Sea buckthorn extract mitigates chronic obstructive pulmonary disease by suppression of ferroptosis via scavenging ROS and blocking p53/MAPK pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Sea buckthorn (Hippophae rhamnoides), a traditional Tibetan medicinal herb, exhibits protective effects against cardiovascular and respiratory diseases. Although Sea buckthorn extract (SBE) has been confirmed to alleviate airway inflammation in mice, its therapeutic effect and underlying mechanism on chronic obstructive pulmonary disease (COPD) requires further clarification. AIM OF THE STUDY: To elucidate the alleviative effect and molecular mechanism of SBE on lipopolysaccharides (LPS)/porcine pancreatic elastase (PPE)-induced COPD by blocking ferroptosis. METHODS: The anti-ferroptotic effects of SBE were evaluated in human BEAS-2B bronchial epithelial cells using CCK8, RT-qPCR, western blotting, and transmission electron microscopy. Transwell was employed to detect chemotaxis of neutrophils. COPD model was induced by intranasally administration of LPS/PPE in mice and measured by alterations of histopathology, inflammation, and ferroptosis. RNA-sequencing, western blotting, antioxidant examination, flow cytometry, DARTS, CETSA, and molecular docking were then used to investigate its anti-ferroptotic mechanisms. RESULTS: In vitro, SBE not only suppressed erastin- or RSL3-induced ferroptosis by suppressing lipid peroxides (LPOs) production and glutathione (GSH) depletion, but also suppressed ferroptosis-induced chemotactic migration of neutrophils via reducing mRNA expression of chemokines. In vivo, SBE ameliorated LPS/PPE-induced COPD phenotypes, and inhibited the generation of LPOs, cytokines, and chemokines. RNA-sequencing showed that p53 pathway and mitogen-activated protein kinases (MAPK) pathway were implicated in SBE-mediated anti-ferroptotic action. SBE repressed erastin- or LPS/PPE-induced overactivation of p53 and MAPK pathway, thereby decreasing expression of diamine acetyltransferase 1 (SAT1) and arachidonate 15-lipoxygenase (ALOX15), and increasing expression of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11). Mechanistically, erastin-induced elevation of reactive oxygen species (ROS) was reduced by SBE through directly scavenging free radicals, thereby contributing to its inhibition of p53 and MAPK pathways. CETSA, DARTS, and molecular docking further showed that ROS-generating enzyme nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) may be the target of SBE. Overexpression of NOX4 partially impaired the anti-ferroptotic activity of SBE. CONCLUSION: Our results demonstrated that SBE mitigated COPD by suppressing p53 and MAPK pro-ferroptosis pathways via directly scavenging ROS and blocking NOX4. These findings also supported the clinical application of Sea buckthorn in COPD therapy.

Lung microbiota: implications and interactions in chronic pulmonary diseases.

The lungs, as vital organs in the human body, continuously engage in gas exchange with the external environment. The lung microbiota, a critical component in maintaining internal homeostasis, significantly influences the onset and progression of diseases. Beneficial interactions between the host and its microbial community are essential for preserving the host's health, whereas disease development is often linked to dysbiosis or alterations in the microbial community. Evidence has demonstrated that changes in lung microbiota contribute to the development of major chronic lung diseases, including chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), asthma, and lung cancer. However, in-depth mechanistic studies are constrained by the small scale of the lung microbiota and its susceptibility to environmental pollutants and other factors, leaving many questions unanswered. This review examines recent research on the lung microbiota and lung diseases, as well as methodological advancements in studying lung microbiota, summarizing the ways in which lung microbiota impacts lung diseases and introducing research methods for investigating lung microbiota.

Reducing Health Care Resource Utilization in COPD: A Retrospective Matched Control Analysis of a Digital Quality Improvement Program.

