A 49-Year-Old Man With Fever and Dyspnea After Endobronchial Ultrasound-Guided Transbronchial Fine Needle Aspiration Biopsy.

CASE PRESENTATION: A 49-year-old man, a farmer, had been experiencing coughing, phlegm, and difficulty breathing for 2 months. He underwent a CT scan at a local hospital that showed a mediastinal mass. Bronchoscopy showed no obstruction in the tracheal lumen, and an endobronchial ultrasound-guided transbronchial fine needle aspiration (EBUS-TBNA) biopsy was performed on the mediastinal mass. The cytologic smear of the mediastinal mass showed a few atypical epithelial cells; the possibility of a tumor could not be ruled out. The patient visited our thoracic surgery outpatient department; based on the advice of the thoracic surgeon, the patient underwent another endobronchial ultrasound-guided transbronchial fine needle aspiration biopsy of the mediastinal mass 4 days before this admission. The patient went home and waited for the results. Two days later, the patient experienced a fever and palpitations accompanied by chills, yellow phlegm, and orthopnea. The patient visited our ED, underwent tracheal intubation, and was admitted to our ICU. The patient had had occasional coughing and phlegm for the past 10 years, which were not taken seriously or investigated. The patient does not smoke or drink alcohol, and there is no history of cancer in the family.

Blood Eosinophil Count and Its Determinants in a Chinese Population-Based Cohort.

INTRODUCTION: Blood eosinophil count has been shown markedly variable across different populations. However, its distribution in Chinese general population remains unclear. We aimed to investigate blood eosinophil count and its determinants in a Chinese general population. METHODS: In this population-based study, general citizens of Sichuan province in China were extracted from the China Pulmonary Health study. Data on demographics, personal and family history, living condition, lifestyle, spirometry, and complete blood count test were obtained and analyzed. A stepwise multivariate binary logistic regression analysis was performed to identify determinants of high blood eosinophils (>75th percentile). RESULTS: A total of 3,310 participants were included, with a mean age (standard deviation) of 47.0 (15.6) years. In total population, the median blood eosinophil count was 110.0 (interquartile range [IQR]: 67.2-192.9) cells/µL, lower than that in smokers (133.4 cells/µL, IQR: 79.3-228.4) and patients with asthma (140.7 cells/µL, IQR: 79.6-218.2) or post-bronchodilator airflow limitation (141.5 cells/µL, IQR: 82.6-230.1), with a right-skewed distribution. Multivariate analyses revealed that oldness (aged ≥60 years) (odds ratio [OR]: 1.66, 95% confidence interval [CI]: 1.11-2.48), smoking ≥20 pack-years (OR: 1.90, 95% CI: 1.20-3.00), raising a dog/cat (OR: 1.72, 95% CI: 1.17-2.52), and occupational exposure to dust, allergen, and harmful gas (OR: 1.58, 95% CI: 1.15-2.15) were significantly associated with high blood eosinophils. CONCLUSION: This study identifies a median blood eosinophil count of 110.0 cells/µL and determinants of high blood eosinophils in a Chinese general population, including oldness (aged ≥60 years), smoking ≥20 pack-years, raising a dog/cat, and occupational exposure to dust, allergen, and harmful gas.

Elevated soluble death receptor 5 can predict poor prognosis in patients with acute respiratory distress syndrome.

