Pulmonary Biomarkers Research Articles

Long-term docosahexaenoic acid (DHA) supplementation in cystic fibrosis patients: a randomized, multi-center, double-blind, placebo-controlled trial

Cystic fibrosis (CF) patients have an alteration in fatty acid (FA) metabolism, associated with increased omega-6 and low omega-3 FA. Previous studies on supplementation with omega-3 FA in CF had contradictory results, and to date there is no evidence to recommend routine use of omega-3 supplements in CF patients. We hypothesized that long-term supplementation with docosahexaenoic acid (DHA) will have beneficial effects in these patients, by reducing pulmonary, systemic and intestinal inflammation. This was a randomized, double-blind, parallel, placebo-controlled trial. CF patients (age >2 months) were randomized to receive a seaweed DHA oil solution (50 mg/Kg/day) or matching placebo for 48 weeks. Primary outcomes were pulmonary (interleukin [IL]-8), systemic (IL-8) and intestinal (calprotectin) inflammatory biomarkers. Secondary outcomes included other pulmonary (IL-1β, IL-6, neutrophil elastase, lactate and calprotectin) and systemic (serum-IL-1β, IL-6) inflammatory biomarkers, as well as clinical outcomes (FEV1, pulmonary exacerbations, antibiotic use, nutritional status and quality of life). Ninety six CF patients, 44 female, age 14.6±11.9 years (48 DHA and 48 placebo) were included. At trial completion, there were no differences in all primary outcomes [serum-IL-8 (p=0.909), respiratory-IL-8 (p=0.384) or fecal calprotectin (p=0.948)], all secondary inflammatory biomarkers, or in any of the clinical outcomes evaluated. There were few adverse events, with similar incidence in both study groups. In this study, long-term DHA supplementation in CF patients was safe, but did not offer any benefit on inflammatory biomarkers, or in clinical outcomes compared with placebo. (NCT01783613).

Modeling Invasive Aspergillosis: How Close Are Predicted Antifungal Targets?

Animal model systems are a critical component of the process of discovery and development of new antifungal agents for treatment and prevention of invasive aspergillosis. The persistently neutropenic rabbit model of invasive pulmonary aspergillosis (IPA) has been a highly predictive system in identifying new antifungal agents for treatment and prevention of this frequently lethal infection. Since its initial development, the persistently neutropenic rabbit model of IPA has established a strong preclinical foundation for dosages, drug disposition, pharmacokinetics, safety, tolerability, and efficacy for deoxycholate amphotericin B, liposomal amphotericin B, amphotericin B lipid complex, amphotericin B colloidal dispersion, caspofungin, micafungin, anidulafungin, voriconazole, posaconazole, isavuconazole, and ibrexafungerp in treatment of patients with invasive aspergillosis. The findings of combination therapy with a mould-active triazole and an echinocandin in this rabbit model also predicted the outcome of the clinical trial for voriconazole plus anidulafungin for treatment of IPA. The plasma pharmacokinetic parameters and tissue disposition for most antifungal agents approximate those of humans in persistently neutropenic rabbits. Safety, particularly nephrotoxicity, has also been highly predictive in the rabbit model, as exemplified by the differential glomerular filtration rates observed in animals treated with deoxycholate amphotericin B, liposomal amphotericin B, amphotericin B lipid complex, and amphotericin B colloidal dispersion. A panel of validated outcome variables measures therapeutic outcome in the rabbit model: residual fungal burden, markers of organism-mediated pulmonary injury (lung weights and infarct scores), survival, and serum biomarkers. In selected antifungal studies, thoracic computerized tomography (CT) is also used with diagnostic imaging algorithms to measure therapeutic response of pulmonary infiltrates, which exhibit characteristic radiographic patterns, including nodules and halo signs. Further strengthening the predictive properties of the model, therapeutic response to successfully developed antifungal agents for treatment of IPA has been demonstrated over the past two decades by biomarkers of serum galactomannan and (1→3)-β-D-glucan with patterns of resolution, that closely mirror those documented responses in patients with IPA. The decision to move from laboratory to clinical trials should be predicated upon a portfolio of complementary and mutually validating preclinical laboratory animal models studies. Other model systems, including those in mice, rats, and guinea pigs, are also valuable tools in developing clinical protocols. Meticulous preclinical investigation of a candidate antifungal compound in a robust series of complementary laboratory animal models will optimize study design, de-risk clinical trials, and ensure tangible benefit to our most vulnerable immunocompromised patients with invasive aspergillosis.

Comparative effects of neurally adjusted ventilatory assist and variable pressure support on lung and diaphragmatic function in a model of acute respiratory distress syndrome: A randomised animal study.

