Metabolic syndrome is a common extrapulmonary comorbidity in patients with chronic obstructive pulmonary disease (COPD). However, the reported relationship of COPD with dyslipidemia, an important component of metabolic syndrome, is ambiguous. The aim of this meta-analysis is to investigate the association between COPD and the serum levels of high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), total cholesterol (TC), and triglyceride (TG). The PubMed and Embase databases were searched to find potential studies using the search terms of (“dyslipidemia” or “HDL” or “LDL” or “cholesterol” or “triglyceride”) and COPD. We also performed subgroup analysis enrolling patients who were not receiving treatment for dyslipidemia. Mean differences (MD) with 95% confidence intervals (CI) were estimated with random effects models. A total of 11 studies comprising 615 cases and 471 controls were included in the study. No significant differences were found in the HDL (MD = −2.55, 95% CI [−6.03, 0.93], P = 0.15), LDL (MD = −2.25, 95% CI [−13.36, 8.86], P = 0.69), TC (MD = −2.69, 95% CI [−13.30, 7.92], P = 0.62), and TG (MD = 6.90, 95% CI [−2.81, 16.60], P = 0.16) levels of the 2 groups. However, subgroup analysis enrolling patients who were not receiving treatment for dyslipidemia showed that TG levels were higher in patients with stable COPD than in healthy individuals (MD = 16.35, 95% CI [5.90, 26.80], P = 0.002). Excluding the impact of hypolipidemic treatment on serum lipid profile, TG levels were higher in patients with COPD than in healthy individuals. This meta-analysis suggested that physicians should screen COPD patients for elevated TG levels to reduce the risk of cardiovascular morbidity and mortality.

Histone deacetylase 2 (HDAC2) is a class I histone deacetylase family member that plays a critical role in suppressing inflammatory gene expression in the airways, lung parenchyma, and alveolar macrophages in patients with chronic obstructive pulmonary disease (COPD). However, the expression of HDAC2 in peripheral blood monocytes (PBMCs), nuclear factor kappa B (NF-κB) p65, and serum inflammatory cytokine levels in COPD patients, smokers, and non-smokers remains unclear. PBMCs were obtained from COPD patients, healthy smokers, and healthy nonsmokers. The HDAC2 and NF-κB p65 expression were quantified by Western Blot. HDAC activity was assessed by an HDAC fluorometric immunoprecipitation activity assay kit. Serum tumor necrosis factor-alpha (TNF-α) and interleukin-8 (IL-8) levels were measured by ELISA. HDAC2 expression and HDAC activity were decreased in PBMCs in COPD patients compared with smokers and non-smokers. Increased NF-κB p65 expression, serum TNF-α and IL-8 levels were observed in COPD patients compared with nonsmokers. The FEV₁%pred was positively correlated with HDAC2 expression and HDAC activity in COPD patients. Smokers had decreased HDAC activity, increased NF-κB p65 expression and serum TNF-α compared with nonsmokers. HDAC2 expression was decreased in PBMCs of COPD patients and was correlated with disease severity. The reduction of HDAC2 expression not only directly enhances the expression of inflammatory genes, but may account for the activation of NF-κB mediated inflammation. Decreased HDAC2 may serve as a potential biomarker of COPD and predict the decline of lung function.

Background: Ceramide, a bioactive lipid, plays an essential role in the development of several pulmonary inflammatory diseases. Matrix metallopeptidase 9 (MMP-9) regulates the synthesis and degradation of extracellular matrix, and is associated with airway remodeling and tissue injury. This study was conducted to investigate the effects and underlying mechanisms of ceramide on MMP-9 expression in airway epithelium. Methods: BEAS-2B cells, normal human bronchial epithelium cell lines, were pretreated with AG490, a selective janus tyrosine kinase 2 (JAK2) inhibitor, or Stattic, a selective signal transducer and activator of transcription 3 (STAT3) inhibitor. The cells were then stimulated with C6-ceramide. The levels of MMP-9 were determined by ELISA and real-time quantitative PCR (RT-qPCR). JAK2, phosphorylated JAK2 (p-JAK2), STAT3, and phosphorylated STAT3 (p-STAT3) expression was examined by Western blotting. BALB/c mice were pretreated with AG490 or Stattic before intratracheally instillated with C6-ceramide. Pathological changes in lung tissues were examined by Hematoxylin and Eosin staining, Periodic-acid Schiff staining, and Masson’s trichrome staining. MMP-9, JAK2, p-JAK2, STAT3, and p-STAT3 expression in the lung tissues was examined by Western blotting. Results: The expression of MMP-9, p-JAK2 and p-STAT3 in BEAS-2B cells was significantly increased after the treatment of C6-ceramide. Furthermore, the increased expression of MMP-9 induced by C6-ceramide was inhibited by AG490 and Stattic. Similar results were obtained in the lung tissues of C6-ceramide-exposed mice which were treated with AG490 or Stattic. Conclusions: Ceramide could up-regulate MMP-9 expression through the activation of the JAK2/STAT3 pathway in airway epithelium. Targeted modulation of the ceramide signaling pathway may offer a potential therapeutic approach for inhibiting MMP-9 expression. This study points to a potentially novel approach to alleviating airway remodeling in inflammatory airway diseases.

