Urinary volatile organic compound metabolites and COPD among US adults: mixture, interaction and mediation analysis.

BACKGROUND: Volatile organic compounds (VOCs) encompass hundreds of high production volume chemicals and have been reported to be associated with adverse respiratory outcomes such as chronic obstructive pulmonary disease (COPD). However, research on the combined toxic effects of exposure to various VOCs on COPD is lacking. We aimed to assess the effect of VOC metabolite mixture on COPD risk in a large population sample. METHODS: We assessed the effect of VOC metabolite mixture on COPD risk in 5997 adults from the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2020 (pre-pandemic) using multivariate logistic regression, Bayesian weighted quantile sum regression (BWQS), quantile-based g-Computation method (Qgcomp), and Bayesian kernel machine regression (BKMR). We explored whether these associations were mediated by white blood cell (WBC) count and total bilirubin. RESULTS: In the logistic regression model, we observed a significantly increased risk of COPD associated with 9 VOC metabolites. Conversely, N-acetyl-S-(benzyl)-L-cysteine (BMA) and N-acetyl-S-(n-propyl)-L-cysteine (BPMA) showed insignificant negative correlations with COPD risk. The overall mixture exposure demonstrated a significant positive relationship with COPD in both the BWQS model (adjusted odds ratio (OR) = 1.30, 95% confidence interval (CI): 1.06, 1.58) and BKMR model, and with marginal significance in the Qgcomp model (adjusted OR = 1.22, 95% CI: 0.98, 1.52). All three models indicated a significant effect of the VOC metabolite mixture on COPD in non-current smokers. WBC count mediated 7.1% of the VOC mixture associated-COPD in non-current smokers. CONCLUSIONS: Our findings provide novel evidence suggesting that VOCs may have adverse associations with COPD in the general population, with N, N- Dimethylformamide and 1,3-Butadiene contributing most. These findings underscore the significance of understanding the potential health risks associated with VOC mixture and emphasize the need for targeted interventions to mitigate the adverse effects on COPD risk.

[Pesticide exposure and chronic respiratory diseases]. / Exposition aux pesticides et maladies respiratoires chroniques.

INTRODUCTION: Pesticides are used worldwide, mainly in agriculture as a means of controlling pests and protecting crops. That said, the entire world population is ultimately subject to pesticide exposure (consumption of fruits and vegetables, living near treated fields…), with varying degrees of toxicity involved. STATE OF THE ART: In recent decades, epidemiological studies have contributed to the identification of chemical pesticide families with detrimental effects on human health: cognitive disorders, Parkinson's disease, prostate cancer… and impairment in respiratory functioning. Current scientific evidence points to the implication of the active substances in insecticides, herbicides and fungicides in chronic respiratory diseases, two examples being chronic obstructive pulmonary disease (COPD) in exposed workers, and asthmatic wheezing in children during prenatal or postnatal exposure. PERSPECTIVES: The safety of individuals exposed to pesticides is of key importance in public health. Further epidemiological investigations are needed to identify the chemical families affecting certain populations. CONCLUSIONS: The scientific literature suggests strong links between pesticide exposure and respiratory health. Whether it be environmental or occupational, pesticide exposure can lead to respiratory disorders and symptoms of varying severity.

Joint effect of long-term exposure to ambient air pollution on the prevalence of chronic obstructive pulmonary disease using the Korea National Health and Nutrition Examination Survey 2010-2019.

BACKGROUND: Little is known about the relationship between long-term joint exposure to mixtures of air pollutants and the prevalence of chronic obstructive pulmonary disease (COPD). We aimed to assess the joint impact of long-term exposure to ambient air pollution on the prevalence of COPD in Korea, especially in areas with high levels of air pollution. METHODS: We included 22,387 participants who underwent spirometry tests in 2010-2019. The community multiscale air quality model was used to estimate the levels of ambient air pollution at residential addresses. The average exposure over the 5 years before the examination date was used to calculate the concentrations of air pollution. Forced expiratory volume in 1 s and forced vital capacity were used to define restrictive lung disease, COPD, and moderate-to-severe COPD. Quantile-based g-computation models were used to assess the joint impact of air pollution on COPD prevalence. RESULTS: A total of 2535 cases of restrictive lung disease, 2787 cases of COPD, and 1399 cases of moderate-to-severe COPD were identified. In the individual pollutant model, long-term exposure was significantly associated with both restrictive lung disease and COPD. In the mixture pollutant model, the odds ratios (ORs, 95% confidence intervals) for restrictive lung disease increased with each quartile increment in the 1- to 5-year average mixtures: 1.14 (1.02-1.28, 1 year), 1.25 (1.11-1.41, 2 years), 1.26 (1.11-1.42, 3 years), 1.32 (1.16-1.51, 4 years), and 1.37 (1.19-1.58, 5 years), respectively. The increase in ORs of restrictive lung disease accelerated over time. By contrast, the ORs of COPD showed a decreasing trend over time. CONCLUSIONS: Long-term exposure to air pollutants, both individually and jointly, was associated with an increased risk of developing COPD, particularly restrictive lung disease. Our findings highlight the importance of comprehensively assessing exposure to various air pollutants in relation to COPD.

