Benefits of budesonide/glycopyrronium/formoterol fumarate dihydrate on lung function and exacerbations of COPD: a post-hoc analysis of the KRONOS study by blood eosinophil level and exacerbation history.

BACKGROUND: Japanese guidelines recommend triple inhaled corticosteroid (ICS)/long-acting muscarinic antagonist (LAMA)/long-acting ß2-agonist (LABA) therapy in patients with chronic obstructive pulmonary disease (COPD) and no concurrent asthma diagnosis who experience frequent exacerbations and have blood eosinophil (EOS) count ≥ 300 cells/mm3, and in patients with COPD and asthma with continuing/worsening symptoms despite receiving dual ICS/LABA therapy. These post-hoc analyses of the KRONOS study in patients with COPD and without an asthma diagnosis, examine the effects of fixed-dose triple therapy with budesonide/glycopyrronium/formoterol fumarate dihydrate (BGF) versus dual therapies on lung function and exacerbations based on blood EOS count - focusing on blood EOS count 100 to < 300 cells/mm3 - as a function of exacerbation history and COPD severity. METHODS: In KRONOS, patients were randomized to receive treatments that included BGF 320/14.4/10 µg, glycopyrronium/formoterol fumarate dihydrate (GFF) 14.4/10 µg, or budesonide/formoterol fumarate dihydrate (BFF) 320/10 µg via metered dose inhaler (two inhalations twice-daily for 24 weeks). These post-hoc analyses assessed changes from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV1) over 12-24 weeks and moderate or severe COPD exacerbations rates over 24 weeks. The KRONOS study was not prospectively powered for these subgroup analyses. RESULTS: Among patients with blood EOS count 100 to < 300 cells/mm3, least squares mean treatment differences for lung function improvement favored BGF over BFF in patients without an exacerbation history in the past year and in patients with moderate and severe COPD, with observed differences ranging from 62 ml to 73 ml across populations. In this same blood EOS population, moderate or severe exacerbation rates were reduced for BGF relative to GFF by 56% in patients without an exacerbation history in the past year, by 47% in patients with moderate COPD, and by 50% in patients with severe COPD. CONCLUSIONS: These post-hoc analyses of patients with moderate-to-very severe COPD from the KRONOS study seem to indicate clinicians may want to consider a step-up to triple therapy in patients with persistent/worsening symptoms with blood EOS count > 100 cells/mm3, even if disease severity is moderate and there is no recent history of exacerbations. TRIAL REGISTRATION: ClinicalTrials.gov registry number NCT02497001 (registration date, 13 July 2015).

Polyhexamethylene guanidine aerosol causes irreversible changes in blood proteins that associated with the severity of lung injury.

Polyhexamethylene guanidine (PHMG) is a positively charged polymer used as a disinfectant that kills microbes but can cause pulmonary fibrosis if inhaled. After the long-term risks were confirmed in South Korea, it became crucial to measure toxicity through diverse surrogate biomarkers, not only proteins, especially after these hazardous chemicals had cleared from the body. These biomarkers, identified by their biological functions rather than simple numerical calculations, effectively explained the imbalance of pulmonary surfactant caused by fibrosis from PHMG exposure. These long-term studies on children exposed to PHMG has shown that blood protein indicators, primarily related to apolipoproteins and extracellular matrix, can distinguish the degree of exposure to humidifier disinfectants (HDs). We defined the extreme gradient boosting models and computed reflection scores based on just ten selected proteins, which were also verified in adult women exposed to HD. The reflection scores successfully discriminated between the HD-exposed and unexposed groups in both children and adult females (AUROC: 0.957 and 0.974, respectively) and had a strong negative correlation with lung function indicators. Even after an average of more than 10 years, blood is still considered a meaningful specimen for assessing the impact of environmental exposure to toxic substances, with proteins providing in identifying the pathological severity of such conditions.

Dupilumab improves pediatric type 2 asthma outcomes independent of patient baseline characteristics.

CLINICAL IMPLICATIONS: Dupilumab, a biological therapy that blocks the shared receptor component for interleukins-4/13, reduced exacerbations and improved lung function in children with uncontrolled moderate-to-severe type 2 asthma independent of most baseline patient and asthma characteristics.