Background: Chronic inflammation is one of the important mediators of colitis-related colon cancer (CRC). Abundant mast cells (MCs) were observed in the tumor microenvironment and mediators released upon MC activation play an important role in the process of chronic inflammation. Previously, we found that activation of intestine mucosal MCs recruited and modulated the inflammatory CD11b+Gr1+ cells to promote the CRC development. In the current study we investigated the effects of Vam3, a resveratrol dimer with potent anti-inflammatory effects, on CRC development. Methods: RBL-2H3 cells, a basophilic leukemia cell line, were pretreated with 2.5 or 5 μΜ Vam3 and then stimulated with dinitrophenol-conjugated bovine serum albumin (DNP-BSA) plus lipopolysaccharide (LPS). The MC degranulation was determined by measuring β-hexosaminidase release. Generation of TNF-α and IL-6 in RBL-2H3 cells or in peritoneal macrophages was determined by ELISA and real-time qPCR. NF-κB p65 and phospho-NF-κB p65 expression was determined by Western blotting. NF-κB activity in RAW264.7 cells was determined by luciferase reporter assay. CRC was induced in C57BL/6 mice by intraperitoneal injection of azoxymethane (AOM), followed by oral exposure to dextran sodium sulfate (DSS). Vam3 at 50 mg/kg, or disodium cromoglycate (DSCG, MC stabilizer) at 100 mg/kg, or vehicle were administrated to the mice 4 weeks after DSS withdrawal. Levels of TNF-α, IL-6, and mouse MC protease-1 were determined by ELISA. Infiltration of CD11b+Gr1+ cells was determined by flow cytometry analysis. One-way ANOVA was used to compare difference between groups. Results: Pretreatment with Vam3 significantly inhibited RBL-2H3 cell degranulation and inflammatory cytokine production from RBL-2H3 cells and from peritoneal macrophages. After Vam3 treatment, NF-κB activity in RAW264.7 cells, and expressions of phospho-NF-κB p65 in RBL-2H3 cells and in peritoneal macrophages were significantly down-regulated. In the AOM plus DSS-induced CRC murine model, the Vam3 and DSCG-treated mice had less tumor numbers than those treated with vehicle. Expression of phospho-NF-κB p65, production of inflammatory cytokines, and infiltration of MCs and CD11b+Gr1+ cells were attenuated in the Vam3-treated mice. Conclusions: Vam3 treatment could attenuate the CRC development. This effect may be due to its inhibition on NF-κB signaling pathway in MCs and macrophages of the inflamed intestines.

Background: Corticosteroid resistance in asthma, marked by reduced glucocorticoid response, is significantly influenced by cigarette smoke (CS). We sought to explore potential novel biomarkers and therapeutic targets associated with CS-induced corticosteroid resistance in asthma. Methods: GSE230048 (related to corticosteroid resistance) and GSE13896 (from CS-exposed macrophages) were obtained from GEO. Initially, we performed differential gene expression analysis and weighted gene co-expression network analysis (WGCNA) to discover key genes involved in corticosteroid resistance in asthma. Gene Ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted. Receiver operating characteristic (ROC) analysis was used to assess the diagnostic accuracy of these markers. CIBERSORT was applied to clarify immune cell infiltration. Expression of the key biomarker was validated in asthma patients and asthma murine models. Results: Five overlapping genes upregulated in corticosteroid-resistant asthma patients and smokers’ alveolar macrophages were identified. Subsequently, using WGCNA, the most relevant modules were identified and intersected with differentially expressed genes. Tensin 1 (TNS1), ATP-binding cassette subfamily C member 4 (ABCC4), and TNF receptor superfamily member 21 (TNFRSF21) were identified as critical biomarkers for corticosteroid resistance in asthma. ROC analysis showed an AUC of 0.718 for the three-marker combination. Single-cell RNA sequencing confirmed their expression in macrophages from asthmatic patients. Elevated levels of TNS1, ABCC4, TNFRSF21, and M2 macrophage markers (CD301 and CD206) were observed in CS-exposed murine lung tissues and CS condensate-treated Raw264.7 cells. TNS1 knockdown significantly reduced CD301 and CD206 expression, suggesting its role in promoting macrophage M2 polarization. Conclusion: In conclusion, we identified three hub genes (TNS1, ABCC4, and TNFRSF21) associated with CS-induced corticosteroid resistance in asthma. Additionally, TNS1 may be involved in CS-induced corticosteroid resistance in asthma by promoting macrophage M2 polarization.