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.

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.

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.

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.

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.

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.

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.

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.

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.

Individual Risk Factors of PM2.5 Associated With Wintertime Mortality in Urban Patients With COPD.

BACKGROUND: Air pollution contributes to premature mortality, but potential impacts differ in populations with existing disease, particularly for individuals with multiple risk factors. Although COPD increases vulnerability to air pollution, individuals with COPD and other individual risk factors are at the intersection of multiple risks and may be especially susceptible to the effect of acute outdoor air pollution. RESEARCH QUESTION: What is the association between wintertime air pollution and mortality in patients with COPD and the modifying role of individual risk factors? STUDY DESIGN AND METHODS: This study evaluated 19,243 deceased veterans with prior COPD diagnosis who had resided in 25 US metropolitan regions (2016-2019). Electronic health records included patient demographic characteristics; smoking status; and comorbidities such as asthma, coronary artery disease (CAD), obesity, and diabetes. Using geocoded addresses, individuals were assigned wintertime fine particulate matter (particulate matter smaller than 2.5 µg in diameter [PM2.5]) and nitrogen dioxide air pollution exposures. Associations between acute air pollution and mortality were estimated by using a time-stratified case-crossover design with a conditional logistic model, and individual risk differences were assessed according to stratified analysis. RESULTS: A 1.05 (95% CI, 1.02-1.09) mortality risk was estimated for each 10 µg/m3 increase in daily wintertime PM2.5). Older patients and Black individuals displayed elevated risk. Obesity was a substantial air pollution-related mortality risk factor (OR, 1.11; 95% CI, 1.01-1.23), and the estimated risk for individuals with obesity plus CAD or obesity plus diabetes was 16% higher. INTERPRETATION: Wintertime PM2.5 exposure was associated with elevated mortality risk in people with COPD, but individuals with multiple comorbidities, notably obesity, had high vulnerability. Our study suggests that obesity, CAD, and diabetes are understudied modifiers of air pollution-related risks for people with existing COPD.

Particulate matter-induced metabolic recoding of epigenetics in macrophages drives pathogenesis of chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a group of illnesses associated with unresolved inflammation in response to toxic environmental stimuli. Persistent exposure to PM is a major risk factor for COPD, but the underlying mechanism remains unclear. Using our established mouse model of PM-induced COPD, we find that repeated PM exposure provokes macrophage-centered chronic inflammation and COPD development. Mechanistically, chronic PM exposure induces transcriptional downregulation of HAAO, KMO, KYNU, and QPRT in macrophages, which are the enzymes of de novo NAD+ synthesis pathway (kynurenine pathway; KP), via elevated chromatin binding of the CCCTC-binding factor (CTCF) near the transcriptional regulatory regions of the enzymes. Subsequent reduction of NAD+ and SIRT1 function increases histone acetylation, resulting in elevated expression of pro-inflammatory genes in PM-exposed macrophages. Activation of SIRT1 by nutraceutical resveratrol mitigated PM-induced chronic inflammation and COPD development. In agreement, increased levels of histone acetylation and decreased expression of KP enzymes were observed in pulmonary macrophages of COPD patients. We newly provide an evidence that dysregulated NAD+ metabolism and consecutive SIRT1 deficiency significantly contribute to the pathological activation of macrophages during PM-mediated COPD pathogenesis. Additionally, targeting PM-induced intertwined metabolic and epigenetic reprogramming in macrophages is an effective strategy for COPD treatment.

Exposure to outdoor particulate matter and risk of respiratory diseases: a systematic review and meta-analysis.

According to epidemiological studies, particulate matter (PM) is an important air pollutant that poses a significant threat to human health. The relationship between particulate matter and respiratory diseases has been the subject of numerous studies, but these studies have produced inconsistent findings. The purpose of this systematic review was to examine the connection between outdoor particulate matter (PM2.5 and PM10) exposure and respiratory disorders (COPD, lung cancer, LRIs, and COVID-19). For this purpose, we conducted a literature search between 2012 and 2022 in PubMed, Web of Science, and Scopus. Out of the 58 studies that were part of the systematic review, meta-analyses were conducted on 53 of them. A random effect model was applied separately for each category of study design to assess the pooled association between exposure to PM2.5 and PM10 and respiratory diseases. Based on time-series and cohort studies, which are the priorities of the strength of evidence, a significant relationship between the risk of respiratory diseases (COPD, lung cancer, and COVID-19) was observed (COPD: pooled HR = 1.032, 95% CI: 1.004-1.061; lung cancer: pooled HR = 1.017, 95% CI: 1.015-1.020; and COVID-19: pooled RR = 1.004, 95% CI: 1.002-1.006 per 1 µg/m3 increase in PM2.5). Also, a significant relationship was observed between PM10 and respiratory diseases (COPD, LRIs, and COVID-19) based on time-series and cohort studies. Although the number of studies in this field is limited, which requires more investigations, it can be concluded that outdoor particulate matter can increase the risk of respiratory diseases.

