Increased adipose tissue expression of proinflammatory CD40, MKK4 and JNK in patients with very severe chronic obstructive pulmonary disease.

BACKGROUND: CD40, a transmembrane receptor of the tumor necrosis factor gene superfamily, is activated in response to cellular stress, including hypoxia, and orchestrates the process of inflammation via secondary messengers such as mitogen-activated protein kinase kinase 4 (MKK4) and c-Jun NH(2)-terminal kinases (JNK). OBJECTIVES: We hypothesized that CD40, MKK4 and JNK expression is increased in the adipose tissue of patients with very severe chronic obstructive pulmonary disease (COPD). METHODS: In 20 patients with stable COPD, lung function was assessed using body plethysmography, and samples of subcutaneous adipose tissue were analyzed using real-time PCR. Body composition, including fat mass index (FMI), was assessed by bioelectrical impedance. RESULTS: 12 patients in GOLD stage I-III (age 61.6 ± 8.6 years, 4 females, mean partial pressure of oxygen in arterial blood, PaO(2), 9.38 ± 0.21 kPa) were compared to 8 patients in GOLD stage IV (age 62.6 ± 6.3 years, all male, mean PaO(2) 7.70 ± 0.37 kPa). Compared to patients in GOLD stage I-III, patients in GOLD stage IV had lower FMI (p = 0.004), being associated with significantly higher adipose tissue expression of CD40, MKK4 and JNK [ΔΔCt: 2.55 (1.99, 4.40) vs. 1.87 (1.63, 2.23), p = 0.013; 5.19 (3.13, 5.96) vs. 2.98 (2.82, 3.86), p = 0.002; 9.01 (5.12, 11.41) vs. 4.65 (4.42, 6.26), p = 0.001, respectively]. Log-transformed CD40, MKK4 and JNK expression was significantly inversely related to PaO(2), respectively. CONCLUSIONS: Upregulation of proinflammatory CD40, MKK4 and JNK gene expression in adipose tissue in very severe COPD raises the possibility of a role of chronic systemic hypoxia in the pathogenesis of adipose tissue inflammation in COPD.

Metabolic phenotype and adipose tissue inflammation in patients with chronic obstructive pulmonary disease.

Potential links between metabolic derangements and adipose tissue (AT) inflammation in patients with chronic obstructive pulmonary disease (COPD) are unexplored. We investigated AT expressions of interleukin (IL)-6, tumor necrosis factor (TNF)-α, CD68 (macrophage cell surface receptor), caspase-3, and Bax, and their relationships to the metabolic phenotype in nine cachectic, 12 normal-weight, 12 overweight, and 11 obese patients with COPD (age 62.3 ± 7.2 years). With increasing body mass index, increases in AT expressions of IL-6, TNF-α, and CD68 were observed (P < .001; P = .005; P < .001, resp.), in association with reduced insulin sensitivity (P < .001). No differences were observed between cachectic and normal-weight patients in AT expressions of inflammatory or proapoptotic markers. Adipose tissue CD68 and TNF-α expressions predicted insulin sensitivity independently of known confounders (P = .005; P = .025; R(2) = 0.840). Our results suggest that AT inflammation in obese COPD patients relates to insulin resistance. Cachectic patients remain insulin sensitive, with no AT upregulation of inflammatory or proapoptotic markers.

Nutritional status in relation to respiratory impairment and systemic inflammation in patients with acute exacerbations of COPD.

BACKGROUND: Knowledge of the effects of undernourishment on the severity of respiratory impairment, systemic inflammation and oxidative stress during acute exacerbations of COPD (AECOPD) is limited. In patients with AECOPD, we assessed the relationships between BMI, lung function, and markers of systemic inflammation and oxidative stress. MATERIAL/METHODS: We measured pulmonary function, serum C-reactive protein (CRP), tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-8, malondialdehyde (MDA), erythrocytic glutathione-peroxidase (GPx), superoxiddismutase (SOD), and catalase (CAT) in 113 patients admitted to the hospital due to an AECOPD (80 males, age 66.2+/-11.0 years, FEV1 41.5+/-13.7% predicted). RESULTS: From the low (<21 kg/m2) towards the normal (21-24.9 kg/m2), high (25-29.9 kg/m2) and obese (>30 kg/m2) BMI groups, FEV1, FEV1-to-forced vital capacity (FVC) ratio, inspiratory capacity (IC), and the IC-to-total lung capacity (IC/TLC) ratio increased (p<0.01; p<0.001; p=0.039; p=0.002, respectively), while residual volume (RV), TLC and RV/TLC ratio were reduced (p<0.001; p<0.001; p=0.018, respectively). Patients with low BMI had significantly lower FEV1, FEV1/FVC, IC and IC/TLC, and higher RV and TLC values compared to the high and obese BMI groups. From the low towards the normal, high and obese BMI, reductions in serum CRP, and a trend towards increases in erythrocytic GPx were observed (p=0.023; p=0.056, respectively). No differences were seen in circulating TNF-alpha, IL-6 or IL-8, MDA or erythrocytic CAT and SOD between the groups. CONCLUSIONS: In patients with acute exacerbations of COPD, low BMI is associated with higher degree of bronchial obstruction and pulmonary hyperinflation, in association with higher circulating CRP levels.