Variable assisted mechanical ventilation has been shown to improve lung function and reduce lung injury. However, differences between extrinsic and intrinsic variability are unknown. To investigate the effects of neurally adjusted ventilatory assist (NAVA, intrinsic variability), variable pressure support ventilation (Noisy PSV, extrinsic variability) and conventional pressure-controlled ventilation (PCV) on lung and diaphragmatic function and damage in experimental acute respiratory distress syndrome (ARDS). Randomised controlled animal study. University Hospital Research Facility. A total of 24 juvenile female pigs. ARDS was induced by repetitive lung lavage and injurious ventilation. Animals were randomly assigned to 24 h of either: 1) NAVA, 2) Noisy PSV or 3) PCV (n=8 per group). Mechanical ventilation settings followed the ARDS Network recommendations. The primary outcome was histological lung damage. Secondary outcomes were respiratory variables and patterns, subject-ventilator asynchrony (SVA), pulmonary and diaphragmatic biomarkers, as well as diaphragmatic muscle atrophy and myosin isotypes. Global alveolar damage did not differ between groups, but NAVA resulted in less interstitial oedema in dorsal lung regions than Noisy PSV. Gas exchange and SVA incidence did not differ between groups. Compared with Noisy PSV, NAVA generated higher coefficients of variation of tidal volume and respiratory rate. During NAVA, only 40.4% of breaths were triggered by the electrical diaphragm signal. The IL-8 concentration in lung tissue was lower after NAVA compared with PCV and Noisy PSV, whereas Noisy PSV yielded lower type III procollagen mRNA expression than NAVA and PCV. Diaphragmatic muscle fibre diameters were smaller after PCV compared with assisted modes, whereas expression of myosin isotypes did not differ between groups. Noisy PSV and NAVA did not reduce global lung injury compared with PCV but affected different biomarkers and attenuated diaphragmatic atrophy. NAVA increased the respiratory variability; however, NAVA yielded a similar SVA incidence as Noisy PSV. This trial was registered and approved by the Landesdirektion Dresden, Germany (AZ 24-9168.11-1/2012-2).

Association between biomarkers and house dust mite sublingual immunotherapy in allergic asthma.

House dust mite (HDM) sublingual immunotherapy (SLIT) has demonstrated efficacy in clinical trials of patients with asthma. Airway inflammation is a characteristic of respiratory allergy, but its relationship to SLIT remains unclear. We evaluate the association between clinical outcomes with pulmonary function and biomarkers in before and after HDM SLIT (UMIN Number 000022390). One hundred twelve patients with asthma sensitized to HDM were randomized to add-on 6 standardized quality (SQ)-HDM SLIT to pharmacotherapy or pharmacotherapy alone for 48weeks. At baseline and end of study, biomarkers, blood eosinophils, serum IgE, serum periostin, fractional exhaled nitric oxide (FeNO), and spirometry and clinical symptoms were measured. Association between biomarkers and an increase in FEV1 of 120mL or greater were analysed. Sublingual immunotherapy (SLIT) demonstrated a significant reduction of serum periostin (P<.001), FeNO (P<.01), and increase in HDM-specific IgE (P<.05), FEV1 (P<.001) and improvement of clinical symptom scores, when compared to pharmacotherapy. The change in FEV1 correlated with the changes in serum periostin (r=.696, P<.001) and the changes in FeNO (r=.682, P<.001). The independent predictor of improvement in airflow limitation was changed in serum periostin (r2 =.753, P=.013) and FeNO (P=.038). Based on cut-off values derived by receiver operating characteristic analysis (periostin 30.9ng/mL, FeNO 28.0ppb), patients were distinguished responders from non-responders, but with no predictive value for blood eosinophils or total IgE. The proportion of patients with both high periostin and FeNO levels was significantly higher in responder than in non-responder (P=.026). Adding HDM SLIT to pharmacotherapy resulted in reduced serum periostin and FeNO, and improved pulmonary function. Serum periostin and FeNO may be useful biomarkers for prediction of SLIT.

Effect Of Aerobic Exercise And Different Levels Of Pm 2.5 On Pulmonary Response In Wistar Rats

