Yongchang Sun

Disturbance of the OPG/RANK/RANKL pathway and systemic inflammation in COPD patients with emphysema and osteoporosis

BackgroundOsteoporosis is one of the systemic features of COPD. A correlation between the emphysema phenotype of COPD and reduced bone mineral density (BMD) is suggested by some studies, however, the mechanisms underlying this relationship are unclear. Experimental studies indicate that IL-1β, IL-6 and TNF-α may play important roles in the etiology of both osteoporosis and emphysema. The OPG/RANK/RANKL system is an important regulator of bone metabolism, and participates in the development of post-menopausal osteoporosis. Whether the OPG/RANK/RANKL pathway is involved in the pathogenesis of osteoporosis in COPD has not been studied.MethodsEighty male patients (current or former smokers) completed a chest CT scan, pulmonary function test, dual x-ray absorptiometry measurements and questionnaires. Among these subjects, thirty patients with normal BMD and thirty patients with low BMD were selected randomly for measurement of IL-1β, IL-6, TNF-α (flow cytometry) and OPG/RANK/RANKL (ELISA). Twenty age-matched healthy volunteers were recruited as controls.ResultsAmong these eighty patients, thirty-six had normal BMD and forty-four had low BMD. Age, BMI and CAT score showed significant differences between these two COPD groups (p < 0.05). The low-attenuation area (LAA%) in the lungs of COPD patients was negatively correlated with lumbar vertebral BMD (r = 0.741; p < 0.0001). Forward logistic regression analysis showed that only LAA% (p = 0.005) and BMI (p = 0.009) were selected as explanatory variables. The level of IL-1β was significantly higher in the COPD patients as compared to the normal controls (p < 0.05), but the difference between the two COPD groups did not reach significance. The levels of IL-6 and TNF-α among the three groups were significantly different (p < 0.05). The level of RANKL and the RANKL/OPG ratio were significantly higher in COPD patients with low BMD compared to those with normal BMD and the normal controls (p < 0.05), and correlated negatively with lumbar vertebral BMD, but positively with LAA%.ConclusionsRadiographic emphysema is correlated with low BMD in current and former smokers with COPD. IL-1β, IL-6, TNF-α, and the osteoporosis-related protein system OPG/RANK/RANKL may have some synergetic effects on emphysema and bone loss in COPD.

Imbalance between subpopulations of regulatory T cells in COPD

Background Recent evidence indicates that human regulatory T cells (Tregs) are composed of three distinct subpopulations: CD25++ CD45RA+ resting Tregs (rTregs), CD25+++ CD45RA− activated Tregs (aTregs), which are suppressive, and CD25++ CD45RA− cytokine-secreting (Fr III) cells with pro-inflammatory capacity. Objectives To evaluate the dynamic changes in circulating and pulmonary Treg subpopulations in smokers and patients with chronic obstructive pulmonary disease (COPD), and to explore their potential roles in COPD pathogenesis. Methods Blood samples were obtained from 57 never-smokers, 32 smokers with normal lung function and 66 patients with COPD. Bronchoalveolar lavage (BAL) samples were taken from 12 never-smokers, 12 smokers and 18 patients with COPD. The proportions of Treg subpopulations and activated CD8 T cells were evaluated using flow cytometry. Results In peripheral blood, increased proportions of rTregs, aTregs and Fr III cells were found in smokers compared with never-smokers, whereas patients with COPD showed decreased rTregs and aTregs, and significantly increased Fr III cells compared with smokers. The changes in Treg subpopulations, with an overall decrease in the (aTreg+rTreg):(Fr III) ratio, indicated that immune homeostasis favoured inflammation and correlated with enhanced CD8 T-cell activation (r=−0.399, p<0.001) and forced expiratory volume in 1 s (FEV1) % predicted value (r=0.435, p<0.001).The BAL (aTreg+rTreg):(Fr III) ratios displayed more robust correlations with FEV1% predicted value (r=0.741, p<0.01) and activation of effector T cells (r=−0.763, p<0.001). Conclusions The imbalance between the anti-inflammatory subsets (aTreg+rTreg) and the pro-inflammatory subset (Fr III) of Tregs may play an important role in COPD progression.

Direct comparison of the dynamics of IL‐25‐ and ‘allergen’‐induced airways inflammation, remodelling and hypersensitivity in a murine asthma model

Interleukin‐25 has been implicated in the pathogenesis of asthma from studies on human asthmatics and in murine asthma models.

PPARδ Agonist GW501516 Inhibits PDGF-Stimulated Pulmonary Arterial Smooth Muscle Cell Function Related to Pathological Vascular Remodeling

Pulmonary arterial hypertension (PAH) is a severe and progressive disease, a key feature of which is pulmonary vascular remodeling. Growth factors, cytokines, and lipid mediators are involved in this remodeling process. Recent reports suggest that the peroxisome proliferator-activated receptors (PPARs) play important roles in the regulation of cell growth and differentiation as well as tissue wounding and repair. In this study, we examined the role of PPARδ in the regulation of proliferation, migration, collagen synthesis, and chemokine production in human pulmonary arterial smooth muscle cells (HPASMCs). The data showed that PPARδ was the most abundant isoform in HPASMCs. PPARδ was upregulated in HPASMCs treated with PDGF, which is the major mediator in pulmonary vascular remodeling. Activation of PPARδ by GW501516, a specific PPARδ ligand, significantly inhibited PDGF-induced proliferation in HPASMCs. The inhibitory effect of GW501516 on HPASMCs was associated with decreased expression of cyclin D1, cyclin D3, CDK2, and CDK4 as well as increased expression of the cell cycle inhibitory genes G0S2 and P27kip1. Pretreatment of HPASMCs with GW501516 significantly inhibited PDGF-induced cell migration and collagen synthesis. GW501516 also significantly attenuated TNF-mediated expression of MCP-1. These results suggest that PPARδ may be a potential therapeutic target against the progression of vascular remodeling in PAH.