Papel del radiofarmacéutico clínico en la seguridad del paciente durante los estudios de perfusión miocárdica de esfuerzo con vasodilatadores / Role of the clinical radiopharmacist in patient safety during myocardial perfusion imaging with vasodilator stress agents

Objetivos: Evaluar el papel del radiofarmacéutico en un equipo multidisciplinar en la detección de contraindicaciones del regadenosón para su uso seguro en pacientes a los que se solicitó una SPECT de perfusión miocárdica. Métodos: Se estudió ambispectivamente su uso seguro en 1.905 pacientes (54,1% mujeres, edad media: 66,6±11,7 años, rango: 20-95años). Se registraron datos relativos al sexo, a la edad, al historial médico, a la medicación, a las alergias medicamentosas y a las contraindicaciones para el estrés farmacológico, así como las recomendaciones realizadas al médico nuclear responsable. Resultados: Las contraindicaciones detectadas y las correspondientes recomendaciones fueron las siguientes: riesgo de prolongación del intervalo QTc (7,5%): comprobación previa del intervalo QTc y monitorización del ECG; ictus o AIT previo (4,2%): evaluación de estenosis carotídea; alergia a salicilatos y/o sulfamidas (3,1%): empleo de [99mTc]Tc-MIBI; epilepsia o riesgo de convulsiones (2,4%): uso de adenosina o reconsiderar su indicación; tratamiento con corticosteroides sistémicos en EPOC severa (1,3%): reevaluar las condiciones del paciente; EPOC reagudizada (0,8%): posponer hasta la resolución del episodio agudo; asma grave (0,4%): no realizar la prueba; toma de metilxantinas (0,3%): evitar su consumo previo; otras (6,1%): evaluación de cada contraindicación. No se observaron contraindicaciones en el 73,6% de los pacientes. Se anularon el 2,9% de las peticiones debido a contraindicaciones absolutas. Conclusiones: Empleando una metodología de trabajo sistemática, el radiofarmacéutico detectó un elevado número de incidencias, presentando uno de cada cuatro pacientes alguna contraindicación clínica. Las recomendaciones emitidas fueron aceptadas por los médicos nucleares, que modificaron su enfoque, incrementando así la seguridad de estos pacientes.(AU)

Aim: To assess the radiopharmacist's role in a multidisciplinary team focused on the contraindications of regadenoson in order to ensure the safe use of pharmacologic vasodilator stress agents in patients undergoing SPECT-MPI. Methods: We ambispectively studied its safe use in 1905 patients (54.1% female, mean age: 66.6±11.7 years, range: 20-95years). Sex, age, medical history, medications, drug allergies, and contraindications for stress testing were registered together with recommendations for the nuclear physician in charge. Results: Detected contraindications and corresponding recommendations were as follows: risk factors for QTc interval prolongation 7.5% — measurement of QTc interval previously to test and monitor ECG; prior stroke or TIA 4.2% — consider carotid stenosis assessment; salicylates/sulfonamides allergy 3.1% — use 99mTc-sestamibi; epilepsy or risk factors for seizures 2.4% — use of adenosine or reconsider test indication; systemic corticosteroid therapy for severe COPD 1.3% — reassessment of patient's condition; acute exacerbation of COPD 0.8% — defer test until acute episode is over; severe asthma 0.4% — do not perform test; methylxanthine ingestion 0.3% — avoid consumption previously; other 6.1% — evaluation of other contraindications. No contraindications were detected in 73.6% of patients. The test was cancelled due to absolute contraindications in 2.9% of the requests. Conclusions: Working in a systematic way, the radiopharmacist was able to detect a high number of issues related to regadenoson, with one out of four patients presenting some clinical contraindication. The recommendations given by the radiopharmacist were well accepted by the nuclear physicians who changed their approach contributing to increase the safety of patients referred for MPI.(AU)

Airway inflammation in a novel mouse model of asthma-COPD overlap induced by co-exposure to papain and tobacco smoke.