The protein disulfide isomerase A3 and osteopontin axis promotes influenza-induced lung remodelling.

BACKGROUND AND PURPOSE: Fibrotic lung remodelling after a respiratory viral infection represents a debilitating clinical sequela. Studying or managing viral-fibrotic sequela remains challenging, due to limited therapeutic options and lack of understanding of mechanisms. This study determined whether protein disulfide isomerase A3 (PDIA3) and secreted phosphoprotein 1 (SPP1), which are associated with pulmonary fibrosis, can promote influenza-induced lung fibrotic remodelling and whether inhibition of PDIA3 or SPP1 can resolve viral-mediated fibrotic remodelling. EXPERIMENTAL APPROACH: A retrospective analysis of TriNetX data sets was conducted. Serum from healthy controls and influenza A virus (IAV)-infected patients was analysed. An inhibitor of PDIA3, punicalagin, and a neutralizing antibody for SPP1 were administered in mice. Macrophage cells treated with macrophage colony-stimulating factor (M-CSF) were used as a cell culture model. KEY RESULTS: The TriNetX data set showed an increase in lung fibrosis and decline in lung function in flu-infected acute respiratory distress syndrome (ARDS) patients compared with non-ARDS patients. Serum samples revealed a significant increase in SPP1 and PDIA3 in influenza-infected patients. Lung PDIA3 and SPP1 expression increased following viral infection in mouse models. Punicalagin administration 2 weeks after IAV infection in mice caused a significant decrease in lung fibrosis and improved oxygen saturation. Administration of neutralizing SPP1 antibody decreased lung fibrosis. Inhibition of PDIA3 decreased SPP1secretion from macrophages, in association with diminished disulfide bonds in SPP1. CONCLUSION AND IMPLICATIONS: The PDIA3-SPP1 axis promotes post-influenza lung fibrosis in mice and that pharmacological inhibition of PDIA3 or SPP1 can treat virus-induced lung fibrotic sequela.

Mind-body exercise for patients with stable COPD on lung function and exercise capacity: a systematic review and meta-analysis of RCTs.

Chronic Obstructive Pulmonary Disease (COPD) is a global health concern. Mind-body exercises like Tai Chi and Yoga are suggested as non-pharmacological interventions for COPD management. This meta-analysis evaluates mind-body exercises' impact on lung function and exercise capacity in stable COPD patients, aiming to assess their effectiveness in rehabilitation. A systematic search across various databases identified relevant randomized controlled trials until April 2024. Primary outcomes included lung function tests (FEV1, FVC, FEV1/FVC, FEV1%) and Six-Minute Walk Test (6MWT) results. The Standardized Mean Difference (SMD) measured intervention effects. Fifteen studies with 1047 participants were analyzed. Mind-body exercises significantly improved FEV1 (SMD = 0.87), FEV1/FVC (SMD = 0.19), FEV1% (SMD = 0.43), and 6MWT (SMD = 1.21) compared to standard care. Sensitivity and subgroup analyses confirmed result stability despite some heterogeneity.In conclusion, Mind-body exercises enhance lung function and exercise capacity in stable COPD patients. Integrating them into comprehensive rehabilitation programs is advisable. Further research should explore the specific impacts of different exercise types and intensities.

Prevalence, patterns, and factors associated with abnormal lung function among children with sickle cell disease in Uganda: a cross-sectional study.