The prevalence of increased serum IgE and Aspergillus sensitization in patients with COPD and their association with symptoms and lung function

BackgroundAllergy and Aspergillus hypersensitivity (AH) were shown to be associated with severe symptoms or worse lung function in COPD patients. The prevalence of elevated total IgE (T-IgE) and its association with clinical symptoms and lung function in COPD have not been studied. The prevalence of AH and its correlation with clinical characteristics in a COPD cohort of larger sample size is also lacking.Methods273 patients with COPD were evaluated by respiratory symptoms, blood test, chest HRCT, lung function, serum detection of T-IgE and Aspergillus specific IgE. Patients with T-IgE ≥ 1000 KU/L were further investigated for allergic bronchopulmonary aspergillosis (ABPA).ResultsThe prevalence of elevated T-IgE and AH in patients with COPD was 47.3% and 15.0%, respectively. Eight patients (2.9%) met the diagnostic criteria for ABPA. Compared with the normal T-IgE group, patients with elevated T-IgE had a longer history of dyspnea (p < 0.01), an earlier onset of dyspnea after chronic cough/expectoration (p < 0.01), and were more likely to wheeze (p < 0.01). They also showed worse lung functions and more severe GOLD staging (p < 0.01). Analysis of the clinical data in male patients with smoking as the risk factor showed the same results. To evaluate the clinical characteristics of COPD with AH, patients with elevated T-IgE were further divided into subgroups with and without AH. When compared with the normal T-IgE group, both the two subgroups showed longer history of dyspnea (p < 0.01), an earlier onset of dyspnea (p < 0.01) and a worse status of lung function (p < 0.05). Correlation analysis demonstrated that T-IgE was correlated positively with the time length of dyspnea (r = 0.401, p < 0.001), and the ratio of duration of dyspnea to that of chronic cough/expectoration (r = 0.59, p < 0.001), but negatively with FEV1/FVC% (r = −0.194, p = 0.001), and FEV1%predicted (r = −0.219, p < 0.001).ConclusionsThere was a high prevalence of elevated serum T-IgE and AH in patients with COPD. Serum T-IgE level was correlated with symptoms such as dyspnea and impairment of lung function. Allergens other than Aspergillus may have similar effects on disease expression or progression of COPD.

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

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.

Peripheral Tc17 and Tc17/Interferon-γ Cells are Increased and Associated with Lung Function in Patients with Chronic Obstructive Pulmonary Disease

Background:Chronic obstructive pulmonary disease (COPD) is characterized by progressive loss of lung function and local and systemic inflammation, in which CD8+ T-cells are believed to play a key role. Activated CD8+ T-cells differentiate into distinct subpopulations, including interferon-&ggr; (IFN-&ggr;)-producing Tc1 and interleukin (IL)-17-producing Tc17 cells. Recent evidence indicates that Tc17 cells exhibit considerable plasticity and may convert into IL-17/IFN-&ggr;-double producing (Tc17/IFN-&ggr;) cells when driven by inflammatory conditions. The aim of this study was to investigate the Tc17/IFN-&ggr; subpopulation in peripheral blood of patients with COPD and to evaluate their potential roles in this disease. Methods:Peripheral blood samples were collected from 15 never-smokers, 23 smokers with normal lung function, and 25 patients with COPD (Global Initiative for Chronic Obstructive Lung Disease 2–4). Proportions of the IL-17/IFN-&ggr;-double expressing subpopulation were assessed using flow cytometry. Plasma concentrations of cytokines favoring Tc17/IFN-&ggr; differentiation were measured by enzyme-linked immunosorbent assay. Results:Patients with COPD had higher proportions of Tc17 cells and Tc17/IFN-&ggr; cells in the peripheral blood than smokers and never-smokers. The plasticity of Tc17 cells was higher than that of Th17 cells. The percentages of Tc17 cells and Tc17/IFN-&ggr; cells showed negative correlations with forced expiratory volume in 1 s % predicted value (r = −0.418, P = 0.03; r = −0.596, P = 0.002, respectively). The plasma concentrations of IL-6, transforming growth factor-&bgr;1, and IL-12 were significantly higher in patients with COPD compared with smokers and never-smokers. Conclusions:Peripheral Tc17 cells are increased and more likely to convert to Tc17/IFN-&ggr; cells in COPD, suggesting that Tc17 cell plasticity may be involved in persistent inflammation of the disease.

Answer to ‘COPD and IPF: it's all about regulation and balance’

We thank Tzouvelekis and Bouros1 for their interest in our recent article in Thorax .2 The theory of Hippocrates reminds us of the balance theory informing traditional Chinese medicine. Ancient Chinese scholars believed there were two natural, complementary yet contradictory forces in our universe: yin and yang, with the former being feminine or negative and the latter masculine or positive. Both of them are always in a state of dynamic balance. A balanced state …