Introduction: COPD is a progressive lung disease that adds significant economic burden to the healthcare system in the United States. Digital platforms integrated into clinical workflows have demonstrated success in improving patient outcomes in COPD, but few studies have explored the impact of an integrated digital and clinical approach on drivers of direct healthcare costs (COPD-related prescriptions, emergency department (ED) visits and hospitalizations) in a real-world setting. Methods: We conducted a six-month retrospective matched control analysis to assess the impact of a digital quality improvement (QI) program delivered by clinical pharmacists on healthcare resource utilization among people living with COPD. Results: Compared to matched controls at six months, participants in the digital QI program had a nearly two-third relative reduction in COPD-related ED visits and hospitalizations (p=0.044), as well as a 47% reduction in all-cause ED visits and hospitalizations (p=0.059). Participants in the digital QI program also had higher rates of COPD-related prescription fills for antibiotics and oral corticosteroids, as well as a greater number of non-acute care visits compared to matched controls. Conclusion: Digital health platforms integrated into a virtual clinical pharmacist workflow can help reduce costly COPD-related emergency department visits and hospitalizations. Care models integrating digital platforms may also offer a scalable approach to managing COPD and should be explored in different clinical settings.

Hypercapnia as an absolute exclusion criteria for bronchoscopic lung volume reduction.

Bronchoscopic lung volume reduction is a procedure that involves placement of valves into the lung to intentionally cause atelectasis to help with perfusion-ventilation matching. There are strict exclusion criteria, such as hypercapnia, that prevent patients from qualifying for the procedure based on the early trials. We present a case of a patient that became a candidate for the procedure after utilizing AVAPS after BPAP failed to lower his PCO2 to qualify for the procedure. Additionally, newer studies show that patients who are hypercapnic might benefit from the procedure to improve hypercapnia.

Effect of allyl isothiocyanate on 4-HNE induced glucocorticoid resistance in COPD and the underlying mechanism.

Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory condition, and its clinical management primarily targets bronchodilation and anti-inflammatory therapy. However, these treatments often fail to directly address the progression of COPD, particularly its associated glucocorticoid (GC) resistance. This study elucidates the mechanisms underlying GC resistance in COPD and explores the therapeutic potential of allyl isothiocyanate (AITC) in modulating MRP1 transport. We assessed the levels of the oxidative stress product 4-HNE, HDAC2 protein, inflammatory markers, and pulmonary function indices using animal and cell models of GC-resistant COPD. The cascade effects of these factors were investigated through interventions involving AITC, protein inhibitors, and dexamethasone (DEX). Cigarette smoke-induced oxidative stress in COPD leads to the accumulation of the lipid peroxidation product 4-HNE, which impairs HDAC2 protein activity and diminishes GC-mediated anti-inflammatory sensitivity due to disrupted histone deacetylation. AITC regulates MRP1, facilitating the effective efflux of 4-HNE from cells, thereby reducing HDAC2 protein degradation and restoring dexamethasone sensitivity in COPD. These findings elucidate the mechanism of smoking-induced GC resistance in COPD and highlight MRP1 as a potential therapeutic target, as well as the enormous potential of AITC for combined GC therapy in COPD, promoting their clinical applications.

High-frequency chest wall oscillation devices: An umbrella review and bibliometric analysis.

INTRODUCTION: High-frequency chest wall oscillation (HFCWO) devices are used to improve airway clearance in various respiratory conditions. This study comprehensively assesses the evidence on efficacy and safety and identifies trends in scientific publications and patents across geographic regions. METHODS: This study utilized an integrated approach, combining bibliographic and bibliometric research with artificial intelligence (AI) tools. Four databases - PubMed, Europe Pubmed Central, Cochrane Database of Systematic Reviews, and CINAHL - were searched for systematic reviews on the effectiveness of treatment options for HFCWO. The AMSTAR-2 tool was used to evaluate the risk of bias in systematic reviews. Bibliographic research synthesized the evidence following PRISMA and Cochrane guidelines. The Dimensions platform was used for bibliometric analysis to provide insights into the global landscape. AI tools with prompt engineering tools Chain-of-Thoughts (CoT) and Tree of Thoughts (ToT) were used to enhance data extraction capabilities. RESULTS: The umbrella review identified 12 systematic reviews supporting the effectiveness of HFCWO in improving pulmonary function parameters, sputum characteristics, dyspnea, health scores, and quality of life in conditions including cystic fibrosis, bronchiectasis, chronic obstructive pulmonary disease (COPD), or neuromuscular diseases, with varying evidence of certainty. Eight of the twelve reviews had a moderate to high AMSTAR-2 confidence level, while several studies lacked sufficient descriptions of methods, treatment regimens, outcome measures, and adverse effects. Despite the absence of adverse events, the overall evidence quality between studies is evaluated as low to very low. Bibliometric analysis found a significant increase in global interest over the past two decades, with 230 research publications, 137 patents, and 56 clinical trials. CONCLUSIONS: The study highlights the potential of HFCWO devices in respiratory care but demands more robust evidence. The increasing interest in airway clearance devices highlights the necessity for HFCWO mechanism and safety research, underlining its therapeutic relevance in respiratory medicine. The interdisciplinary integration of AI tools and prompt engineering contributes to a nuanced understanding of the available evidence.