Asthma and chronic obstructive pulmonary disease (COPD) are respiratory diseases associated with airway inflammation, which is the main pathogenesis. Although their causes and characteristics differ, in some cases, asthma and COPD may coexist in the same patient in a condition called asthma-COPD overlap (ACO). The prognosis of ACO is more unfavourable than those of asthma or COPD alone, without any treatment strategies demonstrating efficacy. Owing to its intricate spectrum of features, the detailed pathogenesis of how ACO exacerbates respiratory features remains unclear. In this study, we exposed papain-induced asthma model mice to tobacco smoke to establish an ACO mouse model, in which features of airway inflammation observed in both asthma and COPD were incorporated. This model exhibited distinctive mixed and corticosteroid-resistant airway inflammation and emphysematous changes that are characteristic of ACO. The novel mouse model established here is expected to significantly contribute to elucidating the mechanisms of the broad pathologies of ACO and identifying potential therapeutic targets.

PM2.5 exposure-induced senescence-associated secretory phenotype in airway smooth muscle cells contributes to airway remodeling.

Fine particulate matter (PM2.5) has been linked to increased severity and incidence of airway diseases, especially chronic obstructive pulmonary disease (COPD) and asthma. Airway remodeling is an important event in both COPD and asthma, and airway smooth muscle cells (ASMCs) are key cells which directly involved in airway remodeling. However, it was unclear how PM2.5 affected ASMCs. This study investigates the effects of PM2.5 on airway smooth muscle and its mechanism. We first showed that inhaled particulate matter was distributed in the airway smooth muscle bundle, combined with increased airway smooth muscle bundle and collagen deposition in vivo. Then, we demonstrated that PM2.5 induced up-regulation of collagen-I and alpha-smooth muscle actin (α-SMA) expression in rat and human ASMCs in vitro. Next, we found PM2.5 led to rat and human ASMCs senescence and exhibited senescence-associated secretory phenotype (SASP) by autophagy-induced GATA4/TRAF6/NF-κB signaling, which contributed to collagen-I and α-SMA synthesis as well as airway smooth muscle remodeling. Together, our results provided evidence that SASP induced by PM2.5 in airway smooth muscle cells prompted airway remodeling.

Association between per- and polyfluoroalkyl substances exposure and prevalence of chronic obstructive pulmonary disease: The mediating role of serum albumin.

BACKGROUND: No study has examined the association between per- and polyfluoroalkyl substances (PFAS) exposure and chronic obstructive pulmonary disease (COPD) risk. This study aims to explore this relationship. METHODS: This study enrolled 4541 individuals who had available data on PFAS, COPD, and covariates from NHANES 2007-2018. Serum PFAS including perfluorohexane sulfonate (PFHxS), perfluorononanoic acid (PFNA), perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS) were analyzed, because of high detective rates. Considering the skew distribution of PFAS levels, the natural logarithm-transformed PFAS (Ln-PFAS) was used. Logistic regression analysis, restricted cubic spline (RCS), and weighted quantile sum (WQS) regression were performed to explore the single, nonlinear, and mixed effects. A mediating analysis was used to evaluate the mediated effects of albumin. RESULTS: Individuals with COPD had higher levels of PFHxS, PFNA, PFOA, and PFOS compared to those without COPD. Ln-PFNA (OR males: 1.92, 95 % CI:1.31 to 2.80, P: <0.001; OR females: 1.07, 95 % CI: 0.81 to 1.40, P: 0.636) and ln-PFOA (OR males: 2.17, 95 % CI:1.38 to 3.41, P: <0.001; OR females: 1.49, 95 % CI: 1.08 to 2.05, P: 0.016) were associated with COPD risk especially in males. The interaction between PFNA exposure and sex on COPD risk was significant (P interaction: <0.001). The RCS curve demonstrated the nonlinear relationship between the ln-PFOA (P nonlinear:0.001), ln-PFNA (P nonlinear:0.045), and COPD risk in males. WQS analysis showed mixed PFAS exposure was correlated with COPD risk in males (OR: 1.44, 95 % CI:1.18 to 1.75, P: <0.001). Albumin mediated the relationship between PFOA and COPD (mediated proportion: -17.94 %). CONCLUSION: This study concludes PFOA and PFNA are linked to a higher COPD risk in males, and serum albumin plays a mediating role in the relationship between PFOA and COPD. Thess findings are beneficial for the prevention of COPD. Further studies are required to explore potential mechanisms.