BACKGROUND: The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and its receptor, death receptor 5 (DR5), participate in pulmonary cell apoptosis. This study aimed to investigate the clinical value of soluble DR5 and TRAIL for prognosis assessment in acute respiratory distress syndrome (ARDS). RESEARCH DESIGN AND METHODS: Serum and bronchoalveolar lavage fluid (BALF) samples were collected from ARDS patients and controls. Patients were followed-up until death or discharge. Soluble DR5, TRAIL, TNF-α, soluble receptor for advanced glycation end-products (sRAGE), and albumin levels were measured using the Magnetic Luminex or enzyme-linked immunosorbent assays. Data were analyzed according to their distributions and statistical purposes. RESULTS: Serum and BALF DR5 levels were elevated in patients with ARDS; TRAIL elevation and reduction was observed in BALF and serum, respectively. Serum DR5 was higher in non-survivors compared to survivors. Serum DR5 was positively correlated with serum TNF-α and critical illness scores and negatively correlated with serum TRAIL. Serum DR5 exhibited potential for predicting mortality in patients with ARDS. CONCLUSIONS: Serum soluble DR5 elevation, a valuable prognosis predictor in ARDS, may be associated with alveolar epithelial cell apoptosis. TRIAL REGISTRATION: http://www.chictr.org.cn/index.aspx.Uniqueidentifier:ChiCTR-DDD-17013370.

Identifying miRNA Modules and Related Pathways of Chronic Obstructive Pulmonary Disease Associated Emphysema by Weighted Gene Co-Expression Network Analysis.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a heterogeneous chronic inflammatory disease characterized by progressive airflow limitation that causes high morbidity and mortality. MicroRNA, a short-chain noncoding RNA, regulates gene expression at the transcriptional level. microRNA modules with a role in the pathogenesis of COPD may serve as COPD biomarkers. METHODS: We downloaded the GSE33336 microarray data set from the Gene Expression Omnibus (GEO) database, the data are derived from 29 lung samples of patients with emphysema undergoing curative resection for lung cancer. We used weighted gene co-expression network analysis (WGCNA) to construct co-expression modules and detect trait-related microRNA modules. We used the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis to predict the biological function of the interest modules, and we screened out candidate hub microRNAs based on their module membership (MM) value and top proteins on the results of the protein-protein interaction (PPI) network. RESULTS: Three microRNA modules (royal blue, light yellow and grey60) were highly associated with COPD. Axon guidance, proteoglycans in cancer and mitogen-activated protein kinases (MAPK) signaling pathway were common pathways in these three modules. Keratin18 (KRT18) was the top protein in our study. miR-452, miR-149, miR-133a, miR-181a and miR-421 in hub microRNAs may play a role in COPD. CONCLUSION: These findings provide evidence for the role of miRNAs in COPD and identify biomarker candidates.

Clinical Predictors of High Blood Eosinophils in Chronic Obstructive Pulmonary Disease.

Purpose: Elevated blood eosinophils have been implicated in chronic obstructive pulmonary disease (COPD) progression and exacerbation. We aim to investigate clinical predictors of high blood eosinophils in a Chinese COPD cohort. Patients and Methods: We conducted a retrospective cohort study in Sichuan province, a Southwest province with high prevalence of COPD in China. All patients in this cohort were extracted from the Chinese Pulmonary Health study, a large cross-sectional study on COPD epidemiology in China. Demographics, personal and family history, living condition, spirometry and blood eosinophil counts were obtained. Univariate and multiple linear regression analyses were performed to determine predictors of high blood eosinophils. Results: A total of 375 COPD patients were included in this cohort. The median absolute blood eosinophil count was 138.8 cells/µL, and the prevalence of COPD with high blood eosinophils was 66.7% and 14.7% when using the thresholds of 100 cells/µL and 300 cells/µL, respectively. Univariate analyses indicated that male gender, lower body mass index, high-density lipoprotein (HDL), lower family income, raising pets and biomass use were significantly associated with high blood eosinophils (p < 0.05). Multiple linear regression model further revealed male gender (unstandardized coefficient (B)=66.125, 95% confidence intervals (CI) 16.350 to 115.900, p=0.009), age (B=2.819, 95% CI 0.639 to 5.000, p=0.012) predicted high blood eosinophil level, whereas HDL (B=-64.682, 95% CI -123.451 to -5.914, p=0.031) was a negative predictor for high blood eosinophils. Conclusion: This retrospective cohort study suggests male gender, oldness and lower HDL could be clinical predictors of high blood eosinophils in Chinese COPD patients.