BACKGROUND: Pulmonary complications are common among children with sickle cell disease (SCD). However, there is little literature on associated lung function abnormalities in Uganda. We aimed to determine the prevalence, patterns, and factors associated with abnormal lung function among children with SCD in a tertiary care hospital in Uganda. METHOD: A cross-sectional study was conducted among children aged 6 to 18 years at the SCD clinic (SCC) of Mulago National Super-Specialized Hospital between January 2020 and April 2021. Data on sociodemographic and clinical characteristics was collected using a standardized questionnaire. Laboratory investigations, including a complete blood count and serum lactate dehydrogenase (LDH), were done. Spirometry was performed following the ATS/ERS standards. Multivariable modified Poisson regression analysis was performed to determine factors associated with abnormal lung function. RESULTS: A total of 332 participants were enrolled. The mean age was 11.7 ± 3.4 years, and 184 (55.4%) were female. Overall, 126 (37.9%) participants had abnormal lung function: 67/126 (53.2%) restrictive, 57/126 (45.2%) obstructive, and 2/126 (1.6%) mixed-ventilatory patterns. Factors associated with abnormal lung function were; serum LDH level > 600UL (aIRR: 1.89 95% CI: 1.2 - 7.4, p = 0.049), a history of acute chest syndrome (aIRR: 1.55, 95% CI: 1.06-2.25, p = 0.024), wasting (aIRR: 1.33, 95%CI: 1.02 - 1.72, p = 0.032), and use of charcoal for household cooking (aIRR: 1.49, 95% CI: 1.03-2.15, p = 0.035). CONCLUSION: More than one-third of children with SCD in Uganda have lung function abnormalities. Strategies to improve nutrition, reduce exposure to charcoal smoke, and monitoring serum LDH levels may be important in preventing or managing abnormal lung function in this population. The identification of reversible and irreversible airway obstruction in children with sickle cell disease also highlights the need for targeted interventions to address these specific patterns of abnormal lung function.

The Nonlinear Relationship Between High-Density Lipoprotein and Changes in Pulmonary Structure Function and Pulmonary Function in COPD Patients in China.

Background: The previous findings on the correlation between spirometry and high-density lipoprotein (HDL) cholesterol are intriguing yet conflicting. The aim of this research is to evaluate the relationship between HDL levels and spirometry as well as imaging parameters in patients with chronic obstructive pulmonary disease (COPD) in China. Methods: This study encompasses a total of 907 COPD patients. Participants with complete data from questionnaire interviews, lipid profile examinations, spirometry testing, and computed tomography (CT) scans were included in the analysis. A generalized additive model was employed to identify the non-linear relationship between HDL levels and both spirometry and imaging parameters. In the presence of non-linear correlations, segmented linear regression model was applied to ascertain threshold effects. Results: After adjusting for various factors, we found a non-linear correlation between HDL levels and spirometry/imaging parameters, with an inflection point at 4.2 (66 mg/dL). When Ln (HDL) was below 4.2, each unit increase correlated significantly with reduced post-bronchodilator FEV1 (0.32L, 95% CI: 0.09-0.55), decreased predicted FEV1% (11.0%, 95% CI: 2.7-19.3), and lowered FEV1/FVC (8.0%, 95% CI: 4.0-12.0), along with notable increases in Ln (LAA-950) by 1.20 (95% CI: 0.60-1.79) and Ln (LAA-856) by 0.77 (95% CI: 0.37-1.17). However, no significant associations were observed when Ln (HDL) was greater than or equal to 4.2. Conclusion: A non-linear correlation existed between HDL levels with lung function and CT imaging in COPD patients. Prior to reaching 66 mg/dL, an elevation in HDL was significantly associated with impaired lung function, more severe gas trapping and emphysema.

Performance of Impulse Oscillometry in Identifying Restrictive Lung Defects in a Veteran Cohort.

Background: Impulse oscillometry (IOs) is a technique used to evaluate lung function that uses sound waves imposed over tidal breathing to characterize the airways and lung parenchyma. IOs has been particularly useful in the identification of obstructive lung defects. The present analysis seeks to explore the use of IOs in the identification of restrictive lung physiology among a group of Gulf War I veterans exposed to depleted uranium (DU). Methods: A total of 36 out of a dynamic 85-veteran cohort attended in-person surveillance visits in 2019 and completed both IOs and PFTs. Performance on IOs was evaluated in a cross-sectional analysis of the group overall and in those identified as having restrictive lung defects defined by either spirometry (FEV1/FVC ≥ LLN and FVC < LLN) or lung volumes (TLC < LLN). Results: A total of 6 individuals were identified as having restriction (4 based on spirometry alone and an additional 2 by lung volumes). When restriction was present, IOs values of both resistance and reactance were significantly more abnormal. Conclusion: In the assessment of lung function, IOs may be advantageous over PFTs because it is faster to perform and effort-independent. Although little is known about the utility of IOs in identifying restrictive lung physiology, our results support its use.