The Real-World Efficacy of Fixed Triple Inhalation Therapy in the Treatment of Moderate COPD Patients (RATIONALE Study).

Purpose: COPD affects more than 300 million people worldwide, requiring inhalation treatment. Novel triple formulations of ICS, LABAs and LAMAs are becoming the mainstay of treatment, however there is still a lack of clinical evidence for personalized therapy. Patients and Methods: RATIONALE was a non-interventional, prospective, 52 week study, assessing the effectiveness of beclometasone/formoterol/glycopyrronium-bromide (BDP/FF/G), in symptomatic COPD patients, with moderate airflow obstruction. The study included 4 visits, where data on demographic parameters, exacerbations, symptoms, quality of life (based on the EQ-5D-3L questionnaire) and lung function were collected. Data on adherence to treatment, based on prescriptions filled was collected from the database of the National Health Insurance Fund, with the patients' consent. The primary objective was the change of adherence to treatment during the study, compared to baseline. Results: Altogether 613 patients had been enrolled. Their average age was 64.56 years and 50.5% were female. The average CAT score was 20.86, and most patients had suffered minimum one exacerbation (82.2%). Average FEV1 was 59.6%. Most patients had some limitation in one or more dimensions of EQ-5D-3L, with an average visual analogue scale score (VAS) of 60.31. After 12 months of treatment, adherence improved significantly - proportion of patients in the highest adherence group increased from 29.8% to 69.7% (p<0.001). The average CAT score improved by 7.02 points (95% CI 5.82-8.21, p<0.001). There was a significant improvement in all dimensions of EQ-5D-3L, with an average increase of 17.91 (95% CI 16.51-19.31, p< 0.001) points in the VAS score. Exacerbation frequency also decreased significantly. Conclusion: Although limitations of observational studies are present, we observed that early introduction of fixed triple combination results in a marked improvement in adherence to treatment, symptom scores, exacerbation frequency and quality of life. The optimal choice of treatment is crucial for reaching the highest possible adherence.

Tracking Real-World Physical Activity in Chronic Obstructive Pulmonary Disease Over One Year: Results from a Monocentric, Prospective, Observational Cohort Study.

Introduction: Lung function constraints and comorbidities such as coronary heart disease, sarcopenia, and mood disorders make chronic obstructive pulmonary disease (COPD) patients avoid physical activity (PA). However, PA represents an important pillar of COPD management and is explicitly recommended by professional associations to enhance physical functioning and positively modulate disease progression. Methods: In this monocentric, prospective, observational feasibility study, it was our primary objective to investigate the association between PA and the evolution of the COPD assessment test (CAT) and the occurrence of acute exacerbations of COPD (AECOPD), respectively. To this end, we equipped 42 COPD patients with an activity tracking wearable and telemonitored their daily PA levels over one year using a dedicated web-based interface. Patients additionally provided weekly CAT scores using the same telehealth platform and came in for 3 study visits to assess functional parameters and biochemical markers related to nutrition and inflammation. Results: A principal study finding was that PA was inversely associated with CAT score (drop of 0.21 points associated with an increase of 1000 daily steps, p = 0.004), and that the 50% of patients with higher PA levels showed less CAT score progression over time (0.42 points per year) than the 50% of patients with lower PA levels (3.26 points per year) (p < 0.001). In addition, higher PA levels were significantly associated with a lower likelihood of experiencing a moderate-to-severe AECOPD (31% risk reduction associated with an increase of 1000 daily steps, p = 0.0097). Discussion: Our study demonstrates the relevance of PA for key COPD outcome metrics in a real-world setting and underpins the importance of PA for COPD self-management in everyday life. Our study paves the way for future intervention trials to prospectively identify medically relevant PA thresholds and establish training recommendations for different patient subgroups.