The prognostic values of neutrophil to lymphocyte ratio for outcomes in chronic obstructive pulmonary disease.

OBJECTIVE: Neutrophil to lymphocyte ratio (NLR) is considered as an inflammatory biomarker for clinical outcomes in patients with chronic obstructive pulmonary disease (COPD). We aimed to conduct a meta-analysis to evaluate the prognostic values of NLR for the exacerbation and mortality in patients with COPD. METHODS: We searched the database of Cochrane Central Register of Controlled Trials, EMBASE, and PubMed, before September 2017. The eligible studies were retrieved by 2 authors independently following the criteria. The pooled odds ratios (ORs) of included studies were used to evaluate the prognostic values of NLR. Subgroup analyses were conducted to make the results more accurate. RESULTS: Nine studies with 5140 patients were enrolled in this analysis. The high NLR was associated with higher risk of exacerbation (OR: 3.81, 95% confidence interval [CI]: 1.20-12.13, P = .02) and mortality (OR: 2.60, 95% CI: 1.48-4.57, P < .01). By subgroup analysis, high NLR could predict the mortality in patients >70 years (OR: 2.16, 95% CI: 1.17-3.98, P = .01) but not in patients <70 years (OR: 4.08, 95% CI: 0.91-18.24, P = .07), and had a higher predictive ability in Asian group (OR: 3.64, 95% CI: 1.87-7.08, P < .01) than Eurasia group (OR: 1.82, 95% CI: 1.43-2.32, P < .01). In addition, high NLR could predict the short-term mortality (OR: 2.70, 95% CI: 1.10-6.63, P = .03) and the long-term mortality (OR: 2.61, 95% CI: 1.20-5.65, P = .02). CONCLUSIONS: The NLR may be an independent predictor for incidence of exacerbation in patients with COPD. In addition, high NLR may be associated with higher mortality in patients with COPD, especially for Asian and the patients with higher mean NLR.

Diagnostic Performance of Bronchoalveolar Lavage Fluid CD4/CD8 Ratio for Sarcoidosis: A Meta-analysis.

BACKGROUND: The usefulness of bronchoalveolar lavage fluid (BALF) CD4/CD8 ratio for diagnosing sarcoidosis has been reported in many studies with variable results. Therefore, we performed a meta-analysis to estimate the overall diagnostic accuracy of BALF CD4/CD8 ratio based on the bulk of published evidence. METHODS: Studies published prior to June 2015 and indexed in PubMed, OVID, Web of Science, Scopus and other databases were evaluated for inclusion. Data on sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) were pooled from included studies. Summary receiver operating characteristic (SROC) curves were used to summarize overall test performance. Deeks's funnel plot was used to detect publication bias. RESULTS: Sixteen publications with 1885 subjects met our inclusion criteria and were included in this meta-analysis. Summary estimates of the diagnostic performance of the BALF CD4/CD8 ratio were as follows: sensitivity, 0.70 (95%CI 0.64-0.75); specificity, 0.83 (95%CI 0.78-0.86); PLR, 4.04 (95%CI 3.13-5.20); NLR, 0.36 (95%CI 0.30-0.44); and DOR, 11.17 (95%CI 7.31-17.07). The area under the SROC curve was 0.84 (95%CI 0.81-0.87). There was no evidence of publication bias. CONCLUSION: Measuring the BALF CD4/CD8 ratio may assist in the diagnosis of sarcoidosis when interpreted in parallel with other diagnostic factors.

Diagnostic value of thyroid transcription factor-1 for pleural or other serous metastases of pulmonary adenocarcinoma: a meta-analysis.