Differences in pulmonary function measured by oscillometry between horses with mild-moderate equine asthma and healthy controls.

BACKGROUND: The diagnosis of mild-moderate equine asthma (MEA) can be confirmed by airway endoscopy, bronchoalveolar lavage fluid (BALf) cytology, and lung function evaluation by indirect pleural pressure measurement. Oscillometry is a promising pulmonary function test method, but its ability to detect subclinical airway obstruction has been questioned. OBJECTIVES: To evaluate the differences in lung function measured by oscillometry between healthy and MEA-affected horses. STUDY DESIGN: Prospective case-control clinical study. METHODS: Thirty-seven horses were divided into healthy and MEA groups, based on history and clinical score; the diagnosis of MEA was confirmed by airway endoscopy and BALf cytology. Horses underwent oscillometry at frequencies ranging from 2 to 6 Hz. Obtained parameters included whole-breath, inspiratory, expiratory, and the difference between inspiratory and expiratory resistance (Rrs) and reactance (Xrs). Differences between oscillometry parameters at different frequencies were evaluated within and between groups by repeated-measures two-way ANOVA and post hoc tests with Bonferroni correction. Frequency dependence was compared between groups by t test. For significant parameters, a receiver operating characteristics curve was designed, cut-off values were identified and their sensitivity and specificity were calculated. Statistical significance was set at p < 0.05. RESULTS: No significant differences in Xrs and Rrs were observed between groups. The frequency dependence of whole-breath and inspiratory Xrs significantly differed between healthy (respectively, -0.03 ± 0.02 and -0.05 ± 0.02 cmH2O/L/s) and MEA (-0.1 ± 0.03 and -0.2 ± 0.02 cmH2O/L/s) groups (p < 0.05 and p < 0.01). For inspiratory Xrs frequency dependence, a cut-off value of -0.06 cmH2O/L/s was identified, with 86.4% (95% CI: 66.7%-95.3%) sensitivity and 66.7% (95% CI: 41.7%-84.8%) specificity. MAIN LIMITATIONS: Sample size, no BALf cytology in some healthy horses. CONCLUSIONS: Oscillometry can represent a useful non-invasive tool for the diagnosis of MEA. Specifically, the evaluation of the frequency dependence of Xrs may be of special interest.

Association of peak expiratory flow with motoric cognitive risk syndrome among older adults.

Background: The association between lung function and motoric cognitive risk syndrome (MCR) is unclear. We aimed to explore the association of peak expiratory flow (PEF) with MCR using cross-sectional and longitudinal analyses. Methods: Within the CHARLS, 5095 participants were included in the cross-sectional analysis, and 4340 MCR-free participants were included in the longitudinal analysis. The PEF was assessed with a lung peak flow meter. MCR was characterized by cognitive complaints and a slow walking speed with normal mobility and without dementia. Logistic regression, Cox regression, and Laplace regression models were employed for data analysis. Results: In this cross-sectional study, logistic regression analyses revealed that continuous PEF was associated with MCR (odds ratio [OR], 0.998; 95% confidence interval [CI], 0.998, 0.999), and the ORs (95% CIs) of MCR prevalence were 0.857 (0.693, 1.061) for the middle tertile and 0.665 (0.524, 0.845) for the highest tertile compared to the lowest tertile. In a longitudinal cohort study, continuous PEF was dose-dependently associated with the risk of MCR. Compared with those in the lowest tertile of PEF, the hazard ratios (95% CIs) of incident MCR were 0.827 (0.661, 1,036) for the middle tertile and 0.576 (0.432, 0.767) for the highest tertile. Furthermore, compared with the lowest tertile, the highest tertile was associated with a delayed onset time of MCR of 0.484 (95% CI: 0.151, 0.817) years. Conclusion: A higher PEF was related to a lower prevalence of MCR and a lower risk for MCR, and a higher PEF also prolonged the onset time of MCR.