Cardiovascular Events with the Use of Long-Acting Muscarinic Receptor Antagonists: An Analysis of the FAERS Database 2020-2023.

PURPOSE: This study aimed to examine reports of cardiovascular adverse events (CV AEs) observed in the real-world during treatment with aclidinium, tiotropium, glycopyrronium, and umeclidinium alone or in combination with a LABA and, in the context of triple therapy, with the addition of an ICS, and submitted to the food and drug administration adverse event reporting system (FAERS). METHODS: A retrospective disproportionality analysis was conducted utilizing CV AE reports submitted to the FAERS from January 2020 to 30 September 2023. Disproportionality was measured by calculating the reporting odds ratio. RESULTS: Compared with ipratropium, tiotropium was associated with fewer reports of CV AEs. Compared with tiotropium, other LAMAs were more likely to be associated with reports of CV AEs. Combinations of glycopyrronium with indacaterol or formoterol and umeclidinium with vilanterol significantly reduced reports of CV AEs compared with the respective LAMA. The addition of an ICS to these combinations further reduced the risk of CV AE reports. CONCLUSION: Our study suggests that inhaled LAMAs are not free from cardiac AE risks. This risk may be more evident when the newer LAMAs are used, but it is generally significantly reduced when COPD patients are treated with dual bronchodilators or triple therapy. However, these results do not prove that LAMAs cause CV AEs, as FAERS data alone are not indicative of a drug's safety profile. Given the frequency with which COPD and cardiovascular disease co-exist, a large study in the general population could shed light on this very important issue.

The association between cadmium exposure and the risk of chronic obstructive pulmonary disease: A systematic review and meta-analysis.

According to the World Health Organization, chronic obstructive pulmonary disease (COPD) was one of the top ten causes of death worldwide in 2019. The ratio of forced expiratory volume in the first second to forced vital capacity (FEV1/FVC) provides a useful indicator for the diagnosis of COPD. Existing data have demonstrated that cadmium (Cd) exposure is associated with COPD. However, data concerning the incidence and progression of cadmium-induced COPD is inconsistent. To explore the relationship between cadmium exposure and the risk of COPD in humans, through January 12, 2023, we conducted a thorough search of the PubMed, Cochrane, Web of Science, Embase and Scopus databases for relevant material. In this study, a meta-analysis was conducted to evaluate the association between cadmium and COPD. This meta-analysis indicated that exposure to cadmium (per 1 µg/L increase) was associated with reduced FEV1/FVC (% change = -47.54%, 95% CI: -54.99% to -40.09%). Subgroup analysis showed that the combined effect estimates were significantly higher in the COPD patient group (% change = -54.66%, 95% CI: -83.32% to -26.00%) than in the general population (% change = -52.11%, 95%CI: -60.53% to -43.70%). Therefore, we conclude that cadmium exposure is associated with reduced FEV1/FVC, which suggests a risk for COPD.

Inhalation exposure to polystyrene nanoplastics induces chronic obstructive pulmonary disease-like lung injury in mice through multi-dimensional assessment.

Nanoplastics are widely distributed in indoor and outdoor air and can be easily inhaled into human lungs. However, limited studies have investigated the impact of nanoplastics on inhalation toxicities, especially on the initiation and progression of chronic obstructive pulmonary disease (COPD). To fill the gap, the present study used oronasal aspiration to develop mice models. Mice were exposed to polystyrene nanoplastics (PS-NPs) at three concentrations, as well as the corresponding controls, for acute, subacute, and subchronic exposure. As a result, PS-NPs could accumulate in exposed mice lungs and influence lung organ coefficient. Besides, PS-NPs induced local and systemic oxidative stress, inflammation, and protease-antiprotease imbalance, resulting in decreased respiratory function and COPD-like lesions. Meanwhile, PS-NPs could trigger the subcellular mechanism to promote COPD development by causing mitochondrial dysfunctions and endoplasmic reticulum (ER) stress. Mechanistically, ferroptosis played an important role in the COPD-like lung injury induced by PS-NPs. In summary, the present study comprehensively and systematically indicates that PS-NPs can damage human respiratory health and increase the risk for COPD.