The role of thyroid transcription factor 1 (TTF-1) in the diagnosis of metastatic pulmonary adenocarcinomas in pleural, pericardial, and peritoneal effusions has not been defined. This study aimed to assess the overall diagnostic accuracy of TTF-1 for metastatic pulmonary adenocarcinomas in pleural or other effusions. Literature search was conducted in PubMed, EMBASE, and other databases to find eligible publications. Quality was assessed according to standardized QUADAS-2 criteria. Sensitivity, specificity, positive/negative likelihood ratio (PLR/NLR), and diagnostic odds ratio (DOR) were pooled. Summary receiver operating characteristic (SROC) curves were used to assess overall performance of the TTF-1 assay. A systematic search revealed 20 studies comprising a total of 1,213 subjects in this meta-analysis. The summary estimates were listed as follows: sensitivity, 0.74 (95% CI: 0.69-0.79); specificity, 0.99 (95% CI: 0.97-1.00); PLR, 78.16 (95% CI: 27.15-225.05); NLR, 0.26 (95% CI: 0.22-0.32); and diagnostic odds ratio, 297.75 (95% CI: 104.16-851.19). Estimated positive and negative post-probability values for metastatic pulmonary adenocarcinomas prevalence of 20% were 95% and 6%, respectively. The area under the SROC curve was 0.96. TTF-1 shows significant potential as a diagnostic marker to differentiate metastatic pulmonary from non-pulmonary adenocarcinomas in pleural or other effusions. These results justify larger, more rigorous studies to confirm such a diagnostic role.

WNT/ß-catenin signaling regulates cigarette smoke-induced airway inflammation via the PPARδ/p38 pathway.

The mechanisms of WNT/ß-catenin signaling involved in airway inflammation of chronic obstructive pulmonary disease (COPD) remain unknown, although recent observations have suggested an important contribution of the pathway in pulmonary parenchymal tissue repair and airway epithelium differentiation. We investigated the role of WNT/ß-catenin signaling in cigarette smoke (CS)-related airway inflammation using patient lung tissues, human bronchial epithelial cells (16HBECs), and mouse models. Reduced activity of WNT/ß-catenin signaling was observed in the airway epithelium of smokers with or without COPD. The mRNA expression of WNT transcription factor TCF4 negatively correlated with the pack year. The mRNA levels of WNT receptor FZD4 negatively correlated with the mRNA levels of IL-1ß. CS exposure decreased the activity of WNT/ß-catenin signaling in both 16HBECs and mice. In vitro studies demonstrated the upregulation of inflammatory cytokines TNF-α and IL-1ß secretion induced by CS extract (CSE) could be attenuated by ß-catenin activator SB216763 and be exacerbated by ß-catenin small-interfering RNA (siRNA), respectively. Furthermore, the decrease in the expression of peroxisome proliferator-activated receptor (PPARδ) induced by CSE stimulation could be rescued by SB216763. SB216763 also attenuated the upregulation of phosphorylated p38 mitogen-activated protein kinase (MAPK) stimulated by CSE. Both PPARδ agonist and p38 MAPK inhibitor could suppress the TNF-α and IL-1ß release induced by CSE treatment. In addition, PPARδ activation could abolish ß-catenin siRNA-mediated aggravation of phosphorylated p38 MAPK in response to CSE. Finally, SB216763 treatment significantly ameliorated peribronchial inflammatory cell infiltration, leukocyte influx, and the release of TNF-α and IL-1ß in the bronchoalveolar lavage fluid of CS-exposed mice. Taken together, our findings indicate that the reduced activity of WNT/ß-catenin signaling induced by CS may promote inflammatory cytokine production in airway epithelium and have an essential role in airway inflammation in COPD by PPARδ/p38 MAPK pathway.

RAGE-ligands axis: A new 'driving force' for cigarette smoke-induced airway inflammation in COPD?

