Citrullinated histone H3, a marker of extracellular trap formation, is increased in blood of stable asthma patients

Background: Emerging data indicates that extracellular traps (ETs), structures formed by various immune cell types, may contribute to the pathology of noninfectious infammatory diseases. Histone hypercitrullination is an important step in ETs formation and citrullinated histone H3 (H3cit) is considered a novel and specifc biomarker of that process. In the present study we have evaluated circulating H3cit in stable asthmatics and investigated its relationship with asthma severity, pulmonary function and selected blood and bronchoalveolar lavage (BAL) biomarkers. Methods: In 60 white adult stable asthmatics and 50 well-matched controls we measured serum levels of H3cit. In asthmatics we also performed bronchoscopy with BAL. We analyzed blood and BAL biomarkers, including interleukin (IL)-4, IL-5, IL-6, IL-10, IL-12p70, IL-17A and interferon γ. For statistical analysis, Mann-Whitney U-test, χ2 test, one-way ANCOVA, ROC curve analysis and univariate linear regression were applied. Independent determinants of H3cit were established in a multiple linear regression model. Results: Asthma was characterized by elevated circulating H3cit (17.49 [11.25–22.58] vs. 13.66 [8.66–18.87] ng/ml, p=0.03). In asthmatics positive associations were demonstrated between serum H3cit and lung function variables, including total lung capacity (TLC) (β=0.37 [95% CI 0.24-0.50]) and residual volume (β=0.38 [95% CI 0.25–0.51]). H3cit was increased in asthma patients receiving systemic steroids (p=0.02), as well as in subjects with BAL eosino‑ philia above 144 cells/ml (p=0.02). In asthmatics, but not in controls, circulating H3cit correlated well with number of neutrophils (β=0.31 [95% CI 0.19–0.44]) and monocytes (β=0.42 [95% CI 0.29–0.55]) in peripheral blood. Further‑ more, BAL macrophages, BAL neutrophils, TLC, high-sensitivity C-reactive protein, Il-12p70 and bronchial obstruction degree were independent determinants of H3cit in a multivariate linear regression model. Conclusions: Asthma is characterized by increased circulating H3cit likely related to the enhanced lung ETs forma‑ tion. Inhibition of ETs might be a therapeutic option in selected asthma phenotypes, such as neutrophilic asthma

The Relationship of Metabolic Syndrome with Stress, Coronary Heart Disease and Pulmonary Function - An Occupational Cohort-Based Study

<div><p>Background and Aims</p><p>Higher levels of stress impact the prevalence of metabolic syndrome (MetS) and coronary heart disease. The association between MetS, impaired pulmonary function and low level of physical activity is still pending assessment in the subjects exposed to stress. The study aimed to examine whether higher levels of stress might be related to MetS and the plaque presence, as well as whether MetS might affect pulmonary function.</p><p>Design and Methods</p><p>The study embraced 235 police officers (mean age 40.97 years) from the south of Poland. The anthropometrics and biochemical variables were measured; MetS was diagnosed using the International Diabetes Federation criteria. Computed tomography coronary angiography of coronary arteries, exercise ECG, measurements of brachial flow-mediated dilation, and carotid artery intima-media thickness were completed. In order to measure the self-perception of stress, 10-item Perceived Stress Scale (PSS-10) was applied. Pulmonary function and physical activity levels were also addressed. Multivariate logistic regression analyses were applied to determine the relationships between: 1/ incidence of coronary plaque and MetS per se, MetS components and the number of classical cardiovascular risk factors, 2/ perceived stress and MetS, 3/ MetS and pulmonary function parameters.</p><p>Results</p><p>Coronary artery atherosclerosis was less associated with MetS (OR = 2.62, 95%CI 1.24–5.52; p = 0.011) than with a co-existence of classical cardiovascular risk factors (OR = 5.67, 95% CI 1.07–29.85, p = 0.03; for 3 risk factors and OR = 9.05; 95% CI 1.24–66.23, p = 0.02; for 6 risk factors, respectively). Perceived stress increased MetS prevalence (OR = 1.07, 95% CI 1.03–1.13; p = 0.03), and impacted coronary plaque prevalence (OR = 1.05, 95% CI 1.001–1.10; p = 0.04). Leisure-time physical activity reduced the chances of developing MetS (OR = 0.98 95% CI 0.96–0.99; p = 0.02). MetS subjects had significantly lower values of certain pulmonary function parameters.</p><p>Conclusions</p><p>Exposure to job-specific stress among police officers increased the prevalence of MetS and impacted coronary plaque presence. MetS subjects had worse pulmonary function parameters. Early-stage, comprehensive therapeutic intervention may reduce overall risk of cardiovascular events and prevent pulmonary function impairment in this specific occupational population.</p></div

Characteristics of the study subjects stratified by metabolic syndrome status.