PURPOSE: Exposure of particulate matter of less than 2.5μm (PM2.5) has been associated with adverse respiratory and the risk of inflammation. While regular physical activity (PA) reduces the risk of many adverse health effects. This study aimed to examine the protection of exercise on adverse pulmonary health induced by PM2.5 exposures in rats. METHODS: 80 Wistar rats were randomly divided into 8 groups: Sedentary (S), Exercise (E), Sedentary+ Low concentration PM2.5 exposures (S+LPM), Exercise+Low concentration PM2.5 exposures (E+LPM), Sedentary+Medium concentration PM2.5 exposures (S+MPM), Exercise+ Medium concentration PM2.5 exposures (E+MPM), Sedentary+High concentration PM2.5 exposures (S+HPM), and Exercise+ High concentration PM2.5 exposures (E+HPM). The rats in all E-related groups went through 8-week aerobic interval treadmill training (5 days/week,1h/day). The PM-related groups of rats were exposed to different concentration PM2.5 exposure in Beijing. After one bout of PM exposure, the pulmonary function, structure of lung tissues and several pulmonary biomarkers were observed. RESULTS: 1) Compared with S group, following changes occurred in various S+PM2.5 exposure groups: lung tissues were seriously damaged, local bleeding, pus exudation, and inflammatory cell infiltration, as well as the decline of the SOD (S+LPM: P=0.020, S+HPM: P=0.370), and CAT (S+HPM: P=0.012) while the incline of Penh (S+MPM: P=0.133, S+HPM: P=0.002), MDA (S+HPM: P=0.007), TNF-α (S+MPM: P=0.018, S+HPM: P=0.008 ) and IL-1β (S+HPM: P=0.014) were observed. 2) Compared with the corresponding different concentration of S+PM2.5 exposure groups, the bleeding and inflammatory infiltration were improved, the Penh (E+HPM: P=0.005), TNF-α (E+HPM: P=0.042) and IL-1β (E+HPM: P=0.036) were decreased and CAT (E+HPM: P=0.039) and GSH (E+HPM: P=0.040) were increased in related E+PM groups respectively. CONCLUSIONS: The aerobic interval training improved the pulmonary function and impeded the lesion progression, which is due to effective in impeding the oxidative stress and inflammation.

Efficacy of oral citrulline supplementation to decrease the risk of pulmonary hypertension after congenital heart disease surgery.

Pulmonary hypertension (PH) is a major cause of morbi-mortality among patients with congenital heart disease (CHD) and also a potentially severe complication after surgical repair. Oral citrulline, a precursor to NO synthesis, is safe and efficacious for decreasing the risk of postoperative PH. Objective: The aim of the present study was to investigate inpediatric patientsthe changes of plasma citrulline, arginine, homocysteine and nitric oxide (NO) metabolites and pulmonary artery pressures (PAP) pre-post cardiac surgery in order to describe our population status with regard to the risk of pulmonary hypertension and look for potential biomarkers for early detection and treatment. Main results/Discussion: 16 Argentine pediatric patients with CHD undergoing cardiopulmonary bypass were randomized in two groups: (A) with and (B) without perioperative citrulline supplementation. We found that plasma citrulline median levels before surgery were lower in both groups respect to referential values, probably due to the poor nutritional status of our patients; only group A surpassed post-surgery the minimum recommended level to avoid PH. Furthermore, none of the patients in group A showed mean PAP higher than 20 mmHg, whereas in group B, 67% of the measurements were ≥ than the reference level. Conclusions: We reaffirm that citrulline supplementation it is effective in reducing postoperative pulmonary hypertension and biomarkers could evidence patient status as a translational medicine application.

Trans-Right-Ventricle and Transpulmonary MicroRNA Gradients in Human Pulmonary Arterial Hypertension.

We investigated whether concentrations of circulating microRNAs differ across the hypertensive right ventricle and pulmonary circulation, and correlate with hemodynamic/echocardiographic variables in patients with pulmonary arterial hypertension versus nonpulmonary arterial hypertension controls. Prospective blood collection during cardiac catheterization from the superior vena cava, pulmonary artery, and ascending aorta in 12 children with pulmonary arterial hypertension and nine matched nonpulmonary arterial hypertension controls, followed by an unbiased quantitative polymerase chain reaction array screen for 754 microRNAs in plasma. Children's hospital at a medical school. Twelve pulmonary arterial hypertension patients included as follows: idiopathic pulmonary arterial hypertension (5), pulmonary arterial hypertension (2), pulmonary arterial hypertension-repaired congenital heart disease (4), portopulmonary pulmonary hypertension (1). Nine nonpulmonary arterial hypertension controls included as follows: mild/moderate left ventricular outflow tract obstruction (7), mediastinal teratoma (1), portal vein stenosis (1). Standard pulmonary arterial hypertension treatment. Analysis of differential concentrations (false discovery rate < 0.05) revealed two trans-right-ventricle microRNA gradients (pulmonary artery vs superior vena cava): miR-193a-5p (step-up in pulmonary arterial hypertension and step-down in control) and miR-423-5p (step-down in pulmonary arterial hypertension and step-up in control) and two transpulmonary microRNA gradients (ascending aorta vs pulmonary artery): miR-26b-5p (step-down only in control) and miR-331-3p (step-up only in pulmonary arterial hypertension). Between-group comparison revealed miR-29a-3p, miR-26a-5p, miR-590-5p, and miR-200c-3p as upregulated in pulmonary arterial hypertension-superior vena cava and miR-99a-5p as downregulated in pulmonary arterial hypertension-pulmonary artery. The differential microRNA-concentrations correlated with prognostic hemodynamic variables (pulmonary vascular resistance, tricuspid annular plane systolic excursion, etc.). We identified for the first time in human disease (pulmonary arterial hypertension) trans-right-ventricle and transpulmonary microRNA gradients in blood plasma. Several of these microRNAs regulate transcripts that drive cardiac remodeling and pulmonary arterial hypertension and are now emerging as epigenetic pulmonary arterial hypertension biomarkers and targets for therapy.