Glucocorticoid Use in Patients Hospitalized with Chronic Obstructive Pulmonary Disease Exacerbations.

Objective of the Study: Systemic glucocorticoid therapy can improve the outcomes of acute exacerbation of chronic obstructive pulmonary disease (AECOPD). The study tried to investigate the use of glucocorticoids in AECOPD patients and the factors associated with the physicians' choice. Methodology: Patients with AECOPD over two periods were divided by the year of 2017 when GOLD and ERS/ATS Guideline for COPD were updated. Data of patients regarding the study was retrieved from medical records. Descriptive statistical analysis was used for the illustration of glucocorticoids use, and hypothesis testing for comparison over the periods. Results: Between 2010 and 2016, the proportion of ICS use was 522/640 (81.6%) and 341/452 (75.4%) between 2017 and 2020. COPD severity (GOLD C/D classification), bronchial asthma, percentage of neutrophils, and higher PaCO2 were factors associated with physicians' prescription of systemic glucocorticoids between 2010 and 2016. While the use of ICS at the stable stage, counts of neutrophils, and higher PaCO2 were influencing factors between 2017 and 2020. Over the two periods, 1-year recurrent rate decreased from 32.4% to 20.9%, with a significant statistical difference (P<0.001). Conclusion: The optimized use of glucocorticoids was found after the publishment of 2017 ERS/ATS Guideline for COPD, this improvement was associated with a decreased 1-year recurrence rate among AECOPD patients at our institution, underscoring the positive impact of guideline updates on patient outcomes.

HDAC6-selective inhibitor CAY10603 ameliorates cigarette smoke-induced small airway remodeling by regulating epithelial barrier dysfunction and reversing.

BACKGROUND: Small airway remodelling is a vital characteristic of chronic obstructive pulmonary disease (COPD), which is mainly caused by epithelial barrier dysfunction and epithelial-mesenchymal transition (EMT). Recent studies have indicated that histone deacetylase 6 (HDAC6) plays an important role in the dysregulation of epithelial function. In this study, we investigated the therapeutic effects and underlying mechanisms of an inhibitor with high selectivity for HDAC6 in COPD. METHODS: Cigarette smoke (CS) exposure was used to establish a CS-induced COPD mouse model. CAY10603 at doses of 2.5 and 10 mg/kg was injected intraperitoneally on alternate days. The protective effects of CAY10603 against CS-induced emphysema, epithelial barrier function and small airway remodeling were evaluated using hematoxylin and eosin (H&E) staining, Masson's trichrome staining, immunohistochemical staining, and western blot. The human lung bronchial epithelial cell line (HBE) was used to elucidate the underlying molecular mechanism of action of CAY10603. RESULTS: HDAC6 levels in the lung homogenates of CS-exposed mice were higher than that those in control mice. Compared to the CS group, the mean linear intercept (MLI) of the CAY10603 treatment group decreased and the mean alveolar number (MAN)increased. Collagen deposition was reduced in groups treated with CAY10603. The expression of α-SMA was markedly upregulated in the CS group, which was reversed by CAY10603 treatment. Conversely, E-cadherin expression in the CS group was further downregulated, which was reversed by CAY10603 treatment. CAY10603 affects the tight junction protein expression of ZO-1 and occludin. ZO-1 and occludin expression were markedly downregulated in the CS group. After CAY10603treatment, the protein expression level of ZO-1 and occludin increased significantly. In HBE cells, Cigarette smoke extract (CSE) increased HDAC6 levels. CAY10603 significantly attenuated the release of TGF-ß1 induced by CSE. CAY10603 significantly increased the E-cadherin levels in TGF-ß1 treated HBE cells, while concurrently attenuated α-SMA expression. This effect was achieved through the suppression of Smad2 and Smad3 phosphorylation. CAY10603 also inhibited TGF-ß1 induced cell migration. CONCLUSIONS: These findings suggested that CAY10603 inhibited CS induced small airway remodelling by regulating epithelial barrier dysfunction and reversing EMT via the TGF-ß1/Smad2/3 signalling pathway.