Receptor for advanced glycation end products (RAGE) was recently shown to contribute to cigarette smoke (CS)-induced airway inflammation in chronic obstructive pulmonary disease (COPD). In this study, RAGE small interfering ribonucleic acid (RNA) transfection attenuated increased messenger RNA levels of common RAGE ligands HMGB1, S100A8, S100A9 and S100A12, but not S100B following exposure to CS extract. Our findings and those from recent studies suggest a positive feedback involving RAGE and its ligands as a new 'driving force' for CS-induced airway inflammation in COPD.

The rs7003908 (T>G) polymorphism in the XRCC7 gene and the risk of cancers.

The association between the rs7003908 (T>G) polymorphism in the XRCC7 gene and the risk of cancers had been widely studied; however, the results were inconsistent. The objective of the current study was to investigate the association between the rs7003908 polymorphism in the XRCC7 gene and the risk of cancers by meta-analysis. We searched PubMed, EMbase, CNKI and Wanfang databases; the last search was performed on January 10th, 2014. Statistical analysis was performed using the Revman4.2 and STATA10.0 softwares. A total of 3,684 cancer cases and 5,232 controls from 11 case-control studies were included for data analysis. In the dominant model analysis, the results suggested a lack of association between the polymorphism and the risk of cancers: OR 1.01, 95% CI 0.83-1.16, P = 0.70. In the subgroup analysis by ethnicity, no significant association was found either for Asians or Caucasians. In the subgroup analysis by cancer types, significant association was found for prostate cancer, but not for bladder cancer, breast cancer and glioma. In summary, the current meta-analysis confirmed that the rs7003908 polymorphism in the XRCC7 gene might be a risk factor for prostate cancer. In the future, more studies are needed to validate these results.

Overexpression of RAGE contributes to cigarette smoke-induced nitric oxide generation in COPD.

BACKGROUND: Receptor for advanced glycation end products (RAGE), a multiple-ligands receptor, is implicated in chronic obstructive pulmonary disease (COPD). This study was designed to investigate the potential role of RAGE in nitric oxide (NO) generation, an endogenous marker of nitrosative stress in COPD. METHODS: Lung tissues from COPD patients were used to describe the relationship between RAGE expression and NO level. RAGE expression was assessed by immunohistochemistry, western blot, and ELISA. Human bronchial epithelial cells (16HBE) were cultured with cigarette smoke extract (CSE). Neutralizing antibody against RAGE was used to detect the role of RAGE in CSE-induced NO generation by 16HBE cells. RESULTS: Compared with nonsmoker controls, overexpression of RAGE was significantly detected in COPD smokers (p < 0.01), but not healthy smokers and nonsmokers with COPD, which was dominantly expressed at bronchiolar epithelia. Correlation analysis showed that RAGE in COPD smokers was positively related to NO level, smoking status, and lung function decline. In cultured 16HBE cells treated with CSE, soluble RAGE was reduced; however, full-length RAGE was enhanced significantly as the same trend as NO generation. Moreover, increased NO level and NO synthase activity, decreased total glutathione (a major cellular antioxidant), enhanced nuclear translocation of p65 (a key molecule of nuclear factor (NF)-κB) and release of NF-κB-dependent proinflammatory cytokines were all reversed by pretreatment of anti-RAGE antibody. CONCLUSIONS: These findings suggest that overexpression of RAGE contributes to CS-induced NO generation in COPD with involvement in NF-κB activation.

Resolvin-D1 inhibits interleukin-8 and hydrogen peroxide production induced by cigarette smoke extract in 16HBE cells via attenuating NF-κB activation.