Overexpression of endogenous lipoic acid synthase attenuates pulmonary fibrosis induced by crystalline silica in mice

Oxidative stress and inflammatory processes are proposed to mediate the development of silicosis. However, antioxidant therapy has not produced consistent results during the treatment of silicosis. α-Lipoic acid synthesized by lipoic acid synthase is a powerful anti-oxidant and helps protect mitochondria. Thus far, the effect of endogenous α-Lipoic acid on silicosis has not been elucidated yet. We established an experimental model of silicosis with wildtype and LiasH/H mice, a new antioxidant mouse model which has overexpressed Lias gene (∼150 %) relative to its wild type counterpart. We systemically examined main pathological changes of pulmonary fibrosis, and explored α-lipoic acid effects on oxidative stress, inflammatory and pulmonary fibrosis biomarkers in silica-instillated mice. In LiasH/H mice over-expression of lipoic acid alleviated the severity of major pathological alterations in the early stage of pulmonary fibrosis induced by silica compared with wild type mice. Silica significantly increased oxidative stress in both wild type and LiasH/H mice. The antioxidant defense was strengthen including increased NRF2 and LIAS production in LiasH/H mice. Relieved oxidative stress resulted in decreased inflammatory response and secretion of chemokines. LiasH/H mice reduced chronic inflammatory response and inhibition of NF-κB activity after silica instillation. The LiasH/H mouse model overexpression of lipoic acid synthase gene retarded the development of silica-induced pulmonary fibrosis. Strengthen antioxidant defense by increased lipoic acid synthase is a potential strategy for protection against silica-induced pulmonary fibrosis.

Effect of aerobic exercise and different levels of fine particulate matter (PM2.5) on pulmonary response in Wistar rats

BackgroundExposure of particulate matter of <2.5 μm (PM2.5) has been associated with adverse respiratory and the risk of inflammation. While regular physical activity (PA) reduces the risk of many adverse health effects. This study aimed to examine the protection of exercise on adverse pulmonary health induced by PM2.5 exposures in rats. Methods80 Wistar rats were randomly divided into 8 groups: Sedentary (S), Exercise (E), Sedentary+ Low concentration PM2.5 exposures (S + LPM), Exercise+Low concentration PM2.5 exposures (E + LPM), Sedentary+Medium concentration PM2.5 exposures (S + MPM), Exercise+ Medium concentration PM2.5 exposures (E + MPM), Sedentary+High concentration PM2.5 exposures (S + HPM), and Exercise+ High concentration PM2.5 exposures (E + HPM). The rats in all E-related groups went through 8-week aerobic interval treadmill training (5 days/week, 1 h/day). The PM-related groups of rats were exposed to different concentration PM2.5 exposure in Beijing. After one bout of PM exposure, the pulmonary function, structure of lung tissues and several pulmonary biomarkers were observed. Results1) Compared with S group, following changes occurred in various S + PM2.5 exposure groups: lung tissues were seriously damaged, local bleeding, pus exudation, and inflammatory cell infiltration, as well as the decline of the SOD, CAT and GSH while the incline of Penh, Ti, Te, MDA, TNF-α and IL-1β were observed. 2) Compared with the corresponding different concentration of S + PM2.5 exposure groups, Penh, Ti, Te, MDA, TNF-α and IL-1β were decreased and CAT and GSH were increased in related E + PM groups respectively. ConclusionIn summary, the results suggest that acute PM2.5 with different concentrations can cause different degrees of adverse effects on lung, especially in medium and high concentrations. The aerobic interval training improved the pulmonary function and impeded the lesion progression, which is due to effective in impeding the oxidative stress and inflammation.

Impact of supervised exercise training on pulmonary function parameters, exercise capacity and Irisin Biomarker in Interstitial lung disease patients.

