Ginsenoside Rb3 Alleviates CSE-induced TROP2 Upregulation through p38 MAPK and NF-κB Pathways in Basal Cells.

Smoking-mediated reprogramming of the phenotype and function of airway basal cells (BCs) disrupts airway homeostasis and is an early event in chronic obstructive pulmonary disease (COPD)-associated airway remodeling. Here, we examined the expression and regulation of the transmembrane glycoprotein TROP2 (trophoblast antigen 2), a putative stem cell marker in airway BCs, in lung tissue samples from healthy smokers and healthy nonsmokers and in models in culture to identify therapeutic targets. TROP2 expression was upregulated in the airway epithelia of smokers and positively correlated with the smoking index. In vitro, cigarette smoke extract (CSE) induced TROP2 expression in airway BCs in a time- and dose-dependent manner. The p38 MAPK and NF-κB pathways were also activated by CSE, and their specific antagonists inhibited CSE-induced TROP2 expression. A therapeutic component derived from traditional Chinese medicine, ginsenoside Rb3, inhibited CSE-induced TROP2 expression as well as activation of the p38 MAPK and NF-κB pathways in BCs in monolayer culture. Furthermore, ginsenoside Rb3 prevented the increase in TROP2 expression and antagonized CSE-induced BC hyperplasia and expression of inflammatory factors and epithelial-mesenchymal transition changes in an air-liquid culture model. Thus, CSE-induced TROP2 is a possible biomarker for early changes in the epithelium of smokers, and ginsenoside Rb3 may serve as a therapeutic molecule, preventing the disruption of epithelial homeostasis in COPD.

Increased expression of TROP2 in airway basal cells potentially contributes to airway remodeling in chronic obstructive pulmonary disease.

BACKGROUND: The airway epithelium of chronic obstructive pulmonary disease (COPD) patients undergoes aberrant repair and remodeling after repetitive injury following exposure to environmental factors. Abnormal airway regeneration observed in COPD is thought to originate in the stem/progenitor cells of the airway epithelium, the basal cells (BCs). However, the molecular mechanisms underlying these changes remain unknown. Here, trophoblast cell surface antigen 2 (TROP2), a protein implicated in the regulation of stem cell activity, was examined in lung tissue samples from COPD patients. METHODS: The expression of TROP2 and hyperplasia index Ki67 was assessed in lung epithelium specimens from non-smokers (n = 24), smokers (n = 24) and smokers with COPD (n = 24). Primary airway BCs were isolated by bronchoscopy from healthy individuals and COPD patients and subsequently transfected with pcDNA3.1-TROP2 or siRNA sequence in vitro. The functional consequences of TROP2 overexpression in BCs were explored. RESULTS: Immunohistochemistry and immunofluorescence revealed increased TROP2 expression in airway BCs in smokers with COPD compared to nonsmokers and smokers without COPD, and staining was highly localized to hyperplastic regions containing Ki67 positive cells. TROP2 expression was also inversely correlated with airflow limitation in patients with COPD (r = -0.53, P < 0.01). pcDNA3.1-TROP2-BCs in vitro exhibited improved proliferation with activation of ERK1/2 phosphorylation signaling pathway. In parallel, changes in vimentin and E-cadherin in pcDNA3.1-TROP2-BCs were consistent with an epithelial-mesenchymal transition (EMT)-like change, and secretion of inflammatory factors IL-1ß, IL-8 and IL-6 was increased. Moreover, down-regulation of TROP2 by siRNA significantly attenuated the proliferation of BCs derived from COPD patients. EMT-like features and cytokine levels of COPD basal cells were also weakened following the down-regulation of TROP2. CONCLUSION: The results indicate that TROP2 may play a crucial role in COPD by affecting BC function and thus airway remodeling through increased BC hyperplasia, EMT-like change, and introduction of inflammatory molecules into the microenvironment.

Interleukin-33 gene polymorphisms and chronic obstructive pulmonary disease in the Chinese Han population.

OBJECTIVE: To investigate the relationship between interleukin (IL)-33 gene polymorphisms rs928413 and rs7044343 with chronic obstructive pulmonary disease (COPD) in the Chinese Han population. METHOD: We assessed IL-33 rs928413 and rs7044343 polymorphisms by Sanger sequencing of PCR products amplified from the genomic DNA of 160 COPD patients and 123 healthy controls. RESULTS: There was no significant difference in the distribution of rs928413 AA, AG, or AA genotypes or rs7044343 CC, CT, or TT genotypes between the two groups. However, COPD patients had a significantly higher frequency of the rs928413 G allele G (14.1% vs 7.3%, respectively). This allele was significantly associated with susceptibility to COPD (odds ratio [OR]: 2.04, 95% confidence interval [CI]: 1.12-3.57). The rs928413 dominant inheritance model was associated with COPD susceptibility (OR: 2.08, 95%CI: 1.09-4.04). CONCLUSION: The G allele of rs928413 and the rs928413 dominant inheritance model were associated with susceptibility to COPD in the Chinese Han population.