Diesel exhaust and respiratory dust exposure in miners and chronic obstructive pulmonary disease (COPD) mortality in DEMS II.

BACKGROUND: Diesel exhaust and respirable dust exposures in the mining industry have not been studied in depth with respect to non-malignant respiratory disease including chronic obstructive pulmonary disease (COPD), with most available evidence coming from other settings. OBJECTIVES: To assess the relationship between occupational diesel exhaust and respirable dust exposures and COPD mortality, while addressing issues of survivor bias in exposed miners. METHODS: The study population consisted of 11,817 male workers from the Diesel Exhaust in Miners Study II, followed from 1947 to 2015, with 279 observed COPD deaths. We fit Cox proportional hazards models for the relationship between respirable elemental carbon (REC) and respirable dust (RD) exposure and COPD mortality. To address healthy worker survivor bias, we leveraged the parametric g-formula to assess effects of hypothetical interventions on both exposures. RESULTS: Cox models yielded elevated estimates for the associations between average intensity of REC and RD and COPD mortality, with hazard ratios (HR) corresponding to an interquartile range width increase in exposure of 1.46 (95 % confidence interval (CI): 1.12, 1.91) and 1.20 (95 % CI: 0.96, 1.49), respectively for each exposure. HRs for cumulative exposures were negative for both REC and RD. Based on results from the parametric g-formula, the risk ratio (RR) for COPD mortality comparing risk under an intervention eliminating REC to the observed risk was 0.85 (95 % CI: 0.55, 1.06), equivalent to an attributable risk of 15 %. The corresponding RR comparing risk under an intervention eliminating RD to the observed risk was 0.93 (95 % CI: 0.56, 1.31). CONCLUSIONS: Our findings, based on data from a cohort of nonmetal miners, are suggestive of an increased risk of COPD mortality associated with REC and RD, as well as evidence of survivor bias in this population leading to negative associations between cumulative exposures and COPD mortality in traditional regression analysis.

Suppression of long noncoding RNA SNHG6 alleviates cigarette smoke-induced lung inflammation by modulating NF-κB signaling.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a widespread inflammatory disease with a high mortality rate. Long noncoding RNAs play important roles in pulmonary diseases and are potential targets for inflammation intervention. METHODS: The expression of small nucleolar RNA host gene 6 (SNHG6) in mouse lung epithelial cell line MLE12 with or without cigarette smoke extract (CSE) treatment was first detected using quantitative reverse-transcription PCR. ELISA was used to evaluate the release of inflammatory cytokines (TNF-α, IL-1ß, and IL-6). The binding site of miR-182-5p with SNHG6 was predicted by using miRanda, which was verified by double luciferase reporter assay. RESULTS: Here, we revealed that SNHG6 was upregulated in CS-exposed MLE12 alveolar epithelial cells and lungs from COPD-model mice. SNHG6 silencing weakened CS-induced inflammation in MLE12 cells and mouse lungs. Mechanistic investigations revealed that SNHG6 could upregulate IκBα kinase through sponging the microRNA miR-182-5p, followed by activated NF-κB signaling. The suppressive effects of SNHG6 silencing on CS-induced inflammation were blocked by an miR-182-5p inhibitor. CONCLUSION: Overall, our findings suggested that SNHG6 regulates CS-induced inflammation in COPD by activating NF-κB signaling, thereby offering a novel potential target for COPD treatment.

Fine particulate matter contributes to COPD-like pathophysiology: experimental evidence from rats exposed to diesel exhaust particles.