The Impact of Different Telerehabilitation Methods on Peripheral Muscle Strength and Aerobic Capacity in COPD Patients: A Randomized Controlled Trial.

Lung diseases have profound effects on the aging population. We aimed to hypothesize and investigate the effect of remote pulmonary telerehabilitation and motor imagery (MI) and action observation (AO) methods on the clinical status of elderly chronic obstructive pulmonary disease (COPD) patients. Twenty-six patients were randomly assigned to pulmonary telerehabilitation (PtR) or cognitive telerehabilitation (CtR) groups. The programs were carried out 3 days a week for 8 weeks. The 6-min walk test (6MWT), modified Medical Research Council dyspnea score, blood lactate level (BLL), measurement of peripheral muscle strength (PMS), and electromyography activation levels of accessory respiratory muscles were the main outcomes. There was a statistically significant improvement (p < 0.05) in both groups in the 6MWT distance and in secondary results, except for BLL. Generally, in the mean muscle activity obtained from the electromyography measurement after the program, there were statistically significant increases in the PtR group and decreases in the CtR group (p < 0.05). There was a statistically significant increase in PMS in both groups. An active muscle-strengthening program has the same benefits as applying the muscle-strengthening program to the patient as MI and AO. CtR can be a powerful alternative rehabilitation method in respiratory patients who cannot tolerate active exercise programs.

The association between non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio and chronic obstructive pulmonary disease: the mediating role of dietary inflammatory index.

Background: Numerous studies have indicated a potential correlation between COPD, lipid metabolism, and dietary inflammation. However, the exact mechanisms by which dietary inflammation regulates the pathological processes of COPD related to lipid metabolism remain unclear. NHHR is a novel composite index of atherosclerotic lipid profiles, while the Dietary Inflammatory Index (DII) measures diet-induced inflammation. This study explores the relationship between NHHR and COPD and evaluates whether DII mediates this association. Methods: We employed multivariable logistic regression, smooth curve fitting, threshold effect analysis, and subgroup analysis to explore the relationship between NHHR and the incidence of COPD. Additionally, we conducted a mediation analysis to explore the potential relationship between dietary inflammatory index (DII) levels and the relationship between NHHR and COPD. Results: This analysis encompassed 13,452 participants, with 2,332 reporting incidents of COPD. Following adjustment for all covariates using multivariable logistic regression, each unit increase in NHHR level and DII level was associated with a 10% (OR = 1.10, 95% CI: 1.05, 1.16) and 8% (OR = 1.08, 95% CI: 1.04, 1.13) increase, respectively, in the incidence rate of COPD. Furthermore, compared to the lowest quartile, the highest quartile of NHHR level and DII level was associated with a 47% (p < 0.001) and 50% (p < 0.001) increase, respectively, in the incidence rate of COPD. Smooth curve fitting and threshold effect analysis revealed a nonlinear relationship between NHHR and the risk of COPD, with a breakpoint at 2.60. Mediation analysis indicated that DII mediated 7.24% of the association between NHHR and COPD (p = 0.004). Conclusion: Higher NHHR levels are associated with an increased prevalence of COPD. Moreover, this association is mediated by DII, suggesting that an anti-inflammatory diet may be beneficial.

Muscle endurance, neuromuscular fatigability, and cognitive control during prolonged dual-task in people with chronic obstructive pulmonary disease: a case-control study.