[Respiratory oscillometry: Theoretical foundations and clinical applications]. / L'oscillométrie respiratoire : théorie et applications cliniques.

Oscillometry measures the mechanical properties of the respiratory system. As they are carried out during spontaneous breathing, oscillometry measurements do not require forced breathing maneuvers or the patient's active cooperation. The technique is complementary to conventional pulmonary function testing methods for the investigation of respiratory function, diagnosis and monitoring of respiratory diseases, and assessment of response to treatment. The present review aims to describe the theoretical foundations and practical methodology of oscillometry. It describes the gaps in scientific evidence regarding its clinical utility, and provides examples of current research and clinical applications.

Improvement of pulmonary function parameters in female patients with adolescent idiopathic scoliosis by Schroth rehabilitative therapy.

Objective: This study investigates if an inpatient rehabilitation therapy (brace therapy and Schroth therapy) for six weeks contributes to an improvement in lung function of the patients. Design: Retrospective study. Setting: Scoliosis rehabilitation clinic "Asklepios Katharina-Schroth-Klinik" (Bad Sobernheim, Germany). Participants: In 253 female patients a lung function examination was performed at entry and at the end of their inpatient rehabilitation stay. Of these, 61 patients underwent Schroth therapy (group 1); 192 patients underwent the combination of brace and Schroth therapy (group 2). Intervention: Lung function parameters under the influence of Schroth and Schroth and brace therapy within a rehabilitative stay. Main measures: The parameters of IVC (inspiratory vital capacity), FVC (forced vital capacity), FEV1 (forced expiratory volume in 1 s) and the Tiffeneau index (FEV/FVC) related to patient-specific reference values were evaluated with regard to potential ventilation disorders. Results: There were significant improvements for IVC +2.56 %, FVC +3.99 %, FEV1 +2.36 % for the first stay (IVC and FVC 2nd, 3rd stay). The comparison of patients with vs. without additional brace therapy showed no significances. For the long-term analysis the parameters approached the reference values of age-matched, healthy female subjects. The greater the Cobb angle in the thoracic region, the significantly worse almost each of the measured parameters are. Conclusion: An inpatient rehabilitation therapy contributes to an improvement in lung function (IVC, FVC and FEV1). A second, and even a third, follow-up stay still led to a measurable improvement in lung function, albeit to a lesser extent.

Indoor Allergen Exposure and its Association to Upper Respiratory Infections and Pulmonary Outcomes among Children with Asthma.

BACKGROUND: Certain environmental allergen exposures are more common in disadvantaged communities and may contribute to differences in susceptibility to upper respiratory infections (URI). OBJECTIVES: To examine associations between indoor allergens and: 1) URI; 2) URI + cold symptoms; 3) URI + cold symptoms + pulmonary eosinophilic inflammation (FENO≥20 ppb); and 4) URI + cold symptoms + reduced lung function (percent predicted FEV1<80%). METHODS: We used data from the Environmental Control as Add-on Therapy for Childhood Asthma study. Allergen concentrations were measured in air (mouse) and settled dust (mouse, cockroach, dog, and cat). URI was determined by testing nasal mucus for upper respiratory viruses. We evaluated associations between allergen concentrations and URI-associated outcomes accounting for age, sex, study month, season, health insurance, and household size. RESULTS: 90 participants (92% Black, 92% public insurance) with 192 observations were included; 52 (27%) of observations were positive for URI. A doubling in cockroach allergen concentration increased the odds of a URI with cold symptoms by 18% (odds ratios (OR) =1.18, 95% CI, 0.99-1.40), the odds of a URI + cold symptoms + pulmonary eosinophilic inflammation by 31% (OR=1.31, 95% CI, 1.10-1.57), and the odds of a URI + cold symptoms + reduced lung function by 45% (OR = 1.45, 95% CI, 1.13-1.85). Mouse allergen concentrations were positively associated with all outcomes. Associations were suggestively stronger among children sensitized to pest allergens. CONCLUSIONS: Cockroach and mouse, but not dog or cat, allergen exposure may predispose children with asthma to URIs with colds and lower respiratory outcomes.

Inverse association between lung function and nonalcoholic fatty liver disease: An observational and mendelian randomization study.