BACKGROUND: Ambient fine particulate matter (PM2.5) is considered a plausible contributor to the onset of chronic obstructive pulmonary disease (COPD). Mechanistic studies are needed to augment the causality of epidemiologic findings. In this study, we aimed to test the hypothesis that repeated exposure to diesel exhaust particles (DEP), a model PM2.5, causes COPD-like pathophysiologic alterations, consequently leading to the development of specific disease phenotypes. Sprague Dawley rats, representing healthy lungs, were randomly assigned to inhale filtered clean air or DEP at a steady-state concentration of 1.03 mg/m3 (mass concentration), 4 h per day, consecutively for 2, 4, and 8 weeks, respectively. Pulmonary inflammation, morphologies and function were examined. RESULTS: Black carbon (a component of DEP) loading in bronchoalveolar lavage macrophages demonstrated a dose-dependent increase in rats following DEP exposures of different durations, indicating that DEP deposited and accumulated in the peripheral lung. Total wall areas (WAt) of small airways, but not of large airways, were significantly increased following DEP exposures, compared to those following filtered air exposures. Consistently, the expression of α-smooth muscle actin (α-SMA) in peripheral lung was elevated following DEP exposures. Fibrosis areas surrounding the small airways and content of hydroxyproline in lung tissue increased significantly following 4-week and 8-week DEP exposure as compared to the filtered air controls. In addition, goblet cell hyperplasia and mucus hypersecretions were evident in small airways following 4-week and 8-week DEP exposures. Lung resistance and total lung capacity were significantly increased following DEP exposures. Serum levels of two oxidative stress biomarkers (MDA and 8-OHdG) were significantly increased. A dramatical recruitment of eosinophils (14.0-fold increase over the control) and macrophages (3.2-fold increase) to the submucosa area of small airways was observed following DEP exposures. CONCLUSIONS: DEP exposures over the courses of 2 to 8 weeks induced COPD-like pathophysiology in rats, with characteristic small airway remodeling, mucus hypersecretion, and eosinophilic inflammation. The results provide insights on the pathophysiologic mechanisms by which PM2.5 exposures cause COPD especially the eosinophilic phenotype.

HDAC9 inhibition reduces skeletal muscle atrophy and enhances regeneration in mice with cigarette smoke-induced COPD.

Cigarette smoke (CS) is the major risk factor for chronic obstructive pulmonary disease (COPD), and sarcopenia is one of the significant comorbidities of COPD. However, the pathogenesis of CS-related deficient skeletal muscle regeneration has yet to be clarified. The impact of CS on myoblast differentiation was examined, and then we determined which HDAC influenced the myogenic process and muscle atrophy in vitro and in vivo. Finally, we further investigated the potential mechanisms via RNA sequencing. Long-term CS exposure activated skeletal muscle primary satellite cells (SCs) while inhibiting differentiation, and defective myogenesis was also observed in C2C12 cells treated with CS extract (CSE). The level of HDAC9 changed in vitro and in vivo in CS exposure models as well as COPD patients, as detected by bioinformatics analysis. Our data showed that CSE impaired myogenic capacity and myotube formation in C2C12 cells via HDAC9. Moreover, inhibition of HDAC9 in mice exposed to CS prevented skeletal muscle dysfunction and promoted SC differentiation. The results of RNA-Seq analysis and verification indicated that HDAC9 knockout improved muscle differentiation in CS-exposed mice, probably by acting on the AKT/mTOR pathway and inhibiting the P53/P21 pathway. More importantly, the serum of HDAC9 KO mice exposed to CS alleviated the differentiation impairment of C2C12 cells caused by serum intervention in CS-exposed mice, and this effect was inhibited by LY294002 (an AKT/mTOR pathway inhibitor). These results suggest that HDAC9 plays an essential role in the defective regeneration induced by chronic exposure to CS.

Role of the clinical radiopharmacist in patient safety during myocardial perfusion imaging with vasodilator stress agents.

AIM: To assess the radiopharmacist's role in a multidisciplinary team focused on the contraindications of regadenoson in order to ensure the safe use of pharmacologic vasodilator stress agents in patients undergoing SPECT-MPI. METHODS: We ambispectively studied its safe use in 1905 patients (54.1% female, mean age: 66.6±11.7 years, range: 20-95 years). Sex, age, medical history, medications, drug allergies, and contraindications for stress testing were registered together with recommendations for the nuclear physician in charge. RESULTS: Detected contraindications and corresponding recommendations were as follows: risk factors for QTc interval prolongation 7.5% - measurement of QTc interval previously to test and monitor ECG; prior stroke or TIA 4.2% - consider carotid stenosis assessment; salicylates/sulfonamides allergy 3.1% - use 99mTc-sestamibi; epilepsy or risk factors for seizures 2.4% - use of adenosine or reconsider test indication; systemic corticosteroid therapy for severe COPD 1.3% - reassessment of patient's condition; acute exacerbation of COPD 0.8% - defer test until acute episode is over; severe asthma 0.4% - do not perform test; methylxanthine ingestion 0.3% - avoid consumption previously; other 6.1% - evaluation of other contraindications. No contraindications were detected in 73.6% of patients. The test was canceled due to absolute contraindications in 2.9% of the requests. CONCLUSIONS: Working in a systematic way, the radiopharmacist was able to detect a high number of issues related to regadenoson, with one out of four patients presenting some clinical contraindication. The recommendations given by the radiopharmacist were well accepted by the nuclear physicians who changed their approach contributing to increase the safety of patients referred for MPI.