High prevalence of bronchiectasis in emphysema-predominant COPD patients.

Background: COPD has been identified as an etiology or related disease of bronchiectasis, and bronchiectasis has been classified as a comorbidity of COPD. In this study, we investigated the prevalence of bronchiectasis in different phenotypes of COPD subjects and the correlation between bronchiectasis and different phenotypes, especially emphysema. Methods: COPD patients were recruited from April 2012 to December 2015. The presence of bronchiectasis and related information were statistically analyzed. COPD subjects were separated into subgroups in two ways: COPD with and without bronchiectasis groups and emphysema-predominant (emphysema index, EI≥9.9%) and non-emphysema-predominant (EI<9.9%) groups. Results: In total, 1,739 COPD patients were incorporated into the study, among which 140 cases (8.1%) were accompanied with radiological bronchiectasis. COPD patients with concomitant bronchiectasis presented worse pulmonary function (FEV1% predicted, P<0.001), higher EI (15.0% vs 13.4%, P<0.001), and higher proportion of pulmonary hypertension and cor pulmonale (6.4% vs 2.4%, P=0.005 and 23.6% vs 16.1%, P=0.022) than patients without bronchiectasis. Of all the COPD patients, 787 with EI data were divided into emphysema-predominant (n=369) and non-emphysema-predominant groups (n=418). The proportion of bronchiectasis was 16.5% and 10.3% (P=0.01), respectively. Severity of bronchiectasis increased as the degree of airflow limitation (r=-0.371, P<0.001) and emphysema increased (r=0.226, P=0.021). After adjusting confounding factors, FEV1% predicted (OR, 1.636; 95% CI, 1.219-2.197; P=0.001) and EI (OR, 1.993; 95% CI, 1.199-3.313; P=0.008) were significantly related with the presence of bronchiectasis in COPD patients. Conclusion: The proportion of bronchiectasis is higher in emphysema-predominant COPD subjects. Emphysema measured by EI and FEV1% predicted are independent predictors for bronchiectasis in COPD subjects, while the underlying mechanism deserves further investigation.

Uncertainty quantification and reliability assessment in operational oil spill forecast modeling system.

As oil transport increasing in the Texas bays, greater risks of ship collisions will become a challenge, yielding oil spill accidents as a consequence. To minimize the ecological damage and optimize rapid response, emergency managers need to be informed with how fast and where oil will spread as soon as possible after a spill. The state-of-the-art operational oil spill forecast modeling system improves the oil spill response into a new stage. However uncertainty due to predicted data inputs often elicits compromise on the reliability of the forecast result, leading to misdirection in contingency planning. Thus understanding the forecast uncertainty and reliability become significant. In this paper, Monte Carlo simulation is implemented to provide parameters to generate forecast probability maps. The oil spill forecast uncertainty is thus quantified by comparing the forecast probability map and the associated hindcast simulation. A HyosPy-based simple statistic model is developed to assess the reliability of an oil spill forecast in term of belief degree. The technologies developed in this study create a prototype for uncertainty and reliability analysis in numerical oil spill forecast modeling system, providing emergency managers to improve the capability of real time operational oil spill response and impact assessment.

Disruption of th17/treg balance in the sputum of patients with chronic obstructive pulmonary disease.

BACKGROUND: Amplified inflammation persists in the airways of patients with chronic obstructive pulmonary disease (COPD); however, the underlying mechanism is still unclear. Th17/T regulatory cells (Treg) imbalance may exist in the airways and contribute to this abnormal inflammation. METHODS: This study involved 21 patients with COPD, 21 healthy smokers (HS), and 21 healthy nonsmokers (HNS). We investigated receptor-related orphan receptor (RORC2) and forkhead box P3 (FOXP3) mRNA expression in induced sputum by real-time polymerase chain reaction and assayed IL-17, IL-10, TGF-ß and IL-6 by enzyme-linked immunosorbent assay. Th17 and Treg cells in peripheral blood were analyzed by flow cytometry. RESULTS: The level of sputum FOXP3 mRNA in both COPD and HNS was lower than that in HS (PCOPD = 0.017; PHNS = 0.009). In contrast, the level of RORC2 mRNA was markedly higher in COPD than in either HS or HNS (PHS = 0.005; PHNS < 0.001). There was a correspondingly elevated ratio of sputum RORC2 to FOXP3 mRNA in COPD. Concentrations of IL-17, TGF-ß and IL-6 were elevated in COPD sputum. In peripheral blood, both Th17 and Treg cells were elevated in COPD. CONCLUSIONS: A compartmental imbalance of Th17 over Treg exists in the airways of patients with COPD, suggesting a defect in anti-inflammatory homeostasis in COPD.