BACKGROUND: Cigarette smoke induced airway inflammation plays a role in pathogenesis of airway inflammation. Resolvin-D1 derived from omega-3 polyunsaturated fatty acids is an endogenous anti-inflammatory and proresolving lipid mediator. Resolvin-D1 ameliorated inflammatory responses in lung injury, asthma, peritonitis and atherosclerosis. We investigated whether resolvin-D1 suppressed the productions of chemokines and oxidative stress induced by cigarette smoke extract (CSE) in vitro and its possible mechanism. METHODS: We examined the proinflammatory chemokine interleukin-8 and hydrogen peroxide (H2O2) productions induced by CSE in 16 human bronchial epithelial (16HBE) cells after resolvin-D1 treatment and their mechanisms. 16HBE cells were treated with resolvin-D1 at up to 10 nmol/L, for 30 minutes before CSE up to 16% (v/v) exposure. Release of interlukin-8 proteins was assessed by enzyme linked immunosort assay (ELISA) and its mRNA level by RT-PCR. We evaluated extracellular H2O2 expression in the supernatant. Phosphorylation of NF-κB/p65 and degradation of I-κB in 16HBE cells were determined by Western blotting analysis and NF-κB DNA binding activity by electrophoretic mobility shift assay (EMSA). RESULTS: 16HBE cells treated with 8% CSE showed significantly higher interlukin-8 production. Resolvin-D1 pretreatment inhibited CSE induced interlukin-8 production (mRNA and protein) in a dose and time dependent manner. Extracellular H2O2 level decreased after resolvin-D1 treatment. Resolvin-D1 attenuated CSE triggered I-κB degradation and NF-κB/p65 activation dose dependently and inhibited NF-κB DNA binding activity. CONCLUSION: Resolvin-D1 inhibits CSE induced interlukin-8 and H2O2 production in 16HBE cells by modulating NF-κB activation and has therapeutic potential for pulmonary inflammation.

Increased expression of heat shock protein 70 in chronic obstructive pulmonary disease.

BACKGROUND: Heat shock protein 70 (HSP70) plays a critical role in the process of inflammation and innate immunity response under environmental stress. OBJECTIVES: This study was to investigate HSP70 expression in the peripheral lung tissues of chronic obstructive pulmonary disease (COPD) patients and in human bronchial epithelial cells (16-HBE) exposed to cigarette smoke extract (CSE). METHODS: Peripheral lung tissues were collected after lung cancer resection from 26 patients without COPD, 20 with mild COPD and 15 with advanced COPD, classified by lung function criteria. Among these cases, 37 were smokers and 24 non-smokers. Lung tissues were examined for histopathological changes and levels of HSP70 and IL-8. Cultured 16-HBE cells were stimulated with CSE in the absence or presence of HSP70 neutralizing antibody and the expressions of IL-8 and phospho-EGFR protein were determined. RESULTS: Compared to patients without COPD, the levels of HSP70 and IL-8 were significantly increased in the lung tissues of COPD patients and positively correlated with the severity of the disease. The HSP70 expression was significantly higher in current smokers than that in non-smokers. Moreover, CSE-induced HSP70 significantly enhanced IL-8 production and EGFR phosphorylation in 16-HBE cells. The increases in IL-8 and phospho-EGFR were blocked by anti-HSP70 antibody. CONCLUSIONS: Our study clarified that increased expression of HSP70 is closely related to COPD disease severity and smoking status. Extracellular HSP70 regulated chemokine productions and EGFR phosphorylation and plays an important role in the CSE-induced inflammatory and innate immunity responses in bronchial epithelia cells.

Blocking of thromboxane A2 receptor attenuates airway mucus hyperproduction induced by cigarette smoke.

Cigarette smoking is one of the risk factors for chronic obstructive pulmonary disease (COPD). In this study, we investigated the effects of thromboxane A2 (TxA2) receptor antagonists on airway mucus production induced by cigarette smoke. Rats were exposed to cigarette smoke 1h/day, 6 days/week for 4 weeks. Seratrodast (2, 5, 10mg/kg day) was administered intragastrically prior to smoke exposure. Thromboxane B2 (TxB2) in the bronchoalveolar lavage fluid and lung tissues was determined by enzyme immunoassay. Airway mucus production was determined by alcin-blue/periodic acid sthiff (AB-PAS) staining, Muc5ac immunohistochemical staining, and RT-PCR. The phosphorylation of ERK and p38 was evaluated by Western blotting. Seratrodast reduced the overproduction of TxB2 in both bronchoalveolar lavage fluid and lung tissues. Cigarette smoke exposure markedly increased AB/PAS-stained goblet cells and rat Muc5ac expression in the airway, which was significantly attenuated by seratrodast administration. The induced phosphorylation of ERK and p38 was also attenuated by seratrodast. TxA2 receptor antagonist could reduce Muc5ac production induced by cigarette smoke in vivo, possibly through the mitogen-activated protein kinases (MAPK) signaling pathway.