Glutathione S-transferase and microsomal epoxide hydrolase gene polymorphisms and risk of chronic obstructive pulmonary disease in Slovak population.

AIM: To determine the risk of chronic obstructive pulmonary disease (COPD) associated with polymorphisms in the glutathione S-transferase (GST) M1, GST T1, and microsomal epoxide hydrolase (EPHX1) genes in a cohort of Slovak population. METHODS: Two hundred and seventeen patients with the diagnosis of COPD and 160 control subjects were enrolled in the study. Blood samples were collected from all subjects and the DNA from peripheral blood lymphocytes was used for subsequent genotyping assays, using polymerase chain reaction and restriction fragment-length polymorphism methods. RESULTS: In an unadjusted model, an increased risk for COPD was observed in subjects with EPHX1 His113-His113 genotype (odds ratio [OR], 2.32; 95% confidence interval [CI], 1.20-4.69; P=0.008), compared with the carriers of the Tyr113 allele. However, after the adjustments for age, sex, and smoking status, the risk was not significant (adjusted OR, 1.79; 95% CI, 0.91-3.53; P=0.093). In a combined analysis of gene polymorphisms, the genotype combination EPHX1 His113-His113/GSTM1 null significantly increased the risk of COPD in both, unadjusted (OR, 5.08; 95% CI, 1.70-20.43; P=0.001) and adjusted model (OR, 4.87; 95% CI, 1.57-15.13; P=0.006). CONCLUSION: Although none of the tested gene polymorphisms was significantly related to an increased risk of COPD alone, our results suggest that the homozygous exon 3 mutant variant of EPHX1 gene in the combination with GSTM1 null genotype is a significant predictor of increased susceptibility to COPD in the Slovak population. The findings of the present study emphasize the importance of detoxifying and antioxidant pathways in the pathogenesis of COPD.

Relationship between osteoporosis and adipose tissue leptin and osteoprotegerin in patients with chronic obstructive pulmonary disease.

INTRODUCTION: The role of fat-bone interactions in the pathogenesis of osteoporosis in chronic obstructive pulmonary disease (COPD) is poorly understood. Our aim was to investigate expressions of leptin and osteoprotegerin (OPG) in the adipose tissue, and their relationships to osteoporosis in patients with COPD. METHODS: In 39 patients with stable COPD, bone mineral density (BMD) and body composition was assessed by Dual Energy X-Ray Absorptiometry. Serum leptin was determined by the enzyme-linked immunosorbent assay, and bone turnover markers osteocalcin and ß-crosslaps by the electrochemiluminiscence immunoassays. Subcutaneous adipose tissue samples were analyzed using real-time PCR. RESULTS: Twenty-one patients without, and 18 with osteoporosis were enrolled (35 men; age 62.2 ± 7.3years). Compared to patients without osteoporosis, those with the disease had significantly lower serum levels and adipose tissue expressions of leptin, in association with increased serum ß-crosslaps (p=0.028, p=0.034, p=0.022, respectively). Log adipose tissue leptin was inversely related to serum ß-crosslaps (p=0.015), and directly to serum leptin (p<0.001) and to the total, femoral, and lumbar BMD and T-score (p<0.02 for all relationships). Adipose tissue OPG expression was related to all variables of bone density except for lumbar BMD and T-score (p<0.05 for all relationships). Log adipose tissue leptin and OPG expressions predicted femoral T-score independently of age, gender and pulmonary function (p<0.001, adjusted R(2)=0.383; p=0.008, adjusted R(2)=0.301, respectively). Introducing body mass (or fat mass) index into these models eliminated independent predictive value of leptin and OPG expressions. CONCLUSION: Our results suggest that adipose tissue leptin and OPG expressions are related to osteoporosis in patients with COPD, and appear to act as mediators between fat mass and BMD.