Risk Factors Associated With Prolonged Opioid Use After Revision Total Shoulder Arthroplasty.

INTRODUCTION: The purpose of this study was to determine which preoperative factors are associated with prolonged opioid use after revision total shoulder arthroplasty (TSA). METHODS: The M157Ortho PearlDiver database was used to identify patients undergoing revision TSA between 2010 and 2021. Opioid use for longer than 1 month after surgery was defined as prolonged opioid use. Postoperative opioid use from 1 to 3 months was independently assessed. Multivariable logistic regression was used to evaluate the association between preoperative patient-related risk factors (age, Charlson Comorbidity Index, sex, depression, anxiety, substance use disorder, opioid use between 12 months to 1 week of surgery, tobacco use, hypertension, diabetes mellitus, chronic obstructive pulmonary disease, osteoporosis, previous myocardial infarction, and chronic ischemic heart disease) with prolonged postoperative opioid use. Odds ratios (OR) and their associated 95% confidence intervals (CI) were calculated for each risk factor. RESULTS: A total 14,887 patients (mean age = 67.1 years) were included. Most of the patients were female (53.3%), and a large proportion were opioid familiar (44.1%). Three months after revision TSA, older age (OR = 0.96, CI 0.96 to 0.97) and male sex (OR = 0.90, CI 0.81 to 0.99) were associated with a decreased risk of prolonged postoperative opioid usage. Patients with preexisting depression (OR = 1.21, CI 1.08 to 1.35), substance use disorder (OR = 1.47, CI 1.29 to 1.68), opioid use (OR = 16.25, CI 14.27 to 18.57), and chronic obstructive pulmonary disorder (OR = 1.24, CI 1.07 to 1.42) were at an increased risk of prolonged postoperative opioid use. DISCUSSION: Older age and male sex were associated with a decreased risk of prolonged opioid use after revision TSA. Depression, substance use disorder, opioid familiarity, and COPD were associated with prolonged opioid use after revision TSA.

Use of thiols and implications for the use of inhaled corticosteroids in the presence of oxidative stress in COPD.

BACKGROUND: Oxidative stress and persistent airway inflammation are thought to be important contributors to the development of chronic obstructive pulmonary disease (COPD). This review summarizes the evidence for targeting oxidative stress and inflammation in patients with COPD with mucolytic/antioxidant thiols and inhaled corticosteroids (ICS), either alone or in combination. MAIN BODY: Oxidative stress is increased in COPD, particularly during acute exacerbations. It can be triggered by oxidant air pollutants and cigarette smoke and/or by endogenous reactive oxygen species (ROS) released from mitochondria and activated inflammatory, immune and epithelial cells in the airways, together with a reduction in endogenous antioxidants such as glutathione (GSH). Oxidative stress also drives chronic inflammation and disease progression in the airways by activating intracellular signalling pathways and the release of further inflammatory mediators. ICS are anti-inflammatory agents currently recommended for use with long-acting bronchodilators to prevent exacerbations in patients with moderate-to-severe COPD, especially those with eosinophilic airway inflammation. However, corticosteroids can also increase oxidative stress, which may in turn reduce corticosteroid sensitivity in patients by several mechanisms. Thiol-based agents such as erdosteine, N-acetyl L-cysteine (NAC) and S-carboxymethylcysteine (S-CMC) are mucolytic agents that also act as antioxidants. These agents may reduce oxidative stress directly through the free sulfhydryl groups, serving as a source of reducing equivalents and indirectly though intracellular GSH replenishment. Few studies have compared the effects of corticosteroids and thiol agents on oxidative stress, but there is some evidence for greater antioxidant effects when they are administered together. The current Global Initiative for Chronic Obstructive Lung Disease (GOLD) report supports treatment with antioxidants (erdosteine, NAC, S-CMC) in addition to standard-of-care therapy as they have been demonstrated to reduce COPD exacerbations. However, such studies have demonstrated that NAC and S-CMC reduced the exacerbation risk only in patients not treated with ICS, whereas erdosteine reduced COPD exacerbations irrespective of concomitant ICS use suggesting that erdosteine has additional pharmacological actions to ICS. CONCLUSIONS: Further clinical trials of antioxidant agents with and without ICS are needed to better understand the place of thiol-based drugs in the treatment of patients with COPD.