PURPOSE: Recent studies suggest that, compared to healthy individuals, people with chronic obstructive pulmonary disease (pwCOPD) present a reduced capacity to perform cognitive-motor dual-task (CMDT). However, these studies were focused on short-duration CMDT offering limited insight to prolonged CMDT inducing fatigue, which can be encountered in daily life. The present study aimed to explore the effect of adding a cognitive task during repeated muscle contractions on muscle endurance, neuromuscular fatigability, and cognitive control in pwCOPD compared to healthy participants. METHODS: Thirteen pwCOPD and thirteen age- and sex-matched healthy participants performed submaximal isometric contractions of the knee extensors until exhaustion in two experimental sessions: (1) without cognitive task and (2) with a concurrent working memory task (i.e., 1-back task). Neuromuscular fatigability (as well as central and peripheral components measured by peripheral magnetic stimulation), cognitive performance, and perceived muscle fatigue were assessed throughout the fatiguing tasks. RESULTS: Independently to the experimental condition, pwCOPD exhibited lower muscle endurance compared to healthy participants (p = 0.039), mainly explained by earlier peripheral fatigue and faster attainment of higher perceived muscle fatigue (p < 0.05). However, neither effect of cognitive task (p = 0.223) nor interaction effect (group × condition; p = 0.136) was revealed for muscle endurance. Interestingly, cognitive control was significantly reduced only in pwCOPD at the end of CMDT (p < 0.015), suggesting greater difficulty for patients with dual tasking under fatigue. CONCLUSION: These findings provide novel insights into how and why fatigue develops in COPD in dual-task context, offering a rationale for including such tasks in rehabilitation programs.

Exhaled breath condensate (EBC) in respiratory diseases: recent advances and future perspectives in the age of omic sciences.

Exhaled breath condensate (EBC) is used as a promising noninvasive diagnostic tool in the field of respiratory medicine. EBC is achieved by cooling exhaled air, which contains aerosolized particles and volatile compounds present in the breath. This method provides useful information on the biochemical and inflammatory state of the airways. In respiratory diseases such as asthma, chronic obstructive pulmonary disease and cystic fibrosis, EBC analysis can reveal elevated levels of biomarkers such as hydrogen peroxide, nitric oxide and various cytokines, which correlate with oxidative stress and inflammation. Furthermore, the presence of certain volatile organic compounds in EBC has been linked to specific respiratory conditions, potentially serving as disease-specific fingerprints. The noninvasive nature of EBC sampling makes it particularly useful for repeated measures and for use in vulnerable populations, including children and the elderly. Despite its potential, the standardization of collection methods, analytical techniques and interpretation of results currently limits its use in clinical practice. Nonetheless, EBC holds significant promise for improving the diagnosis, monitoring and therapy of respiratory diseases. In this tutorial we will present the latest advances in EBC research in airway diseases and future prospects for clinical applications of EBC analysis, including the application of the Omic sciences for its analysis.

Suppression of the DNA repair enzyme NEIL2 promotes persistent inflammation and genomic damage in subjects with stable COPD and during severe exacerbations.

Background: Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory airway disease that is an independent risk factor for lung cancer. NEIL2, a DNA glycolase involved in DNA repair during transcription, has also been associated with an increased incidence of malignancies in humans. NEIL2 knockout mouse models have demonstrated increased inflammation and oxidative DNA damage in the lungs after exposure to an inflammatory insult, but data are lacking regarding NEIL2 function in individuals with stable COPD and during severe acute exacerbations of COPD (AECOPD). We investigated whether NEIL2 levels and oxidative DNA damage to the transcribed genome are altered in individuals with stable COPD and AECOPD. Methods: The study was conducted at a single center in the US. Eligible subjects underwent a one-time 30 cc venous blood draw. The population consisted of 50 adults: 16 with stable COPD, 11 hospitalized for AECOPD, and 23 volunteers. We analyzed blood leukocytes for NEIL2 mRNA and DNA damage by RT-qPCR and LA-qPCR, respectively, in all groups. Plasma levels of seven biomarkers, CXCL1, CXCL8, CXCL9, CXCL10, CCL2, CCL11 and IL-6, were analyzed in the COPD groups using a magnetic bead panel (Millipore®). Results: The NEIL2 mRNA levels were lower in individuals with stable COPD and AECOPD than in controls (0.72 for COPD, p = 0.0289; 0.407 for AECOPD, p = 0.0002). The difference in NEIL2 mRNA expression between the stable COPD group and AECOPD group was also statistically significant (p < 0.001). The fold change in DNA lesions per 10 kb of DNA was greater in the stable COPD (9.38, p < 0.0008) and AECOPD (15.81, p < 0.0004) groups than in the control group. The difference in fold change was also greater in the AECOPD group versus stable COPD p < 0.0236). Biomarker levels were not significantly different between the COPD groups. NEIL2 levels were correlated with plasma eosinophil levels in the stable COPD group (r = 0.737, p < 0.0027). Conclusions: NEIL2 mRNA levels are significantly reduced in COPD subjects and are associated with increased DNA damage and inflammation. These results reveal a mechanism that promotes persistent airway inflammation and oxidative genomic damage and increases the risk of malignancy in this population.