Objectives:To assess the impact of supervised exercise training (SET) on pulmonary function Parameters, exercise capacity and Irisin biomarker in Interstitial Lung Disease (ILD) patients.Methods:Ten (10)patients with ILD and 18 healthy controls of age between 30-40+ years were selected for 8-week SET program. Before and after SET all subjects performed exercise capacity six minutes’ walk test (6MWT), heart rate (HR) changes were recorded, shortness of Breath Respiratory Questionnaire (SOBQ) was obtained and Irisin levels were measured by Enzyme-Linked Immunosorbent Assay (ELISA). This interventional study was carried out at Department of Physiology, Faculty of Medicine, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia, from October 2018 to February 2019.Results:Mean six minutes’ walk distance (6MWD) was 395 ± 68.4 m at 1st visit increased significantly (p=0.001) to 458.8± 87.1 mat 15 visit. However, 6MWD values found significantly higher in controls (517.4±84.1 m; 561.7±81.6 m; p=0.013) than ILD patients. Overall change (difference between post and pre exercise) in HRvalue was recorded lower in ILD patients (30-35 bpm) as compared to controls (40-45 bpm). Moreover, ILD patients had overall higher SOBQ score than controls. Pre SET Irisin levels of ILD patients (4.24 ±1.73 pg/ml) and controls (3.43 ±1.04pg/ml) were found unchanged dafter SET (4.48±2.02pg/ml, 3.39 ±1.41pg/ml, p=0.677, p=0.093)respectively. However, patients Irisin values were found higher as compared to controls before and after SET.Conclusion:Exercise capacity and Dyspneain patients with ILD were improved after 8-week of SET program. No major changes in Irisin levels among patients with ILD and controls were observed. Additional research requires to be carried out on large number of subjects to deter Minutese the advantages of exercise in ILD.

Abstract 378: Diagnosing Pneumonia After Cardiac Arrest

Introduction: Post cardiac arrest syndrome, therapeutic hypothermia, and CPR confound the clinical diagnosis of pneumonia. Accurate pneumonia diagnosis is required to improve targeted antibiotic allocation and prevent sequelae of untargeted antibiotic therapy. Hypothesis: We can rigorously define pneumonia after cardiac arrest (CA) using accepted clinical parameters adapted from existing guidelines and innate immune system biomarkers Interleukin-17A (IL-17A), integrin α9β1, and CD11b specific to the response to pulmonary infection. Methods: A prospective cohort of consecutive OHCA patients surviving at least 72 hours from arrival was enrolled. IL-17A, integrin α9β1, and CD11b were measured daily at 4 timepoints from time 0 (arrival) through 72 hours. Chest radiography, pulmonary microbiology, temperature, and white blood cell count were recorded concurrently from the medical record. Pneumonia was defined narrowly (pna_narrow) by the presence of at least 2 of the following criteria in the initial 72 hours of presentation: fever ≥38°C; persistent infiltrate on chest radiography; positive sputum or bronchoalveolar lavage per the hospital microbiology laboratory. Broad criteria (pna_broad) also incorporated persistent leukocytosis ≥15,000 or leukopenia &lt;3,000. Results: Of the 56 subjects with all data, 23% (13 of 56) met pna_narrow criteria while 43% (24 of 56) met pna_broad criteria. Positive clinical pulmonary microbiology was present in 62% (8 of 13) subjects meeting pna_narrow and 46% (11 of 24) subjects meeting pna_broad criteria. Antibiotics were given to 65% (28 of 43) subjects without pna_narrow and 63% (20 of 32) without pna_broad. Overall, 70% (39 of 56) subjects received antibiotics regardless of pneumonia status. Integrin α9β1 at Time 28 hours and Time 72 hours was associated with pna_narrow (p = 0.010, p = 0.049). CD11b at Time 0 and 72 hours was associated with pna_narrow (p = 0.03, p = 0.049). IL-17 at Time 28 and Time 72 was associated with pna_narrow (p = 0.04, p = 0.01). Conclusions: Pneumonia was rigorously defined in 23 to 43% of our sample, yet 70% of subjects received antibiotics. More rigorous definitions for pneumonia after CA, combined with pulmonary infection biomarkers, could be used to improve diagnosis and antibiotic allocation.