BACKGROUND AND AIM: The association between lung function with non-alcoholic fatty liver disease (NAFLD) in the general population remains unknown. We aimed to examine the association between lung function and NAFLD among the general population in an observational and Mendelian randomization (MR) study. METHODS AND RESULTS: 340, 253 participants without prior liver diseases were included from the UK Biobank. Of these, 30,397 participants had liver proton density fat fraction (PDFF) measurements by magnetic resonance image (MRI). Lung function parameters included forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC). The primary outcome was the presence of NAFLD, defined as a PDFF greater than 5.5%. The secondary outcome included incident severe NAFLD and severe liver diseases (including liver cirrhosis, liver failure, hepatocellular carcinoma and liver-related death), defined by the International Classification of Disease codes with different data sources. During a media follow-up duration of 9.3 years, 7335 (24.1%) the presence of NAFLD cases were documented. There was an inverse association of FEV1 (% predicted) (Per SD increment, adjusted OR = 0.91, 95%CI: 0.88-0.94) and FVC (% predicted) (Per SD increment, adjusted OR = 0.90, 95%CI: 0.87-0.92) with the presence of NAFLD. Similar results were found for incident severe NAFLD, severe liver disease, liver cirrhosis, liver failure and liver-related death. MR analyses showed that the genetically predicted FEV1 (adjusted OR = 0.63, 95%CI: 0.46-0.87) and FVC (adjusted OR = 0.69, 95%CI: 0.51-0.95) were both inversely associated with the presence of NAFLD. CONCLUSIONS: There was an inverse causal relationship between lung function and NAFLD in the general population.

Safety, effectiveness, and usefulness of higher-dose tablets of generic pirfenidone in patients with IPF: a nationwide observational study in South Korea.

Background: Pirfenidone is an antifibrotic medication approved for idiopathic pulmonary fibrosis (IPF). Fybro®, a generic version of pirfenidone developed in South Korea, gained approval and is available in 200 mg and in higher-dose formulations of 400 and 600 mg. This real-world prospective cohort study investigated the safety and effectiveness of Fybro®. Methods: A nationwide observational study was conducted in patients with IPF. Patients were followed up for 6 months, with a subset of patients being followed up for 12 months. Data on lung function and adverse events were collected. Patient adherence to fewer-pill (400 and/or 600 mg tablets) and multiple-pill (200 mg tablets) regimens were compared. Results: Of the 359 enrolled patients, 352 received pirfenidone (Fybro®) at least once and were included in the analysis. The mean age was 69.0 years and 82.4% of patients were male. The median treatment duration was 186.0 days. A total of 253 patients (71.9%) experienced adverse events, with decreased appetite being the most common (16.5%). The adjusted decline rates in lung function were -1.5% and -2.2% predicted per year for forced vital capacity and diffusing capacity, respectively. No significant differences were observed based on the pirfenidone dose. For a daily intake of 1,200 or 1800 mg of pirfenidone, a significantly longer duration of drug administration was observed with the fewer-pill regimen than with multiple-pill regimen. Conclusion: The safety and effectiveness of Fybro® observed in this real-world cohort study are consistent with previous studies. Using higher-strength tablets to reduce pill burden may improve medication adherence.

Exploring the associations between elevated plasma SP-D levels and OSCAR gene expression as potential biomarkers in patients with COPD: a cross-sectional study.