Advancements in automated classification of chronic obstructive pulmonary disease based on computed tomography imaging features through deep learning approaches.

Chronic Obstructive Pulmonary Disease (COPD) represents a global public health issue that significantly impairs patients' quality of life and overall health. As one of the primary causes of chronic respiratory diseases and global mortality, effective diagnosis and classification of COPD are crucial for clinical management. Pulmonary function tests (PFTs) are standard for diagnosing COPD, yet their accuracy is influenced by patient compliance and other factors, and they struggle to detect early disease pathologies. Furthermore, the complexity of COPD pathological changes poses additional challenges for clinical diagnosis, increasing the difficulty for physicians in practice. Recently, deep learning (DL) technologies have demonstrated significant potential in medical image analysis, particularly for the diagnosis and classification of COPD. By analyzing key radiological features such as airway alterations, emphysema, and vascular characteristics in Computed Tomography (CT) scan images, DL enhances diagnostic accuracy and efficiency, providing more precise treatment plans for COPD patients. This article reviews the latest research advancements in DL methods based on principal radiological features of COPD for its classification and discusses the advantages, challenges, and future research directions of DL in this field, aiming to provide new perspectives for the personalized management and treatment of COPD.

A Network Meta-Analysis of Aerobic, Resistance, Endurance, and High-Intensity Interval Training to Prioritize Exercise for Stable COPD.

Purpose: While the benefits of exercises for chronic obstructive pulmonary disease (COPD) are well-established, the relative effectiveness of different exercise types for stable COPD remains unclear. This network meta-analysis aims to investigate the comparative effects of aerobic exercise (AE), resistance training (RT), endurance training (ET), and high-intensity interval training (HIIT) in stable COPD. Methods: Electronic searches were performed in PubMed, Embase, and the Cochrane library to identify relevant randomized controlled trials (RCTs) investigating the effects of exercises on 6-minute walk test distance (6MWD), forced expiratory volume in one second (FEV1), and forced vital capacity (FVC), and St. George's Respiratory Questionnaire (SGRQ) score. Two authors screened the retrieved articles, extracted relevant data, and assessed the risk of bias. Network meta-analysis was conducted using Stata 14.0. Results: This study included a total of 19 studies involving 951 patients with stable COPD. HIIT emerged as the most favorable exercise type for enhancing 6MWD, with a probability of 82.9%. RT exhibited the greatest efficacy in reducing SGRQ scores, with probability of 49.8%. Notably, ET demonstrated superiority in improving FEV1 and FVC, with probabilities of being most effective at 78.1% and 42.0%, respectively. Conclusion: This study suggests that HIIT may be a viable intervention for improving exercise capacity in stable COPD patients, compared to AE, RR, and ET. RT may hold promise for improving quality of life, and ET may demonstrate superiority in improving pulmonary function. However, variation in response likely depends on patient characteristics, program parameters, and delivery context. Future research should explore the synergistic effects of combining RT with ET/HIIT, focusing on patient subgroups, optimal dosing, and settings, as current guidelines indicate this combination may offer the most significant benefits.

Hypoxia inducible factor (HIF) 3α prevents COPD by inhibiting alveolar epithelial cell ferroptosis via the HIF-3α-GPx4 axis.