Small RNA-sequence analysis of plasma-derived extracellular vesicle miRNAs in smokers and patients with chronic obstructive pulmonary disease as circulating biomarkers

ABSTRACTExtracellular vesicles (EVs) play a vital role in normal lung physiology to maintain homeostasis in the airways via intercellular communication. EVs include exosomes and microvesicles, and are characterized by their phospholipid bilayers. EVs have been recognized as novel circulating biomarkers of disease, which are released by different cell types. In this study, we used different EV isolation and purification methods to characterize the plasma-derived EV miRNAs from non-smokers, smokers and patients with COPD. A small RNA sequencing (RNA-seq) approach was adapted to identify novel circulating EV miRNAs. We found that plasma-derived EVs from non-smokers, smokers and patients with COPD vary in their size, concentration, distribution and phenotypic characteristics as confirmed by nanoparticle tracking analysis, transmission electron microscopy, and immunoblot analysis of EV surface markers. RNA-seq analysis confirmed the most abundant types of small RNAs, such as miRNAs, tRNAs, piRNAs snRNAs, snoRNAs and other biotypes in plasma-derived EVs. We mainly focused on miRNAs as novel biomarkers in smokers and patients with COPD for further analysis. Differential expression by DESeq2 identified distinct miRNA profiles (up-regulated: miR-22-3p, miR-99a-5p, miR-151a-5p, miR-320b, miR-320d; and down-regulated: miR-335-5p, miR-628-3p, miR-887-5p and miR-937-3p) in COPD versus smokers or non-smokers in a pairwise comparison. Gene set enrichment analysis (GSEA) of differentially expressed miRNAs revealed the top pathways, gene ontology and diseases associated with smokers and patients with COPD. We selectively validated miRNAs in EVs isolated from BEAS-2B cells treated with cigarette smoke extract by quantitative PCR analysis. For the first time, we report that plasma-derived EV miRNAs are novel circulating pulmonary disease biomarkers. Thus, molecular profiling of EV miRNAs has great translational potential for the development of biomarkers that may be used in the diagnosis, prognosis, and therapeutics of COPD.

Low Vitamin D Status Is Associated with Epithelial-Mesenchymal Transition in Patients with Chronic Obstructive Pulmonary Disease.

Vitamin D deficiency is correlated with the increased morbidity of chronic obstructive pulmonary disease (COPD). However, the mechanisms underlying these effects have largely remained elusive. This study analyzed the correlations among COPD, vitamin D concentration, and epithelial-mesenchymal transition (EMT). Ninety-five patients with newly diagnosed COPD and 190 age- and sex-matched healthy subjects were recruited for this research. Serum 25(OH)D levels were detected, and pulmonary EMT biomarkers and TGF-β/Smad signaling were evaluated. Serum 25(OH)D level was remarkably decreased in COPD patients compared with that in control subjects. Furthermore, serum 25(OH)D concentration gradually decreased in COPD patients ranging from grade 1-2 to 4. However, reduced expression of the epithelial biomarker E-cadherin and increased expression of the mesenchymal biomarkers vimentin and α-SMA were found in COPD patients. Mechanistic analysis showed that pulmonary nuclear vitamin D receptor (VDR) was decreased in patients with COPD. In contrast, TGF-β/Smad signaling was obviously activated in COPD patients. Furthermore, the level of serum TGF-β in COPD patients increased in parallel with COPD severity. Serum 25(OH)D concentration was inversely associated with TGF-β levels in COPD patients. In vitro experiments showed that active vitamin D3 inhibits TGF-β-induced Smad2/3 phosphorylation in MRC-5 cells. Furthermore, vitamin D concentration was inversely correlated with TGF-β/Smad signaling and EMT in COPD patients, suggesting EMT as a vital mediator of COPD development in patients with low vitamin D concentrations.

Evolving Concepts in Chronic Obstructive Pulmonary Disease Blood-Based Biomarkers.

In recent years, there has been a great deal of interest in the identification and validation of blood-based biomarkers for clinical use in chronic obstructive pulmonary disease (COPD). We now have panels of blood biomarkers that potentially hold great promise as they show statistically significant associations with COPD, but biomarkers for the diagnosis of COPD remain elusive. In fact, they are yet to demonstrate sufficient accuracy to be accepted in clinical use, and many are not specific to COPDbut more related to inflammation (e.g. interleukin-6) or associated with other chronic diseases such as diabetes (e.g.soluble receptor for advanced glycation endproducts [sRAGE]). Although no single blood-based biomarker has demonstrated clinical utility for either the diagnosis or progression of COPD, it has been suggested that combinations of individual markers may provide important diagnostic or prognostic information; however, the interpretation of COPD biomarker results still requires thought and many questions remain unanswered.