Dietary tannic acid attenuates elastase-induced pulmonary inflammation and emphysema in mice.

Emphysema is one of the major components of chronic obstructive pulmonary disease (COPD), which is characterised by the destruction and enlargement of air spaces, leading to airflow limitation and dyspnoea, finally progressing to oxygen dependency. The alveolar wall destruction is due to chronic inflammation, oxidative stress, apoptosis, and proteinase/anti-proteinase imbalance. So far, there has been no effective therapy for patients with COPD. We evaluated the therapeutic efficacy of tannic acid (TA), a naturally occurring plant-derived polyphenol in the murine emphysema model. In C57BL/6 J mice, we established emphysema by intratracheal instillation of elastase (EL). Then, mice were treated with TA and evaluated 1 and 21 days post-EL instillation. After 24 h, TA treatment significantly reduced EL-induced histopathological alterations, infiltrating leukocytes, and gene expression of markers of inflammation and apoptosis. Similarly, after 21 days, TA treatment suppressed the mean linear intercept, gene expression of proteinases, and increased elastic fiber contents in the lungs when compared to the EL-alone group. Furthermore, EL induced the activation of p38 mitogen-activated protein kinase (MAPK) and nuclear factor kappa light chain enhancer of activated B cells (NF-kB) p65 pathways in the lungs was suppressed by TA treatment. In summary, TA has the potential to mitigate EL-induced inflammation, apoptosis, proteinase/anti-proteinase imbalance, and subsequent emphysema in mice.

COPD Exposed to Air Pollution: A Path to Understand and Protect a Susceptible Population.

TOPIC IMPORTANCE: Air pollution poses a risk to the respiratory health of individuals with COPD. Long- and short-term exposures to higher levels of particulate-rich air pollution are associated with increased COPD exacerbation, hospitalization, and mortality, collectively implicating air pollution as a cause of adverse COPD-related outcomes. REVIEW FINDINGS: This review summarizes the evidence for COPD as a phenotype that confers susceptibility for adverse health outcomes in the face of common air pollution. We highlight how typical contributors to compromised urban air quality, including that from traffic, wildfire smoke, and indoor biomass combustion, adversely affect the COPD patient population. Evidence underscoring the burden of ongoing air pollution exposure on patients with COPD is discussed. We then detail the detrimental impact of that exposure on COPD pathophysiology, which in turn increases the patient's susceptibility. We specifically propose that indoor air is a particularly rational target for increased monitoring and remediation to protect patients with COPD. Because COPD is a heterogeneous disease with several endotypes, future intervention studies need to better include control populations, to highlight COPD-specific risks and identify subpopulations within patients with COPD who will benefit the most from improved indoor air quality. SUMMARY: Regulatory efforts must continue to broadly lower emission standards to protect this susceptible population from the negative health impacts of air pollution.

Topical and Oral Roflumilast in Dermatology: A Narrative Review. / Roflumilast tópico y oral en dermatología. Una revisión narrativa.

Oral roflumilast is a phosphodiesterase-4 inhibitor approved for the prevention of exacerbations of chronic obstructive pulmonary disease and chronic bronchitis. In dermatology, topical roflumilast is authorized by the US Food and Drug Administration for the treatment of plaque psoriasis and mild to moderate seborrheic dermatitis. Several studies have described the off-label use of roflumilast in dermatology, including a randomized controlled trial showing its usefulness in the treatment of psoriasis; case reports and small series have also reported successful outcomes in hidradenitis suppurativa, recurrent oral aphthosis, nummular eczema, lichen planus, and Behçet disease. Roflumilast has a favorable safety profile, similar to that of apremilast, and it is considerably cheaper than new generation drugs and even some conventional immunosuppressants. We review the pharmacokinetics and pharmacodynamics of topical and oral roflumilast and discuss potential adverse effects and both approved and off-label uses in dermatology. Roflumilast is a promising agent to consider.