Rationale: COPD patients are largely asymptomatic until the late stages when prognosis is generally poor. In this study, we shifted the focus to pre-COPD and smoking stages, and found enrichment of hypoxia inducible factor (HIF)-3α is in pre-COPD samples. Smoking induced regional tissue hypoxia and emphysema have been found in COPD patients. However, the mechanisms underlying hypoxia especially HIF-3α and COPD have not been investigated. Methods: We performed bulk-RNA sequencing on 36 peripheral lung tissue specimens from non-smokers, smokers, pre-COPD and COPD patients, and using "Mfuzz" algorithm to analysis the dataset dynamically. GSE171541 and EpCAM co-localization analyses were used to explore HIF-3α localization. Further, SftpcCreert2/+R26LSL-Hif3a knock-in mice and small molecular inhibitors in vitro were used to explore the involvement of HIF-3α in the pathophysiology of COPD. Results: Reactive oxygen species (ROS) and hypoxia were enriched in pre-COPD samples, and HIF-3α was downregulated in alveolar epithelial cells in COPD. In vitro experiments using lentivirus transfection, bulk-RNA seq, and RSL3 showed that the activation of the HIF-3α-GPx4 axis inhibited alveolar epithelial cell ferroptosis when treated with cigarettes smoking extracts (CSE). Further results from SftpcCreert2/+R26LSL-Hif3a knock-in mice demonstrated overexpression of HIF-3α inhibited alveolar epithelial cells ferroptosis and prevented the decline of lung function. Conclusion: Hypoxia and oxidation-related damage begins years before the onset of COPD symptoms, suggesting the imbalance and impairment of intracellular homeostatic system. The activation of the HIF-3α-GPx4 axis is a promising treatment target. By leveraging this comprehensive analysis method, more potential targets could be found and enhancing our understanding of the pathogenesis.

Role of Non-invasive Ventilation (NIV) in Managing Acute Exacerbations of Chronic Obstructive Pulmonary Disease (COPD): A Systematic Review.

Chronic obstructive pulmonary disease (COPD) is a significant global health issue that is characterized by airflow constriction and breathing difficulties. Non-invasive ventilation (NIV) is a recommended treatment for acute exacerbations of COPD (AECOPD), offering benefits over invasive mechanical ventilation (IMV). We aimed to evaluate the effectiveness, safety, and impact of NIV in managing AECOPD. The study adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We searched PubMed, Medline, Cochrane Library, Embase, and Google Scholar for relevant studies published between 2015 and 2024. Inclusion criteria focused on studies involving AECOPD patients treated with NIV, including randomized controlled, cohort, and observational studies. We included 10 studies that fit our inclusion criteria for a thorough review. From the studies selected, NIV demonstrated significant reductions in mortality rates, intubation rates, and hospital stays compared to IMV. Albeit the need to train healthcare providers is essential, high adherence to NIV guidelines was observed. Different NIV modes showed comparable efficacy, and structured weaning protocols reduced relapse rates. NIV is a highly effective and safe treatment for patients with AECOPD than IMV. High-flow nasal therapy (HFNT) is a viable alternative for patients intolerant to NIV. Further research should standardize treatment protocols and optimize NIV use in clinical practice.

Rosmarinic acid suppresses the progression of COPD via Syk by modulating airway inflammation and epithelial apoptosis in vivo and in vitro.

Rosmarinic acid (RosA), a hydrophilic phenolic compound found in various plants, has several biological effects such as anti-inflammatory and anti-apoptosis activities. However, its potential impact on chronic obstructive pulmonary disease (COPD) and its underlying mechanism has not been investigated. In this study, we explored the potential therapeutic effects and mechanism of RosA on COPD airway inflammation and alveolar epithelial apoptosis in vivo and in vitro. Our data suggested that RosA may be a therapeutic candidate for COPD with low toxicity. The corresponding mechanism lies in its anti-inflammatory effect on macrophage and bronchial epithelial cells, as well as protective effect on lung epithelial apoptosis via the jointly cross-target spleen tyrosine kinase (Syk).

Absorption, Distribution, Metabolism, and Excretion of Icenticaftor (QBW251) in Healthy Male Volunteers at Steady State and In Vitro Phenotyping of Major Metabolites.