<p>Data are expressed as mean (SD); BMI, body mass index; W/H, waist/hip; CHD, coronary heart disease; FMD, flow-mediated dilation; IMT, intima-media thickness; LDL, low density lipoprotein; HDL, high density lipoprotein; CRP, C-reactive protein; TNF-α, tissue necrotic factor-α;</p><p>* n (%) subjects who underwent stress ECG;</p><p>** n (%) subjects who underwent computed tomography coronary angiography.</p><p>Characteristics of the study subjects stratified by metabolic syndrome status.</p

Models of logistic regression analysis: assessment of the impact of metabolic syndrome on the coronary plaque prevalence, depending on the correcting variable.

<p>Data are expressed as ORs and corresponding 95% CIs.</p><p>OR, odd ratio; CI, confidence interval;</p><p>Model 0*—perceived stress score, unadjusted;</p><p>Model 1 –metabolic syndrome, unadjusted,</p><p>Models 2–5, metabolic syndrome adjusted for: 2—age; 3—age, sex and smoking;</p><p>4—sex, smoking and perceived stress score; 5—age, sex, smoking and perceived stress score.</p><p>Models of logistic regression analysis: assessment of the impact of metabolic syndrome on the coronary plaque prevalence, depending on the correcting variable.</p

Clinical characteristics of the study subjects.

<p>* Data are expressed as mean (SD); Framingham Risk Score, 10-year risk of developing coronary heart disease; W/H ratio, waist/hip; CHD, coronary heart disease; PCI, percutaneous coronary intervention; BMI, body mass index; ACEI, Angiotensin converting enzyme inhibitors; ARB, Angiotensin II receptor blockers; COPD, chronic obstructive pulmonary disease. Obesity was defined as BMI>30.0 kg/m² and overweight as BMI >25.0 kg/m².</p><p>Clinical characteristics of the study subjects.</p

Spirometry test results and the intensity of physical activity in the study subjects stratified by metabolic syndrome status.

<p>Data (percent predicted) are expressed as mean (SD); FEV1, forced expiratory volume in 1 second; VC, Vital Capacity; FVC, forced vital capacity; FEV₁%VC, Tiffenau index; FEV1/FVC, a ratio of forced expiratory volume in 1 second (FEV1) to a forced vital capacity (FVC); FEF, forced expiratory flow; ERV, expiratory reserve volume; MET, Metabolic Equivalent of Task.</p><p>Spirometry test results and the intensity of physical activity in the study subjects stratified by metabolic syndrome status.</p

Results of logistic regression analysis: odds ratios for coronary plaque prevalence according to MetS components adjusted for age, sex, smoking and perceived stress score.

<p>Data are expressed as ORs and corresponding 95% CIs.</p><p>OR, odd ratio; CI, confidence interval; PSS, perceived stress score.</p><p>* ≥ 94/80 cm (men/women). Hypertension was defined as blood pressure systolic/diastolic ≥130/≥85 mm Hg or treatment of previously diagnosed hypertension; hypertriglyceridemia was defined as total triglycerides ≥1.7 mmol/L (150.0 mg/dL) or specific treatment for this lipid abnormality, low HDL-cholesterol was defined when cholesterol in this lipoprotein fraction was <1.03 mmol/L (40.0 mg/dL) in men and <1.29 mmol/L (50.0 mg/dL) in women; elevated fasting blood glucose (FBG) was defined when fasting glucose ≥5.6 mmol/L (100.0 mg/dL) or previously diagnosed type 2 diabetes.</p><p>Results of logistic regression analysis: odds ratios for coronary plaque prevalence according to MetS components adjusted for age, sex, smoking and perceived stress score.</p