Phosphodiesterase inhibitors and lung diseases.

Phosphodiesterase enzymes (PDE) have long been known as regulators of cAMP and cGMP, second messengers involved in various signaling pathways and expressed in a variety of cell types implicated in respiratory diseases such as airway smooth muscle and inflammatory cells making them a key target for the treatment of lung diseases as chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis, and pulmonary hypertension (PH). The first reported PDE inhibitor was the xanthine, theophylline, described as a non-specific PDE inhibitor and whilst this drug is effective, it also has a range of unwanted side effects. In an attempt to improve the therapeutic window of xanthines, a number of selective PDE inhibitors have been developed for the treatment of respiratory diseases with only the selective PDE 4 inhibitor, roflumilast, being approved for the treatment of severe COPD. However, roflumilast also has a very narrow therapeutic window due to a number of important doses limiting side effects, particularly in the gastrointestinal tract. However, there continues to be research carried out in this field to identify improved selective PDE inhibitors, both by targeting other PDE subtypes (e.g., PDE 7 found in a number of inflammatory and immune cells) and through development of selective PDE inhibitors for pulmonary administration to reduce systemic exposure and improve the side effect profile. This approach has been exemplified by the development of ensifentrine, a dual PDE 3-PDE 4 inhibitor, an inhaled drug that has recently completed two successful Phase III clinical trials in patients with COPD.

Pacenta polypeptide injection alleviates the fibrosis and inflammation in cigarette smoke extracts-induced BEAS-2B cells by modulating MMP-9/TIMP-1 signaling.

Chronic obstructive pulmonary disease (COPD) has high morbidity and mortality. Here, we aimed to explore the roles and potential correlation of placenta polypeptide injection (PPI) and MMP-9/TIMP-1 signaling pathway in COPD. BEAS-2B cells were treated with cigarette smoke extract (CSE) to establish a COPD cell model in vitro. The cell survival and cytotoxic effect were measured by CCK-8, LDH release and flow cytometry assays. The inflammatory responses were determined by western blot and ELISA assay. Cell fibrosis was assessed by immunofluorescence and western blot assays. PPI treatment had no cytotoxic effect on BEAS-2B cells until the final concentration reached to 10%. In the range of 0%-8% final concentration, PPI treatment weakened CSE-induced the decrease of cell viability and the increase of LDH level in a concentration-dependent manner. Four percent PPI treatment enhanced cell viability and decreased cell apoptosis of CSE-treated cells in a time-dependent manner. Moreover, 4% PPI treatment significantly decreased inflammatory responses and fibrosis induced by CSE, while AMPA (MMPs agonist) had opposite effects. Notably, AMPA reversed the protective roles of PPI on CSE-induced inflammation and fibrosis. Mechanistically, 4% PPI treatment significantly suppressed MMP-1, MMP-2, MMP-3, MMP-9, MMP-13, and MMP-19 levels, but enhanced TIMP-1, TIMP-2, TIMP-3, and TIMP-4 levels. Among them, MMP-9 and TIMP-1 might be the main target of PPI. PPI effectively attenuated CSE-induced inflammation and fibrosis in vitro by regulating MMP-9/TIMP-1 signaling pathway.

Airway smooth muscle area to predict steroid responsiveness in COPD patients receiving triple therapy (HISTORIC): a randomised, placebo-controlled, double-blind, investigator-initiated trial.

BACKGROUND: Although inhaled corticosteroids (ICS) are highly effective in asthma, they provide significant, but modest, clinical benefit in COPD. Here, we tested the hypothesis that high bronchial airway smooth muscle cell (ASMC) area in COPD is associated with ICS responsiveness. METHODS: In this investigator-initiated and -driven, double-blind, randomised, placebo-controlled trial (HISTORIC), 190 COPD patients, Global Initiative for Chronic Obstructive Lung Disease stage B-D, underwent bronchoscopy with endobronchial biopsy. Patients were divided into groups A and B, with high ASMC area (HASMC: >20% of the bronchial tissue area) and low ASMC area (LASMC: ≤20% of the bronchial tissue area), respectively, and followed a run-in period of 6 weeks on open-label triple inhaled therapy with aclidinium (ACL)/formoterol (FOR)/budesonide (BUD) (400/12/400 µg twice daily). Subsequently, patients were randomised to receive either ACL/FOR/BUD or ACL/FOR/placebo and followed for 12 months. The primary end-point of the study was the difference in post-bronchodilator forced expiratory volume in 1 s (FEV1) over 12 months between patients with LASMC and HASMC receiving or not receiving ICS. RESULTS: In patients with LASMC, ACL/FOR/BUD did not significantly improve FEV1 over 12 months, as compared to ACL/FOR/placebo (p=0.675). However, in patients with HASMC, ACL/FOR/BUD significantly improved FEV1, as compared to ACL/FOR/placebo (p=0.020). Over 12 months, the difference of FEV1 change between the ACL/FOR/BUD group and the ACL/FOR/placebo group was 50.6 mL·year-1 within the group of patients with LASMC and 183.0 mL·year-1 within the group of patients with HASMC. CONCLUSION: COPD patients with ΗASMC respond better to ICS than patients with LASMC, suggesting that this type of histological analysis may predict ICS responsiveness in COPD patients receiving triple therapy.