Susceptibility of prediabetes to the health effect of air pollution: a community-based panel study with a nested case-control design

BackgroundRecent studies suggest that people with diabetes or who are at risk of developing diabetes, i.e. prediabetic (preDM), are potentially susceptible to air pollution, but the underlying mechanisms remain unclear because the existing epidemiological studies did not include healthy control groups and only focused on limited health outcomes. We hypothesized that acute exposure to ambient fine particles (PM2.5) will lead to enhanced pulmonary and cardiometabolic changes in preDM than healthy individuals.MethodsWe recruited 60 preDM and 60 healthy individuals from a community of 22,343 adults in Beijing China, and arranged each subject to complete up to seven repeated clinical visits with measures of 6 cardiopulmonary biomarkers, 6 cytokines, 4 blood pressure and endothelial function outcomes and 4 glucose metabolism biomarkers.. Moving averaged daily ambient PM2.5 in preceding 1–14 days was matched to each subject and the PM2.5 associated effect on multiple biomarkers was estimated and compared between PreDM and healthy subjects based on linear mixed effect model.ResultsAll the subjects exhibited significant acute elevation of exhaled nitric oxide, white blood cells, neutrophils, interleukin-1α, and glycated haemoglobin with increased exposure to PM2.5. PreDM subjects had significant stronger adverse changes compared to healthy subjects in 6 cardiometabolic biomarkers, namely, interleukin-2, interleukin-8, systolic and diastolic blood pressure, augmentation pressure, and glucose. The maximum elevation of these 6 biomarkers in PreDM subjects were 8.6% [CI: 4.1–13.3%], 10.0% [CI: 3.9–16.4%], 1.9% [CI: 0.2–3.6%], 1.2% [CI: − 0.1-2.4%], 5.7% [CI: − 0.1-11.8%], 2.4% [CI: 0.7–4.2%], respectively, per an interquartile increase of ambient PM2.5 (61.4 μg m− 3) throughout the exposure window of the preceding 1–14 days. No significant difference was observed for the changes in pulmonary biomarkers between the two groups.ConclusionsPreDM individuals are more susceptible to the acute cardiometabolic effect of air pollution than the healthy individuals. A considerable public health burden can be inferred, given the high prevalence of prediabetes and the ubiquity of air pollution in China and worldwide.

Deep semantic lung segmentation for tracking potential pulmonary perfusion biomarkers in chronic obstructive pulmonary disease (COPD): The multi-ethnic study of atherosclerosis COPD study.

Chronic obstructive pulmonary disease (COPD) is associated with high morbidity and mortality. Identification of imaging biomarkers for phenotyping is necessary for future treatment and therapy monitoring. However, translation of visual analytic pipelines into clinics or their use in large-scale studies is significantly slowed by time-consuming postprocessing steps. To implement an automated tool chain for regional quantification of pulmonary microvascular blood flow in order to reduce analysis time and user variability. Prospective. In all, 90 MRI scans of 63 patients, of which 31 had a COPD with a mean Global Initiative for Chronic Obstructive Lung Disease status of 1.9 ± 0.64 (μ ± σ). 1.5T dynamic gadolinium-enhanced MRI measurement using 4D dynamic contrast material-enhanced (DCE) time-resolved angiography acquired in a single breath-hold in inspiration. [Correction added on August 20, 2019, after first online publication: The field strength in the preceding sentence was corrected.] ASSESSMENT: We built a 3D convolutional neural network for semantic segmentation using 29 manually segmented perfusion maps. All five lobes of the lung are denoted, including the middle lobe. Evaluation was performed on 61 independent cases from two sites of the Multi-Ethnic Study of Arteriosclerosis (MESA)-COPD study. We publish our implementation of a model-free deconvolution filter according to Sourbron et al for 4D DCE MRI scans as open source. Cross-validation 29/61 (# training / # testing), intraclass correlation coefficient (ICC), Spearman ρ, Pearson r, Sørensen-Dice coefficient, and overlap. Segmentations and derived clinical parameters were processed in ~90 seconds per case on a Xeon E5-2637v4 workstation with Tesla P40 GPUs. Clinical parameters and predicted segmentations exhibit high concordance with the ground truth regarding median perfusion for all lobes with an ICC of 0.99 and a Sørensen-Dice coefficient of 93.4 ± 2.8 (μ ± σ). We present a robust end-to-end pipeline that allows for the extraction of perfusion-based biomarkers for all lung lobes in 4D DCE MRI scans by combining model-free deconvolution with deep learning. 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2020;51:571-579.

Sulphurous thermal water inhalation impacts respiratory metabolic parameters in heavy smokers.

