilm formation, and two-component regulatory system were enriched in IPF patients' microbiome. Here we shown the microbiology characteristics in IPF patients. The microbiome may participate in altering internal conditions and involving in generating antibiotic resistance in IPF patients

Characteristics of Proinflammatory Cytokines and Chemokines in Airways of Asthmatics:Relationships with Disease Severity and Infiltration of Inflammatory Cells

Background: Increased proinflammatory cytokines and chemokines might contribute to infiltration of inflammatory cells and remodeling in airways of asthma. Although these molecules may be associated with asthma, there is lack of systemic evidence showing which and how important these events are in the disease. We aimed to analyze the concentrations of these molecules in the airways and relationships with disease severity and with airway infiltration of inflammatory cells in a large cohort of asthmatics (n = 70, including 37 mild and 33 moderate/severe asthmatics) compared with controls (n = 30). Methods: Meso scale discovery system and commercial ELISA kits were used to measure the concentrations of proinflammatory cytokines interleukin (IL)-1β; tumor necrosis factor-alpha (TNF-α); IL-6; and IL-17 and CC and CXC chemokines CCL2, CCL4, CCL11, CCL13, CCL17, CCL22, and CCL26 and CXCL8, CXCL9, CXCL10, and CXCL11 in bronchoalveolar lavage fluid of asthmatics and controls. Results: The concentrations of IL-1, TNF-α, IL-6, CXCL8 and CXCL10, and CCL4, CCL11, CCL17, and CCL22 were significantly elevated in asthmatics compared with controls (P < 0.05). The concentrations of TNF-α and CXCL8, but not others, were negatively correlated with severity of disease (lung function forced expiratory volume in 1 s) (TNF-α vs. total: r = −0.359, P= 0.002 vs. moderate/severe: r= −0.541, P= 0.001; CXCL8 vs. total: r = −0.327, P= 0.006 vs. moderate/severe: r = −0.625, P= 0.0001, respectively). In addition, concentrations of these two molecules were also correlated with the absolute numbers of infiltrating eosinophils and neutrophils in asthmatic airways. Conclusions: Increased concentrations of TNF-α and CXCL8 are associated with pathogenesis of asthma. Targeting these molecules might provide an alternative therapeutic for this disease

IL-33 Initiates Vascular Remodelling in Hypoxic Pulmonary Hypertension by up-Regulating HIF-1α and VEGF Expression in Vascular Endothelial Cells

IL-33 may play a role in the vascular remodelling of hypoxic pulmonary hypertension (PH) but the precise mechanisms are still unclear. We hypothesized that hypoxia promotes expression of IL-33 and its receptor ST2 on vascular endothelial cells, which in turn leads to dysfunction of vascular endothelial cells and smooth muscle cells contributing to PH. Immunohistochemistry showed that immunoreactivity for IL-33 and ST2 was significantly increased in lung tissue of murine model of hypoxia-induced PH (HPH) and of subjects with bronchiectasis-PH. trans-Thoracic echocardiography showed that haemodynamic changes and right ventricular hypertrophy associated with HPH were significantly abrogated in St2−/− compared with WT mice. Administration of IL-33 further exacerbated these changes in the hypoxia-exposed WT mice. In vitro, hypoxia significantly increased IL-33/ST2 expression by human pulmonary arterial endothelial cells (HPAECs), while exogenous IL-33 enhanced proliferation, adhesiveness and spontaneous angiogenesis of HPAECs. Knockdown of endogenous Il33 or St2 using siRNA transfection significantly suppressed these effects in both normoxic and hypoxic culture-conditions. Deletion of the St2 gene attenuated hypoxia-induced, elevated lung expression of HIF-1α/VEGFA/VEGFR-2/ICAM-1, while administration of exogenous VEGFA partially reversed the attenuation of the haemodynamic indices of PH. Correspondingly, knockdown of the St2 or Hif1α genes almost completely abrogated IL-33-induced expression of HIF-1α/VEGFA/VEGFR-2 by HPAECs in vitro. Further, IL-33-induced angiogenesis by HPAECs was extensively abrogated by knockdown of the Hif1α/Vegfa or Vegfr2 genes. These data suggest that hypoxia induces elevated expression of IL-33/ST2 by HPAECs which, at least partly by increasing downstream expression of HIF-1α and VEGF initiates vascular remodelling resulting in HPH. Keywords: IL-33, Hypoxic pulmonary hypertension, Hypoxia inducible factor 1, Vascular endothelial growth facto