Resolvin D1 attenuates inflammation in lipopolysaccharide-induced acute lung injury through a process involving the PPARγ/NF-κB pathway.

BACKGROUND: Docosahexaenoic acid (DHA) and DHA-derived lipid mediators have recently been shown to possess anti-inflammatory and pro-resolving properties. In fact, DHA can down-regulate lipolysaccharide (LPS)-induced activation of NF-κB via a PPARγ-dependent pathway. We sought to investigate the effects of the novel DHA-derived mediator resolvin D1 (RvD1) on LPS-induced acute lung injury and to determine whether these effects occur via a PPARγ-dependent pathway. METHODS: BALB/c mice aged 6-8 weeks were randomly divided into seven groups: two control groups receiving saline or RvD1 (600 ng) without LPS; a control group receiving LPS only; an experimental group receiving RvD1 (300 ng) or RvD1 (600 ng), followed by LPS; a group receiving the PPARγ antagonist GW9662; and a group receiving GW9662, then RvD1 (600 ng) and finally LPS. LPS (50 µM) and saline were administered intratracheally. RvD1 was injected intravenously 24 h and 30 min before LPS, while GW9662 was injected intravenously 30 min before RvD1. Mice were killed at 6, 12, and 24 h. Samples of bronchoalveolar lavage fluid (BALF) were analyzed for cell counts and cytokine analysis. Lung tissues were collected for histology, Western blotting and electrophoretic mobility shift assays (EMSAs). RESULTS: At all three time points, groups receiving either dose of RvD1 followed by LPS had significantly lower total leukocyte counts and levels of TNF-α and IL-6 levels in BALF than did the group given only LPS. RvD1 markedly attenuated LPS-induced lung inflammation at 24 h, based on hematoxylin-eosin staining of histology sections. RvD1 activated PPARγ and suppressed IκBα degradation and NF-κB p65 nuclear translocation, based on Western blots and EMSAs. The PPARγ inhibitor GW9662 partially reversed RvD1-induced suppression of IκBα degradation and p65 nuclear translocation. CONCLUSIONS: These results suggest that RvD1 may attenuate lung inflammation of LPS-induced acute lung injury by suppressing NF-κB activation through a mechanism partly dependent on PPARγ activation.

Enhanced expression of human ß-defensin 2 in peripheral lungs of patients with chronic obstructive pulmonary disease.