Sulphurous thermal water inhalations have been traditionally used in the treatment of airway diseases. In vivo and in vitro studies reported that they ameliorate mucus rheology, mucociliary clearance and reduce inflammation. Cigarette smoking induces an inflammatory damage, with consequent remodeling of respiratory airways, which in turn affect pulmonary functions. Despite the anti-inflammatory effects of H2S are clinically documented in several airway inflammatory diseases, data on the effects of sulphurous thermal water treatment on pulmonary function and biomarkers of airways inflammation in smokers are still scant. Therefore, we investigated whether a conventional cycle of sulphurous thermal water inhalation produced changes in markers of respiratory inflammation and function. A cohort of 504 heavy current and former smokers underwent 10-day cycles of sulphurous thermal water inhalation. Pulmonary function and metabolic analyses on exhaled breath condensate were then performed at day 0 and after the 10-day treatment. Spirometric data did not change after spa therapy, while exhaled breath condensate analysis revealed that a single 10-day cycle of sulphurous water inhalation was sufficient to induce a statistically significant increase of citrulline levels along with a decrease in ornithine levels, thus shifting arginine metabolism towards a reduced nitric oxide production, i.e. an anti-inflammatory profile. Overall, sulphurous thermal water inhalation impacts on arginine catatabolic intermediates of airways cells, shifting their metabolic balance towards a reduction of the inflammatory activity, with potential benefits for smokers.

The progress of chronic obstructive pulmonary disease biomarker

近年研究发现慢阻肺有不同表型，而一些生物标志物与疾病的表型、严重程度和急性加重相关。随着检测技术的发展和数据挖掘能力的提高，对慢阻肺生物标志物研究蓬勃发展，本综述通过归纳和总结近5年来与慢阻肺生物标志物研究相关的基础和临床研究，分析现有生物标志物研究方法的可行性和局限性，初步探讨已有生物标志物的可能临床价值，并展望了未来发展方向和面临的挑战。.

Microparticles in systemic sclerosis: Potential pro-inflammatory mediators and pulmonary hypertension biomarkers.

Endothelial microparticles (EMP) are submicron vesicles released from endothelial cells. We aimed to determine the utility of EMP as biomarkers of pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc) patients and the pathogenic role of microparticles (MP) in vascular inflammation. Levels of EMP (CD144+, CD31+, CD62E+ and CD143+) were compared between three groups (10 SSc patients with PAH, 10 SSc patients without pulmonary hypertension (no-PH) and 10 healthy age- and sex-matched controls). Human pulmonary artery endothelial cells (HPAEC) were exposed in vitro to MP obtained from SSc patients or healthy controls, and levels of cytokines and inflammatory adhesion molecules were compared. CD144+ EMP were significantly higher in the SSc-PAH group compared to either the SSc-no PH or healthy controls (diagnostic accuracy 80%, P = 0.02). Compared to controls, SSc patients had higher CD31+/CD62E+ ratios, indicating larger contributions of apoptosis to EMP release (P = 0.04). Patients with limited SSc had significantly higher levels of CD143+ EMP compared to those with diffuse subtype (P = 0.008). When HPAEC were exposed to MP from SSc patients, there was a significant increase in inflammatory cytokines and adhesion molecules. Interestingly, exposure to healthy control MP caused a reduction in inflammatory markers. EMP (particularly CD144+) are promising biomarkers of PAH in SSc but require further study. MP isolated from SSc patients induced an increase in endothelial cell inflammation and may be an important pathogenic factor in SSc.

Elevated pulmonary tuberculosis biomarker miR-423-5p plays critical role in the occurrence of active TB by inhibiting autophagosome-lysosome fusion

ABSTRACT Rapid diagnosis of pulmonary tuberculosis is an effective measure to prevent the spread of tuberculosis. However, the grim fact is that the new, rapid, and safe methods for clinical diagnosis are lacking. Moreover, although auto-lysosome is critical in clearing Mycobacterium tuberculosis, the pathological significance of microRNAs, as biomarkers of tuberculosis, in autophagosome maturation is unclear. Here, these microRNAs were investigated by Solexa sequencing and qPCR validation, and a potential diagnostic model was established by logistic regression. Besides that, the mechanism of one of the microRNAs involved in the occurrence of tuberculosis was studied. The results showed that the expression of miR-423-5p, miR-17-5p, and miR-20b-5p were significantly increased in the serum of patients with tuberculosis. The combination of these three microRNAs established a model to diagnose tuberculosis with an accuracy of 78.18%, and an area under the curve value of 0.908. Bioinformatics analysis unveiled miR-423-5p as the most likely candidate in regulating autophagosome maturation. The up-regulation of miR-423-5p could inhibit autophagosome maturation through suppressing autophagosome–lysosome fusion in macrophages. Further investigations showed that VPS33A was the direct target of miR-423-5p, and the two CUGCCCCUC domains in VPS33A 3’-UTR were the direct regulatory sites for miR-423-5p. In addition, an inverse correlation between VPS33A and miR-423-5p was found in peripheral blood mononuclear cells of patients with tuberculosis. Since the inhibition of autolysosome formation plays a critical role in tuberculosis occurrence, our findings suggests that miR-423-5p could suppress autophagosome–lysosome fusion by post-transcriptional regulation of VPS33A, which might be important for the occurrence of active tuberculosis.