Icenticaftor (QBW251) is a potentiator of the CFTR protein and is currently in clinical development for the treatment of chronic obstructive pulmonary disease and chronic bronchitis. An absorption, distribution, metabolism, and excretion (ADME) study was performed at steady state to determine the pharmacokinetics, mass balance, and metabolite profiles of icenticaftor in humans. In this open-label study, six healthy men were treated with unlabeled oral icenticaftor (400 mg b.i.d.) for 4 days. A single oral dose of [14C]icenticaftor was administered on Day 5, and unlabeled icenticaftor was administered b.i.d. from the evening of Day 5 to Day 12. Unchanged icenticaftor accounted for 18.5% of plasma radioactivity. Moderate to rapid absorption of icenticaftor was observed (median Tmax: 4 hours), with 93.4% of the dose absorbed. It exhibited moderate distribution (Vz/F: 335 L) and was extensively metabolized, principally through N-glucuronidation, O-glucuronidation, and/or O-demethylation. The metabolites M8 and M9, formed by N-glucuronidation and O-glucuronidation of icenticaftor, respectively, represented the main entities detected in plasma (35.3% and 14.5%, respectively) in addition to unchanged icenticaftor (18.5%). The apparent mean T1/2 of icenticaftor was 15.4 hours in blood and 20.6 hours in plasma. Icenticaftor was eliminated from the body mainly through metabolism followed by renal excretion, and excretion of radioactivity was complete after 9 days. In vitro phenotyping of icenticaftor showed that cytochrome P450 and uridine diphosphate glucuronosyltransferase were responsible for 31% and 69% of the total icenticaftor metabolism in human liver microsomes, respectively. This study provided invaluable insights into the disposition of icenticaftor. Significance Statement The ADME of a single radioactive oral dose of icenticaftor was evaluated at steady state to investigate the nonlinear pharmacokinetics observed previously with icenticaftor. [14C]Icenticaftor demonstrated good systemic availability after oral administration and was extensively metabolized and moderately distributed to peripheral tissues. The most abundant metabolites, M8 and M9, were formed by N-glucuronidation and O-glucuronidation of icenticaftor, respectively. Phenotyping demonstrated that [14C]icenticaftor was metabolized predominantly by UGT1A9 with a remarkably low Km value.

Effect of low climate impact vs. high climate impact inhalers for patients with asthma and COPD-a nationwide cohort analysis.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) and asthma can be treated with inhaled corticosteroids (ICS) delivered by low climate impact inhalers (dry powder inhalers) or high climate impact inhalers (pressurized metered-dose inhalers containing potent greenhouse gasses). ICS delivered with greenhouse gasses is prescribed ubiquitously and frequent despite limited evidence of superior effect. Our aim was to examine the beneficial and harmful events of ICS delivered by low and high climate impact inhalers in patients with asthma and COPD. METHODS: Nationwide retrospective cohort study of Danish outpatients with asthma and COPD treated with ICS delivered by low and high climate impact inhalers. Patients were propensity score matched by the following variables; age, gender, tobacco exposure, exacerbations, dyspnoea, body mass index, pulmonary function, ICS dose and entry year. The primary outcome was a composite of hospitalisation with exacerbations and all-cause mortality analysed by Cox proportional hazards regression. RESULTS: Of the 10,947 patients with asthma and COPD who collected ICS by low or high climate impact inhalers, 2,535 + 2,535 patients were propensity score matched to form the population for the primary analysis. We found no association between high climate impact inhalers and risk of exacerbations requiring hospitalization and all-cause mortality (HR 1.02, CI 0.92-1.12, p = 0.77), nor on pneumonia, exacerbations requiring hospitalization, all-cause mortality, or all-cause admissions. Delivery with high climate impact inhalers was associated with a slightly increased risk of exacerbations not requiring hospitalization (HR 1.10, CI 1.01-1.21, p = 0.03). Even with low lung function there was no sign of a superior effect of high climate impact inhalers. CONCLUSION: Low climate impact inhalers were not inferior to high climate impact inhalers for any risk analysed in patients with asthma and COPD.