Human ß-defensin 2 (hBD-2) has antimicrobial activity and may play a role in airway mucosal defense, but studies have not yet examined its expression in lung tissue of patients with chronic obstructive pulmonary disease (COPD). Here we investigated hBD-2 levels in lung tissues of COPD patients and analyzed their correlations with IL-8, IL-1ß, cigarette smoking and lung function in order to see whether the protein may be involved in pathogenesis of the disease. Peripheral lung tissue specimens were obtained from 51 patients who underwent lung resection for peripheral lung cancer: healthy non-smokers (n=8), healthy current smokers (n=7), non-smokers with COPD (n=11), and current smokers with COPD (n=25). RT-PCR and immunohistochemical staining were used to detect expression levels of hBD-2, IL-8 and IL-1ß. Expression of hBD-2 mRNA was significantly higher in COPD patients than in healthy controls, and significantly higher in current smokers than in non-smokers (p<0.05). Among healthy controls, hBD-2 mRNA levels were similar between current smokers and non-smokers. Immunohistochemistry showed hBD-2 protein to be expressed mainly in epithelia of distal bronchioles and its expression pattern among our patient groups mirrored that of the mRNA. IL-8 mRNA levels were significantly higher in COPD patients than in healthy controls (p<0.05), while IL-1ß mRNA levels did not differ significantly among the groups. Levels of hBD-2 mRNA positively correlated with levels of IL-8 mRNA (r=0.545, p=0.002), and negatively correlated with FEV1/FVC ratios and with predicted FEV1% values (r=-0.406, p=0.011). Our results indicate that hBD-2 expression is elevated in distal airways of COPD patients and that it may be involved in pathogenesis of the disease. Our data implicate cigarette smoking as a factor that may elevate hBD-2 levels in lung tissues of COPD patients.

Silencing of c-kit with small interference RNA attenuates inflammation in a murine model of allergic asthma.

Asthma is a chronic respiratory disease characterized by the inflammation of the airways due to infiltration and activation of several inflammatory cells that produce cytokines. c-kit, a proto-oncogene that encodes a tyrosine kinase receptor, has been found to be associated with allergic inflammation. The aim of the present study was to assess whether silencing of c-kit with small interference RNA (siRNA) would attenuate inflammation in allergic asthma. A mouse model of ovalbumin (OVA)-induced allergic asthma was treated with systemic administration of anti-c-kit siRNA to inhibit the expression of the c-kit gene. siRNAs were injected through the vena caudalis. We measured inflammatory response in both anti-c-kit siRNA-treated and control mice. Systemic administration of siRNA could effectively inhibit the expression of the c-kit gene and reduce the infiltration of inflammatory cells (eosinophils and lymphocytes) into the lung tissue and bronchoalveolar lavage fluid. In addition, we found that c-kit siRNA can decrease the production of the T-helper type 2 (Th2) cytokines, interleukin 4 (IL-4) and IL-5, but has no influence on IFN-γ generation. These results show that inhibition of c-kit expression with siRNA can reduce the inflammatory response in allergic asthma.

Quercetin attenuates airway inflammation and mucus production induced by cigarette smoke in rats.

Mucus hypersecretion is a feature of many chronic airway diseases induced by cigarette smoke (CS), and evidence suggests that the antioxidant and anti-inflammatory flavonoid quercetin may protect against CS-induced respiratory pathology. In this study, the ability of quercetin to protect against CS-induced mucin expression was examined in vivo and in vitro. Quercetin or 0.2% Tween aqueous solution was administered intraperitoneally to rats,which were then exposed to CS for 28 days. Cell counts and pro-inflammatory cytokine levels were measured in bronchoalveolar lavage fluid (BALF). Lung tissue was examined for total glutathione (GSH) and total antioxidant capacity (T-AOC), histopathological lesions, goblet cell hyperplasia, epidermal growth factor receptor (EGFR) phosphorylation and NF-κB pathway activation. To complement these in vitro studies, human airway epithelial NCI-H292 cells were pretreated with quercetin and then exposed to cigarette smoke extract (CSE). Cell lysates were examined for Muc5ac expression, EGFR phosphorylation and NF-κB pathway activation. In vivo, quercetin pretreatment suppressed CS-induced goblet cell hyperplasia, inflammation, oxidative stress, EGFR phosphorylation and NF-κB pathway activation in rat lung. In vitro, quercetin pretreatment attenuated the CSE-induced Muc5ac expression, NF-κB activation and EGFR phosphorylation. Our results suggest that quercetin attenuates CS-induced mucin protein synthesis in rat lung, possibly by inhibiting oxidative stress and inflammation via a mechanism involving NF-κB pathway activation and EGFR phosphorylation. These findings suggest that quercetin has a potential for treating chronic airway diseases.