Use of glucocorticoids in patients with COPD exacerbations in China: a retrospective observational study

Background: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are common in patients with underlying moderate to severe COPD and are associated with increased health and economic burden. International and Chinese guidelines recommend using glucocorticoids for the management of AECOPD because glucocorticoid therapy has been shown to benefit clinical outcomes. However, only scant data are available for current status of glucocorticoid therapy in hospitalized AECOPD patients in China. The aim of the study was to identify current use of glucocorticoids for the treatment of AECOPD in China. Methods: This retrospective, multicenter, noninterventional study evaluated the treatment pattern of AECOPD in patients hospitalized from January 2014 to September 2014 at 43 sites (41 tertiary hospitals and two secondary hospitals) in China. The endpoints of the study were the percentage of patients receiving glucocorticoids by different routes of administration, doses and duration, mortality, and the mean length of hospitalization. Results: A total of 4569 patients (90.17%) received glucocorticoids for AECOPD treatment. A combination of nebulized and systemic route was most frequently used (40.51%), followed by using nebulized route alone (38.00%), systemic route alone (15.45%), and inhaled route other than nebulization (6.04%). Furthermore, the most commonly prescribed glucocorticoids of the nebulized, intravenous, inhaled (other than nebulized) and oral route was budesonide (69.4%), methylprednisolone sodium succinate (45.31%), fluticasone propionate (19.54%), and prednisone acetate (11.90%), respectively. The in-hospital mortality rate was 1.24% and the mean length of hospitalization was 12.22 ± 6.20 days (± SD). Conclusions: Our study was the first study of the treatment pattern of glucocorticoids in the management of hospitalized AECOPD patients in China. Data indicates that there is a gap in the implementation of international guidelines for the treatment of AECOPD in China. Further studies are warranted to clarify the appropriate glucocorticoids strategy for the management of AECOPD to determine the optimal route of administration, dose and duration, and resulting clinical outcomes

Validation of the Generalized Anxiety Disorder-7 in patients with COPD: a cross-sectional study

Abstract Background Patients with chronic obstructive pulmonary disease (COPD) often have comorbid generalized anxiety disorder (GAD), which requires early screening in respiratory clinics. The Generalized Anxiety Disorder-7 (GAD-7) questionnaire is a brief and commonly used screening tool for GAD but has not been validated among patients with COPD in China. Methods Stable patients with COPD from a cross-sectional observational study were assessed using the GAD-7 questionnaire and then assessed by a senior psychiatrist to confirm a diagnosis of GAD according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Demographic characteristics, spirometry, and patient-reported outcomes were collected. Cronbach’s α coefficient was calculated, and receiver operating curve (ROC) analysis was performed to validate the GAD-7. Results A total of 226 patients with COPD were enrolled, and 50 (22.1%) of these patients were diagnosed with GAD. The Cronbach’s α coefficient for the GAD-7 was 0.869, which indicated good internal consistency. ROC curve analysis showed that the GAD-7 had an area under the curve (AUC) value of 0.829 (95% CI: 0.774–0.876) for identifying GAD. The optimal cut-off score was ≥ 4, with a sensitivity of 66.0% and a specificity of 89.2%. Higher GAD-7 scores were significantly associated with health-related quality of life and the symptom burden of COPD. The discriminatory power of GAD-7 did not differ statistically when stratified by COPD severity. Conclusions The GAD-7 was shown to be a reliable and valid screening tool for patients with COPD in China, and its screening performance for GAD was not influenced by disease severity