Association of multiple air pollutants with oxygen saturation during sleep in COPD patients: Effect modification by smoking status and airway inflammatory phenotypes.

Air pollution contributes substantially to the development of chronic obstructive pulmonary disease (COPD). To date, the effect of air pollution on oxygen saturation (SpO2) during sleep and potential susceptibility factors remain unknown. In this longitudinal panel study, real-time SpO2 was monitored in 132 COPD patients, with 270 nights (1615 h) of sleep SpO2 recorded. Exhaled nitric oxide (NO), hydrogen sulfide (H2S) and carbon monoxide (CO) were measured to assess airway inflammatory characteristics. Exposure levels of air pollutants were estimated by infiltration factor method. Generalized estimating equation was used to investigate the effect of air pollutants on sleep SpO2. Ozone, even at low levels (<60 µg/m3), was significantly associated with decreased SpO2 and extended time of oxygen desaturation (SpO2 < 90%), especially in the warm season. The associations of other pollutants with SpO2 were weak, but significant adverse effects of PM10 and SO2 were observed in the cold season. Notably, stronger effects of ozone were observed in current smokers. Consistently, smoking-related airway inflammation, characterized by higher levels of exhaled CO and H2S but lower NO, significantly augmented the effect of ozone on SpO2 during sleep. This study highlights the importance of ozone control in protecting sleep health in COPD patients.

Protective effect of oleo-gum resin of Commiphora wightii against elastase-induced chronic obstructive pulmonary disease-linked lung inflammation and emphysema: Isolation and identification of key bioactive phytoconstituent.

ETHNOPHARMACOLOGICAL RELEVANCE: Oleo-gum resin of Commiphora wightii (Arnott) Bhandari of family Burseraceae, commonly known as 'guggul', is a well known Ayurvedic drug used traditionally to treat various disorders including respiratory ailments. However, role of C. wightii in chronic obstructive pulmonary disease (COPD) is not known. AIM: The present work was designed to investigate the protective potential of standardized C. wightii extract/and its fractions against elastase-induced COPD-linked lung inflammation and to identify key bioactive constituent(s). MATERIAL AND METHODS: C. wightii oleo-gum resin extract was prepared using Soxhlet extraction technique and the resultant extract was standardized on basis of guggulsterone content using HPLC. The extract was partitioned by different solvents in increasing order of polarity. Standardized extract/its partitioned fractions were orally administered to male BALB/c mice 1 h prior to intra-tracheal instillation of elastase (1U/mouse). Anti-inflammatory effect was evaluated by analyzing inflammatory cells and myeloperoxidase activity in lungs. The various fraction(s) were subjected to column chromatography to isolate bioactive compound. Isolated compound was identified using 1H and 13C-NMR and analyzed for assessment of several inflammatory mediators using techniques like ELISA, PCR, and gelatin zymography. RESULTS: C. wightii extract attenuated elastase-induced lung inflammation in dose-dependent manner and Ethyl acetate fraction (EAF) provided maximum protection. EAF was subjected to column chromatography followed by assessment of bioactivity of each sub-fraction, ultimately leading towards isolation of two compounds i.e. C1 and C2. C1 seems to be the key active principle of C. wightii, as it displayed significant anti-inflammatory activity against elastase induced lung inflammation while C2 largely remains ineffective. C1 was identified as mixture of E- and Z-guggulsterone (GS). Reduction in the elastase induced lung inflammation by GS was associated with downregulation of expression of several COPD linked pro-inflammatory factors such as IL-6/TNF-α/IL-1ß/KC/MIP-2/MCP-1/G-CSF as well as normalization of redox imbalance as indicated by levels of ROS/MDA/protein carbonyl/nitrite/GSH etc. Further, 21 days prolonged administration of GS (10 mg/kg b.wt; once daily) protected against elastase-induced emphysema by mitigating expression/activity of MMP-2/-9 and increasing TIMP-1 expression. CONCLUSION: Overall, guggulsterone seems to be the key bioactive constituent responsible for exerting beneficial effects of C. wightii against COPD.