Background: Chronic obstructive pulmonary disease (COPD) imposes a substantial burden on patients and healthcare systems. Spirometry is the most widely used test to diagnose the disease; however, a surrogate marker is required to predict the disease pattern and progression. Objectives: The aim of the current study was to explore the association of elevated levels of plasma surfactant protein D (SP-D) with gene expression of osteoclast-associated receptor (OSCAR) and lung functions as potential diagnostic biomarkers of COPD. Methods: This cross-sectional study employed convenience sampling. As men compose the majority of patients in the outpatient department and with smoking being common among Pakistani men, choosing men offered a representative sample. Using a post-bronchodilator forced expiratory volume in the first second (FEV1) to a forced vital capacity (FVC) of less than 0.70 (FEV1/FVC <0.7), COPD patients were diagnosed on spirometry (n = 41). Controls were healthy individuals with FEV1/FVC >0.7 (n = 41). Plasma SP-D levels were measured using an enzyme-linked immunosorbent assay (ELISA). The gene expression of OSCAR was determined by real-time polymerase chain reaction (qPCR) and subsequently analyzed by the threshold cycle (Ct) method. Statistical Package for Social Sciences (SPSS) version 20 was used for statistical analysis. Results: The mean BMI of controls (25.66 ± 4.17 kg/m2) was higher than that of cases (23.49 ± 2.94 kg/m2 (p = .008)). The median age of controls was 49 years (interquartile range (IQR) 42.0-65.0 years) and that of cases was 65 years (IQR = 57.50-68.50). SP-D concentration was not significantly higher in COPD patients [4.96 ng/mL (IQR 3.26-7.96)] as compared to controls [3.64 ng/mL (IQR 2.60-8.59)] (p = .209). The forced expiratory ratio (FEV1/FVC) and FEV1 were related to gene expression of OSCAR (p = <.001). The gene expression of OSCAR was significantly related to SP-D (p = .034). A multiple regression model found FEV1 and FVC to have a significant effect on the gene expression of OSCAR (p-values <0.001 and 0.001, respectively). Conclusion: Gene expression of OSCAR was increased in COPD patients and related directly to SP-D levels and inversely to lung functions in cohort of this study, suggesting that OSCAR along with SP-D may serve as a diagnostic biomarker of COPD.

Adam19 Deficiency Impacts Pulmonary Function: Human GWAS Follow-up in a Mouse Knockout Model.

PURPOSE: Over 550 loci have been associated with human pulmonary function in genome-wide association studies (GWAS); however, the causal role of most remains uncertain. Single nucleotide polymorphisms in a disintegrin and metalloprotease domain 19 (ADAM19) are consistently related to pulmonary function in GWAS. Thus, we used a mouse model to investigate the causal link between Adam19 and pulmonary function. METHODS: We created an Adam19 knockout (KO) mouse model and validated the gene targeting using RNA-Seq and RT-qPCR. Mouse body composition was assessed using dual-energy X-ray absorptiometry. Mouse lung function was measured using flexiVent. RESULTS: Contrary to prior publications, the KO was not neonatal lethal. KO mice had lower body weight and shorter tibial length than wild-type (WT) mice. Their body composition revealed lower soft weight, fat weight, and bone mineral content. Adam19 KO had decreased baseline respiratory system elastance, minute work of breathing, tissue damping, tissue elastance, and forced expiratory flow at 50% forced vital capacity but higher FEV0.1 and FVC. Adam19 KO had attenuated tissue damping and tissue elastance in response to methacholine following LPS exposure. Adam19 KO also exhibited attenuated neutrophil extravasation into the airway after LPS administration compared to WT. RNA-Seq analysis of KO and WT lungs identified several differentially expressed genes (Cd300lg, Kpna2, and Pttg1) implicated in lung biology and pathogenesis. Gene set enrichment analysis identified negative enrichment for TNF pathways. CONCLUSION: Our murine findings support a causal role of ADAM19, implicated in human GWAS, in regulating pulmonary function.

Co-exposure effects of urinary polycyclic aromatic hydrocarbons and metals on lung function: mediating role of systematic inflammation.

BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) and metals were associated with decreased lung function, but co-exposure effects and underlying mechanism remained unknown. METHODS: Among 1,123 adults from National Health and Nutrition Examination Survey 2011-2012, 10 urinary PAHs, 11 urinary metals, and peripheral white blood cell (WBC) count were determined, and 5 lung function indices were measured. Least absolute shrinkage and selection operator, Bayesian kernel machine regression, and quantile-based g-computation were used to estimate co-exposure effects on lung function. Mediation analysis was used to explore mediating role of WBC. RESULTS: These models demonstrated that PAHs and metals were significantly associated with lung function impairment. Bayesian kernel machine regression models showed that comparing to all chemicals fixed at median level, forced expiratory volume in 1 s (FEV1)/forced vital capacity, peak expiratory flow, and forced expiratory flow between 25 and 75% decreased by 1.31% (95% CI: 0.72%, 1.91%), 231.62 (43.45, 419.78) mL/s, and 131.64 (37.54, 225.74) mL/s respectively, when all chemicals were at 75th percentile. In the quantile-based g-computation, each quartile increase in mixture was associated with 104.35 (95% CI: 40.67, 168.02) mL, 1.16% (2.11%, 22.40%), 294.90 (78.37, 511.43) mL/s, 168.44 (41.66, 295.22) mL/s decrease in the FEV1, FEV1/forced vital capacity, peak expiratory flow, and forced expiratory flow between 25% and 75%, respectively. 2-Hydroxyphenanthrene, 3-Hydroxyfluorene, and cadmium were leading contributors to the above associations. WBC mediated 8.22%-23.90% of association between PAHs and lung function. CONCLUSIONS: Co-exposure of PAHs and metals impairs lung function, and WBC could partially mediate this relationship. Our findings elucidate co-exposure effects of environmental mixtures on respiratory health and underlying mechanisms, suggesting that focusing on highly prioritized toxicants would effectively attenuate adverse effects.

Bilirubin metabolism in early life and respiratory health during preschool age: A combined analysis of two independent birth cohorts.

BACKGROUND: Bilirubin has antioxidant properties, and elevated levels within the normal range have been associated with improved lung function and decreased risk of asthma in adults, but studies of young children are scarce. Here, we investigate associations between bilirubin in early life and respiratory health endpoints during preschool age in two independent birth cohorts. METHODS: Bilirubin metabolites were assessed at ages 0.5, 1.5, and 6 years in COPSAC2010 (Copenhagen Prospective Studies on Asthma in Childhood 2010) and ages 1, 3, and 6 years in the VDAART (The Vitamin D Antenatal Asthma Reduction Trial) cohort. Meta-analyses were done to summarize the relationship between levels of bilirubin metabolites and asthma, infections, lung function, and allergic sensitization until age 6 across the cohorts. Interaction with the glucuronosyltransferase family 1 member A1 (UGT1A) genotype encoding for an enzyme in the bilirubin metabolism was explored, and metabolomics data were integrated to study underlying mechanisms. FINDINGS: Increasing bilirubin (Z,Z) at ages 1.5-3 years was associated with an increased risk of allergic sensitization (adjusted relative risk [aRR] = 1.85 [1.20-2.85], p = 0.005), and age 6 bilirubin (Z,Z) also showed a trend of association with allergic sensitization at age 6 (aRR = 1.31 [0.97-1.77], p = 0.08), which showed significant interaction for the age 6 bilirubin (Z,Z)xUGT1A genotype. Further, increasing bilirubin (E,E), bilirubin (Z,Z), and biliverdin at ages 1.5-3 years was associated with a lower forced expiratory volume at age 6 (aRR range = 0.81-0.91, p < 0.049) but without a significant interaction with the UGT1A genotype (p interactions > 0.05). Network analysis showed a significant correlation between bilirubin metabolism and acyl carnitines. There were no associations between bilirubin metabolites and the risk of asthma and infections. CONCLUSIONS: Bilirubin metabolism in early life may play a role in childhood respiratory health, particularly in children with specific UGT1A genotypes. FUNDING: The Lundbeck Foundation (Grant no R16-A1694), The Ministry of Health (Grant no 903516), Danish Council for Strategic Research (Grant no 0603-00280B), and The Capital Region Research Foundation have provided core support to the COPSAC research center. This project has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement No. 946228). The Vitamin D Antenatal Asthma Reduction Trial (VDDART, ClinicalTrials.gov identifier: NCT00920621) was supported by grant U01HL091528 from NHLBI, U54TR001012 from the National Centers for Advancing Translational Sciences (NCATS). Metabolomics work by VDAART was supported by the National Heart, Lung, and Blood Institute (NHLBI) grant R01HL123915 and R01HL141826. S.T.W. was supported by R01HL091528 from the NHLBI, UG3OD023268 from Office of The Director, National Institute of Health, and P01HL132825 from the NHLBI.